Advanced Drug Delivery Reviews 159 (2020) 94–119

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Interaction between high-density lipoproteins and inflammation:

Function matters more than concentration!
Sumra Nazir a,b, Vera Jankowski a, Guzide Bender a,b, Stephen Zewinger c,d,
Kerry-Anne Rye e, Emiel P.C. van der Vorst a,b,f,g,h,⁎
a
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
b
Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
c
Department of Internal Medicine 4, Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany
d
Department of Nephrology, Hôpitaux Robert Schuman, Hôpital Kirchberg, Luxembourg, Luxembourg
e
Lipid Research Group, School of Medical Sciences, The University of New South Wales Sydney, New South Wales, Australia
f
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
g
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany
h
German Centre for Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Munich, Germany

a r t i c l e i n f o a b s t r a c t

Article history: High-density lipoprotein (HDL) plays an important role in lipid metabolism and especially contributes to the re-
Received 6 January 2020 verse cholesterol transport pathway. Over recent years it has become clear that the effect of HDL on immune-
Received in revised form 20 September 2020 modulation is not only dependent on HDL concentration but also and perhaps even more so on HDL function.
Accepted 13 October 2020
This review will provide a concise general introduction to HDL followed by an overview of post-translational
Available online 17 October 2020
modifications of HDL and a detailed overview of the role of HDL in inflammatory diseases. The clinical potential
Keywords:
of HDL and its main apolipoprotein constituent, apoA-I, is also addressed in this context. Finally, some conclu-
High-density lipoproteins sions and remarks that are important for future HDL-based research and further development of HDL-focused
Inflammation therapies are discussed.
Metabolic diseases © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
Infectious diseases (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Auto-immune diseases
Neurological diseases
Chronic kidney disease

Contents

1. General introduction and aim of this review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

2. Introduction of the HDL metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
2.1. Discovery of HDL particle(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
2.2. HDL structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
2.3. HDL biogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
3. Post translational modifications of apoA-I and HDL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
3.1. Oxidation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
3.2. Carbamylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
3.3. Glycation and advanced glycation end products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
4. HDL and immune-mediated diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
4.1. Metabolic diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
4.1.1. Cardiovascular disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
4.1.2. Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
4.1.3. Liver disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
4.1.4. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

⁎ Corresponding author at: Pauwelstraße 30, 52074 Aachen, Germany.

E-mail address: evandervorst@ukaachen.de (E.P.C. van der Vorst).

https://doi.org/10.1016/j.addr.2020.10.006
0169-409X/© 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
S. Nazir, V. Jankowski, G. Bender et al. Advanced Drug Delivery Reviews 159 (2020) 94–119

4.2. Infectious diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

4.2.1. Bacterial, viral and parasitic infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
4.2.2. Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
4.3. Auto-immune diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.3.1. Rheumatoid arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.3.2. Systemic lupus erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.3.3. Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.3.4. Inflammatory bowel disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
4.4. Neurological disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
4.4.1. Effects of HDL on the pathogenesis of neurological disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
4.4.2. Clinical potential of apoA-I and HDL in neurological disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
4.5. Chronic kidney disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
4.5.1. Effects of HDL on the pathogenesis of chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
4.5.2. Clinical potential of apoA-I and HDL in chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
4.6. Other diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
5. Discussion and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Sources of funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

1. General introduction and aim of this review
High-density lipoprotein (HDL) comprises of a wide range of parti-
cles, varying in size, composition and density. HDL particles can be sep-
arated from other lipoproteins, based on their unique physicochemical
properties. Gofman et al., identified the first clinically beneficial role of
HDL, demonstrating that low levels of HDL were positively associated
with the development of atherosclerosis [1]. Over the years, this inverse
correlation between the risk for developing coronary heart disease and
the levels of HDL cholesterol (HDL-C) has been widely confirmed, sug-
gesting a protective role of HDL-C in atherosclerosis development [2].
However, several recent investigations, including many clinical trials fo-
cusing on raising HDL-C levels that did not show any beneficial effect on
cardiovascular event rates [3,4], started a lively debate about the appro-
priateness of HDL as a therapeutic target. This debate was further fueled
by Mendelian randomization studies, which demonstrated that poly-
morphisms that exclusively alter HDL-C levels did not affect the risk of
myocardial infarction (MI) [5]. This led to the suggestion that the func-
tionality of HDL, that is determined by its composition and post-
translational modifications are more important determinants for pro-
tection against cardiovascular disease (CVD) than the levels of HDL-C
[6,7]. Over the last years, the question whether HDL function is more im-
portant than HDL-C has also been investigated in other pathologies, es-
pecially since it has been shown that HDL influences immune cell
reactivity in inflammatory and infectious diseases. In this review these
interactions will be discussed as well as the importance of HDL function
vs concentration in the context of pathogenesis and clinical application.
apolipoproteins apoA-I and apoA-II [11,12]. Due to differences in apoli-
poproteins, phospholipids, cholesterol and cholesteryl esters, HDLs
have differences in surface charge and density and can thereby be clas-
sified into γ-, α- or preβ-migrating particles or HDL2 and HDL3, respec-
tively [13,14].
2.2. HDL structure
HDL particles are heterogeneous with respect to charge, density,
size, and shape, chemical and physiologic properties [15]. In their ma-
ture form, HDL contains a nonpolar lipid core (mainly consisting of
cholesteryl esters and triglycerides) surrounded by a single surface
monolayer of phospholipids (mainly phosphatidylcholine), unesterified
cholesterol and amphipathic apolipoproteins (Fig. 1). Based the pres-
ence of absence of cholesteryl esters, HDL has either a discoidal or a
spherical shape. The density of HDL varies from 1.063–1.21 g/ml, with
a size-range of 8-10 nm [16,17]. HDL can be further subdivided into
larger-sized, lower-density (HDL2a and HDL2b) and smaller-sized,
higher-density (HDL3a, HDL3b, and HDL3c) sub-classes [18]. Apolipopro-
teins associated with HDL can undergo post-translational modifications
as will be discussed in more detail later. The major apolipoprotein con-
stituents of HDL are apoA-I (70%) and apoA-II (20%), with small
amounts of other apoproteins such as apoA-IV, apoA-V, apoC and apoE
[19]. Additionally, HDL has been shown to contain a lot more proteins
(>80) like the lipocalins apoD and apoM [20].
2.3. HDL biogenesis

2. Introduction of the HDL metabolism
2.1. Discovery of HDL particle(s)
“HDL” was discovered in 1929 when a lipid rich α-globulin was iso-
lated from horse serum by Macheboeuf at the Pasteur Institute in Paris
[8]. Several years later, lipoproteins were also isolated from human
plasma using density gradient ultra-centrifugation [9]. The use of repet-
itive ultra-centrifugations was a big breakthrough as it was shown that
raising the serum density by the addition of concentrated salt solutions
allows the flotation and isolation of three different lipoprotein fractions
with densities ranging from <1.019 g/ml, 1019–1.063 g/ml, and
1.063–1.21 g/ml [10]. This results in the classification of these lipopro-
tein fractions, defined as very low density lipoprotein (VLDL), low
density lipoprotein (LDL) and HDL [10]. Over the years, more
detailed analysis of HDL revealed the existence of two major HDL
HDL formation is initiated by the secretion of lipid free apoA-I by the
liver (comprising about 70% of total apoA-I production) [21] and the in-
testine (comprising about 30% of total apoA-I production) [22]. This
lipid free apoA-I interacts with the ATP-binding cassette transporter
A1 (ABCA1) on peripheral cells, leading to the transfer of cholesterol
and cellular phospholipids from the cell membrane to apoA-I (Fig. 2).
Through a series of intermediate steps, the lipidated apoA-I is progres-
sively converted into discoidal pre-β-migrating HDL particles that con-
sist of a phospholipid bilayer surrounded by two apoA-I molecules/
particle [23]. Subsequently, the enzyme lecithin:cholesterol acyltrans-
ferase (LCAT) mediates the esterification of cholesterol, converting dis-
coidal pre-β-migrating HDL particles into α-migrating, spherical HDL
particles with a central core of cholesteryl esters [24] and two molecules
of apoA-I. Small spherical HDL subsequently acquire additional free cho-
lesterol that effluxes from peripheral cells via ABCA1 and ABCG1. Ester-
ification of this newly acquired cholesterol by LCAT generates large HDL

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Fig. 1. Generalized structure of spherical HDL. High-density-lipoproteins particles consist of a core of triglycerides and cholesteryl esters. This core is surrounded by a phospholipid
monolayer containing unesterified cholesterol and several apoproteins (mostly apoA-I).

Fig. 2. General overview of HDL metabolism. ApoA-I is produced in the liver and intestines and subsequently forms discoidal HDL after interacting with the ATP-binding cassette
transporter A1 (ABCA1). Continued cholesterol export via ABCG1 (and via scavenger receptor class B member 1 (SR-B1) in macrophages) and enzymatic reactions mediated by
lecithin-cholesterol acyltransferase (LCAT) result in the conversion into spherical high-density-lipoproteins (HDL)3 and HDL2 particles. Cholesterol and cholesteryl esters can be
transferred to the liver by two main pathways, directly through binding to SR-B1 in the liver and subsequent excretion via the kidneys, or indirectly by being transferred to very-low-
density lipoproteins (VLDL), intermediate-density-lipoproteins (IDL) and low-density lipoproteins (LDL) by cholesteryl ester transfer protein (CETP), followed by uptake of these
lipoproteins via the LDL receptor (LDLR) in hepatocytes. Additionally, HDL can be catabolized in the liver via its uptake as holoparticles through a yet to be identified HDL receptor
(HDLR). HDL2 can be remodeled by processes that are catalyzed by hepatic lipase (HL), endothelial lipase (EL) and plasma phospholipid transfer protein (PLTP), resulting in the
formation of lipid-poor HDL particles which again interact with ABCA1 for a next lipidation cycle.

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S. Nazir, V. Jankowski, G. Bender et al.
particles with three or more apoA-I molecules/particle. Furthermore,
phospholipid transfer protein (PLTP) plays a vital role in the remodel-
ling of HDL, by transferring phospholipids from chylomicrons and
VLDL to HDL [25]. This transfer of phospholipids can destabilize HDL,
leading to fusion and the formation of larger α-migrating HDL particles
[26]. Spherical HDL particles can also undergo modification through bi-
directional exchange of cholesteryl esters and triglycerides with apoB
containing lipoproteins (VLDL and LDL) mediated by cholesteryl ester
transfer protein (CETP). As CETP predominately supports the transfer
of cholesteryl esters from HDL towards apoB containing lipoproteins
in exchange for triglycerides, this process will result in triglyceride–
rich HDL [27,28]. The exact mechanism of the HDL-CETP interactions re-
mains part of active research, as some studies suggest that CETP bind to
HDL by hydrophobic interaction whereas others suggest it is rather a
protein-protein interactions [29]. The formation of a hydrophobic chan-
nel by SR-B1, allowing cholesterol diffusion from HDL into the plasma
membrane, can further remodel HDL [30]. Additionally, hepatic lipase
can hydrolyse HDL phospholipids and triglycerides, driving the transi-
tion of HDL2 into HDL3 particles [31]. This remodelling is accompanied
by the dissociation of lipid-free or lipid-poor apoA-I, while endothelial
lipase remodels HDL without such dissociation [32]. In the kidney, this
lipid-free apoA-I undergoes glomerular filtration and can subsequently
either be degraded, excreted through the urine or partially reabsorbed,
thereby regulating the plasma levels of apoA-I and HDL [33,34].
3. Post translational modifications of apoA-I and HDL
Here, three well-described Post translational modifications (PTMs)
of apoA-I, being oxidation, carbamylation and glycation will be briefly
highlighted.
3.1. Oxidation
Oxidation of HDL takes predominantly place in inflammatory micro-
environments [35]. For example, activated phagocytes secrete superox-
ide anion radical (O− 2 ), H2O2 and myeloperoxidase (MPO) which all
have oxidative capacities [36]. The clinical relevance of such modifica-
tions has been shown by a study that demonstrated that the apoA-I in
patients with cardiovascular disease contains a higher degree of MPO-
dependent oxidative modifications (nitration and chlorination) [37].
These modifications impair the lipid binding potential of apoA-I and
thereby result in a dose-dependent loss of ABCA1-mediated cholesterol
efflux from macrophages [37]. More recent studies additionally demon-
strate that (patho) physiologically relevant levels of MPO also results
in the loss of the anti-apoptotic and anti-inflammatory functions
of HDL [38].
In addition, sulfur oxidation of the methionine residues in apoC-I, C-
III and A-I of HDL regulates the activity of these proteins [39,40]. For ex-
ample, methionine oxidation of apoA-I caused partial unfolding of the
protein, decreased its stability and reduced the formation of apoA-I di-
mers and tetramers [41]. Methionine sulfoxidation of apoA-I causes
HDL to become pro-inflammatory, as it induces pro-inflammatory cyto-
kine secretion (TNFα and IL-6) in mouse bone marrow-derived macro-
phages as well as mouse monocytes [42].
Furthermore, tryptophan residues were identified as major oxida-
tion sites in proteins because of the high reactivity of sulfur atoms and
aromatic rings towards various reactive oxygen species causing a signif-
icant reduction in the viability of tryptophan of the organism [43,44]. In
addition, it was recently shown that tryptophan oxidation of apoA-I oc-
curs during inflammation and is characterized by its pro-inflammatory
properties on endothelial cells and impairs the ABCA1-dependent HDL
biogenesis [45]. Tryptophan oxidation has been recently extensively
reviewed in [46,47].
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Advanced Drug Delivery Reviews 159 (2020) 94–119
3.2. Carbamylation
Carbamylation is a non-enzymatic and irreversible PTM, catalyzed
by urea and MPO, that results from the interaction between isocyanic
acid and amino groups of proteins. Various studies have confirmed
that apoA-I can be carbamylated and that this is associated with CVD,
with higher levels of apoA-I carbamylation being observed in human
atherosclerotic plaques compared to normal arterial tissues [48]. There-
fore, carbamylation of HDL-associated apolipoproteins might be one of
the mechanisms linking inflammation and CVD.
3.3. Glycation and advanced glycation end products
Advanced glycation end products (AGEs) are formed when a non-
enzymatic reaction takes place between a protein and reducing sugars.
These compounds have been associated with the development of vari-
ous cardiovascular disorders such as endothelial dysfunction, increased
myocardial and vascular stiffness, diastolic dysfunction, and the forma-
tion of atherosclerotic lesions [49]. Non-enzymatic glycation of apoA-I
adversely affects the metabolism of HDL and impairs the ability of
LCAT to esterify cholesterol [50]. This could be explained by the observa-
tion that modifications of lysine, arginine and tryptophan residues me-
diated by methylglyoxal altered the conformation of an epitope of
apoA-I in regions required for LCAT activation and binding of lipids
[50]. Glycation of apoA-I also impairs the anti-inflammatory properties
of HDL and reduces its ability to inhibit expression of intercellular adhe-
sion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1)
on endothelial cells, and its ability to reduce neutrophil infiltration into
the intima of carotid arteries [51]. Combined with the recent observa-
tion that glycation of apoA-I reduces its half-life by threefold [52],
these studies clearly demonstrate the important detrimental effects of
non-enzymatic glycation on the anti-inflammatory functions of HDL.
4. HDL and immune-mediated diseases
It has been shown that HDL plays an important role in a wide-range
of immune cells, inflammatory and infectious diseases. In this chapter,
the role of HDL in various pathologies will be described, especially to
elucidate the role of HDL concentration vs. function. Besides the role
of HDL in the pathophysiology, also the clinical potential of HDL therapy
will be discussed for the specific diseases.
4.1. Metabolic diseases
4.1.1. Cardiovascular disease
4.1.1.1. Effects of HDL on the pathogenesis of cardiovascular disease. CVD is
still the major cause of hospitalization and mortality worldwide. The
main underlying cause of CVD is atherosclerosis, a chronic inflammatory
disease of the arteries that develops over time. It has been demonstrated
that a multitude of immune cells play an important role in atherosclero-
sis [53]. Here we will limit ourselves to the description of four main cell-
types that are of paramount importance in this pathology and have been
demonstrated to interact with HDL (Fig. 3).
4.1.1.1.1. Macrophages. Macrophages, the most essential immune
cells in various CVDs, have recently been highlighted in a seminal re-
view series [54–57]. During atherosclerosis, lesional macrophages accu-
mulate large amounts of cholesterol esters forming foam cells. Since
HDL can only remove unesterified cholesterol from macrophages it is
important that intracellular cholesterol ester hydrolyses occurs [58].
Macrophages comprise a heterogeneous population of innate myeloid
cells that acclimatise in response to a variety of signals from the
micro-environment. For example, stimulation by interferon gamma
(IFN-γ) or lipopolysaccharide (LPS) induces classically activated, pro-
inflammatory M1 macrophages. In contrast, non-classically activated
M2 macrophages are induced, for example, by IL-4 or IL-13 and are
S. Nazir, V. Jankowski, G. Bender et al.
Fig. 3. Overview of selected Immune-HDL crosstalk mechanisms in atherosclerosis. Increasing HDL levels has several effects on immune cells that play a crucial role in atherosclerosis
development. Although some of these effects are still rather contradictory, it is clear that there are significant interactions between HDL and the described immune cells in this pathology.
known to decrease inflammation by secreting IL-10 [59]. A more elabo-
rate review focusing on the understanding of macrophage heterogene-
ity in the context of atherosclerosis has recently been published by
Nagenborg et al. [59].
HDL has been linked to lesional macrophage polarization. Increasing
the levels of HDL by overexpression of human apoA-I in mice not only
decreased the size of atherosclerotic lesions and lesion lipid content,
but also changed the phenotypic polarization of monocyte-derived
cells (predominantly macrophages) from an M1 to M2 phenotype [2].
However, the effects of HDL on macrophage inflammation turned out
to be not so straightforward. Several studies over the last decade evalu-
ated the effects of HDL and apoA-I on macrophage inflammation with
seemingly contradicting results [60–63]. One of the studies showed
that HDL exerts anti-inflammatory effects by down regulating type 1 in-
terferon responses in macrophages downstream of TRAM/TRIF signal-
ling [62]. These inhibitory effects of HDL on IFN signalling were
confirmed in a later study in which the anti-inflammatory effects of
HDL (CSL-111, reconstituted HDL) are attributed to the induction of
Atf3, a transcriptional repressor, expression in macrophages [60].
Additionally, It has been reported that apoA-I may also mediate
anti-inflammatory effects by modulating Toll-like receptor (TLR)
4-dependent signalling in macrophages [64].
In sharp-contrast to the previously described studies, it has been
shown that HDL can have pro-inflammatory effects in macrophages.
These effects seem to be mediated by passive cholesterol efflux from
the cell membrane, which activates a protein kinase C (PKC)-NF-κB-
STAT1-IRF1 signalling axis [63]. Some of these discrepancies could be ex-
plained by significant differences in experimental conditions, but also in
the HDL preparations, highlighting the importance of HDL composition
and function [65]. For example, the reconstituted HDL product, CSL-111
consists of apoA-I complexed to soybean-derived phospholipids, which
are anti-inflammatory. The importance of the phospholipid component
will be discussed in more detail in chapter 5. Interestingly, a recent pub-
lication by Fotakis et al. is the first study to provide evidence for both
anti- and pro-inflammatory effects of HDL in macrophages [61]. These
investigators proposed that these effects follow a biphasic pattern at
the gene expression level where initially anti-inflammatory effects dom-
inate and pro-inflammatory effects prevail later on. Moreover, pro-
inflammatory effects were suggested to be highly dependent on cellular
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Advanced Drug Delivery Reviews 159 (2020) 94–119
cholesterol levels, which mediate IRE1a/ASK1/p38 MAPK activation and
endoplasmic reticulum (ER) stress. Although further studies using differ-
ent HDL preparations with varying composition are still needed to fully
elucidate how these seemingly contradictory findings can be explained,
it indicates that HDL composition plays an important role in how HDL in-
fluences inflammatory responses in macrophages.
Several other observations stress the importance of HDL function,
rather than HDL-C concentration, on inflammation in macrophages.
For example, apoA-I and HDL have been shown to exert their
anti-inflammatory effects in macrophages by stimulating cholesterol ef-
flux via ABCA1 and ABCG1and attenuation of inflammatory TLR-
signalling [66]. ApoA-I and HDL not only extract intracellular cholesterol
from the cells but also cholesterol which is present in the cell membrane
in lipid rafts. Lipid rafts are specific regions in the membrane which are
enriched in glycosphingolipids, cholesterol and protein receptors [67].
Signalling of many TLRs is highly dependent on the presence of
cholesterol in lipid rafts, and this can be modulated by apoA-I or HDL.
For example, macrophages deficient in ABCA1 display enlarged
cholesterol-rich lipid rafts with high TLR4 expression and an elevated
response to stimulation by LPS [68–70]. Similarly, in monocyte-
derived macrophages treated with LPS, the apoA-I mimetic peptide 4F
down-regulates the expression of several TLRs by reducing the choles-
terol content of lipid rafts, which reduces the expression of various
inflammatory genes [71,72].
In recent years, considerable attention has also been paid to the role
of sphingosine-1-phosphate (S1P), a bioactive sphingolipid that modu-
lates the inflammatory effects of HDL on macrophages [73]. In general
five receptors are described for S1P of which two are highly expressed
on macrophages, the S1P1 and S1P2 receptor. It has been shown that
the S1P1 receptor is responsible for the anti-inflammatory effects of
S1P and induces a shift in macrophage polarization from the classical
pro-inflammatory M1 to the anti-inflammatory M2 phenotype [74]. Ad-
ditionally, S1P has been shown to selectively decrease the activation of
TLR2 in macrophages, thereby mediating the inhibition of pro-
inflammatory cytokine expression [75]. HDL-associated S1P also in-
hibits the apoptosis of macrophages by stimulating STAT3 signalling
and survivin expression [76]. These effects of HDL-associated S1P illus-
trate how small changes in HDL composition can influence atheroscle-
rosis and CVD.
S. Nazir, V. Jankowski, G. Bender et al.
PTMs, such as oxidation, also determine how HDL influences inflam-
mation [77]. For example, the acute phase protein, serum amyloid A
(SAA), is clearly linked to macrophage inflammation and CVD. HDL iso-
lated from acute coronary syndrome patients have increased levels of
HDL-bound SAA [78]. Furthermore, in patients undergoing coronary an-
giography a low SAA, and a high plasma HDL-C was associated with
lower all-cause and cardiovascular mortality. On the other hand, in pa-
tients with high SAA, a high HDL-C was associated with increased mor-
tality, indicating that SAA may impair the cardioprotective functions of
HDL by reducing its anti-inflammatory function [55,56,79,80]. The bind-
ing of SAA to HDL also reduces the ability of HDL to mediate cholesterol
efflux from macrophages [81–83], which inherently limits the anti-
atherogenic potential of HDL. It has also been confirmed that SAA is
present in the atherosclerotic lesions of both mice [84] and humans
[85,86]. Combined, these studies highlight that HDL-associated SAA
clearly has detrimental effects and that pathological conditions can
change HDL composition and thereby also shift the balance between
anti- or pro-inflammatory effects of HDL [87–89].
4.1.1.1.2. Dendritic cells. Dendritic cells (DCs) are potent antigen pre-
senting cells that initiate T-cell mediated immune responses [90]. Sev-
eral studies have demonstrated that DCs play an important but
complex role in atherosclerosis. Mature DCs are pro-atherogenic,
while immature DCs appear to be anti-atherogenic [91,92].
Similar to their effects on macrophages, apoA-I and HDL have also
been shown to mediate anti-inflammatory effects on DCs by regulating
lipid rafts. These effects are again highly dependent on a completely
functional HDL particle. The major histocompatibility complex (MHC)
class II, which is required for the antigen presentation to T-cells and
their subsequent activation, resides in lipid rafts [93]. Treatment of
DCs with either apoA-I or HDL disrupts lipid rafts, which decreases
DC-dependent activation of T-cells and IL-2 production. Further
supporting the notion that HDL function and composition play are im-
portant in relation to DCs is the observation that S1P plays an important
role in the anti-inflammatory effects of HDL. Treatment of mature DCs
with S1P inhibits the secretion of the pro-inflammatory cytokines
TNF-α and IL-12, and stimulates secretion of anti-inflammatory cyto-
kine, IL-10, thereby facilitating immunosuppressive effects [94]. This
has been confirmed in a more recent study which showed that S1P
stimulates the S1P1 receptor in activated DCs, thereby inducing an
anti-inflammatory cytokine profile with reduced IL-12 and IL-23 pro-
duction and a concomitant increase in IL-27 production [95]. The com-
position of HDL has also been shown to play an important role on the
effects of HDL on DC-mediated activation of T-cells. It could be observed
that the phospholipid fraction of HDL (in particular 1-palmitoyl-2-
linoleyl-phosphatidylcholine (PLPC)) was primarily responsible for the
inhibitory effects of HDL on DC-mediated induction of a Th1 response
of T-cells [96]. Taken together, although the exact role of DCs in athero-
sclerosis and CVD remains a matter of debate, apoA-I and HDL composi-
tion have clearly been shown to modulate DC function, making this
interaction an interesting target for future therapeutic interventions.
4.1.1.1.3. T-cells. It was reported several years ago that 7–20% of infil-
trating cells within human atherosclerotic plaques are T-cells [97]. Over
the years, the role of T-cells in atherosclerosis has become more clear,
although there is still a great need to better understand their exact con-
tribution to disease development. For example, regulatory T-cells (Treg)
have an athero-protective phenotype and modulate inflammation by
secreting anti-inflammatory molecules including IL-10 and TGF-β
[98,99]. Administration of apoA-I or HDL in mice has been shown to in-
hibit inflammation by increasing Treg cell counts in the spleen of Ldlr−/−
mice [100,101]. In line with this and highlighting the importance of HDL
function in this context, the infusion of oxidized, dysfunctional HDL into
Ldlr−/− mice reduces Treg cell counts and thereby promotes atheroscle-
rosis development [100]. These positive effects of HDL on Treg cell counts
may be caused by improved cell survival, as it was recently shown that
HDL increases Treg cell survival by increasing oxidative phosphorylation
in the mitochondria [102].
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Advanced Drug Delivery Reviews 159 (2020) 94–119
Moreover, apoA-I modulates the cellular fate of Treg cells during ath-
erosclerotic lesion development. Normally, during atherogenesis Foxp3
expression decreases in Treg cells which reduces their immunosuppres-
sive function and leads to pro-atherogenic T follicular helper (Tfh) cells
formation [103]. Injection of apoA-I into Apoe−/− mice reduced the con-
version of Treg cells into Tfh cells and therefore had an athero-protective
effect [103]. A similar result was obtained when Apoe−/− and Ldlr−/−
mice were injected with apoA-I, resulting in increased Treg cell counts
in the lymph nodes, with a concomitant decrease in effector memory
T-cells [101]. Interestingly, and seemingly in contrast to the above
described studies, HDL-associated S1P inhibits the differentiation
of Treg cells, while reciprocally increasing the development of pro-
atherogeneic Th1 cells [104]. Therefore, the exact role of HDL composi-
tion in this process remains an active area of research.
HDL also influences activation of the T-cell receptor (TCR) which,
upon activation, associates with lipid rafts [105]. As described above,
this association is highly dependent on the modulation of lipid raft cho-
lesterol content by apoA-I or HDL and is therefore highly dependent on
HDL cholesterol efflux capacity [106]. This has been confirmed in an ath-
erogenic Ldlr−/− mouse model, in which apoA-I inhibited the activation
of T-cells by preventing the accumulation of cholesterol in lymph nodes
[107]. Further supporting the importance of HDL composition is the ob-
servation that HDL-S1P inhibits lymphopoiesis and consequently adap-
tive immune responses [108]. In conclusion, these observations indicate
that HDL can influence T-cells on multiple levels: by modulating the in-
flammatory profile, by determining cellular fate and by activation of TCR
which all have been shown to be influenced by HDL composition and
function.
4.1.1.1.4. B-cells. B-cells, which play an important role in humoral im-
munity by secreting antibodies, have emerged as an important immune
cell in cardiovascular disease. Over the years, it has become clear that
various B-cell subsets have differential effects on atherosclerosis devel-
opment, which is comprehensively reviewed in [109].
Although the effects of HDL on B-cells has not been extensively stud-
ied, it seems that HDL cholesterol efflux capacity plays an important
role. Similar to the TCR, the B-cell receptor (BCR) is also located in
lipid rafts which play an important role in B cell activation. Removal of
cholesterol, by apoA-I or HDL, from lipid rafts decreases BCR-initiated
signal transduction, loading of antigenic peptides onto MHC-II mole-
cules, endocytosis of BCR–antigen complexes and MHC-II associated an-
tigen presentation to T-cells [110]. This suggests that HDL influences B-
cell functions in a manner that is dependent on the capacity of HDL to
act as cholesterol acceptor. Further studies are needed to investigate
the exact effects of HDL on different B-cell subsets and the influence of
HDL composition and function in this context.
4.1.1.2. Clinical potential of apoA-I and HDL in cardiovascular disease. In
this chapter various approaches that have been used to develop agents
for increasing HDL levels and function will be discussed in the context of
cardiovascular disease (Fig. 4).
4.1.1.2.1. Dietary intervention. A direct but rather difficult way of in-
creasing HDL levels are lifestyle interventions, such as consumption of
a low-fat diet and regular exercise. Several studies have focussed on
the effects of lifestyle changes on HDL functionality.
4.1.1.2.1.1. Macronutrients. A well-studied dietary intervention aiming to
increase apoA-I and thereby HDL concentrations, is supplementation
with various fatty acids. A recent meta-analysis, demonstrated that a
significant increase in serum apoA-I concentrations is observed when
only 1% of the carbohydrate energy is replaced by saturated or unsatu-
rated fatty acids [111]. Oleic acid and linoleic acid are among the most
effective unsaturated fatty acids in this respect. Another meta-analysis
described similar effects on apoA-I concentrations, at least in a fasting
state, when carbohydrates are replaced by trans-fatty acids [112]. Inter-
estingly, it has been shown that omega-3 fatty acids, such as
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), do not
influence apoA-I concentrations [113]. A recent study also confirmed
S. Nazir, V. Jankowski, G. Bender et al. Advanced Drug Delivery Reviews 159 (2020) 94–119

Fig. 4. Highlighted mechanism of action of HDL-focussed therapies. Therapies focussing on modulating HDL metabolism or plasma HDL-cholesterol levels have different sites of interaction,
as discussed in more detail in the text below. Abbreviations: ABCA1: ATP-binding cassette subfamily A member 1; ABCG1: ATP-binding cassette subfamily G member 1; CETP: cholesteryl
ester transfer protein; EL: endothelial lipase; FFA: free-fatty acids; HDL: high-density-lipoproteins; HDLR: HDL receptor; HL: hepatic lipase; IDL: intermediate-density-lipoproteins; LCAT:
lecithin-cholesterol acyltransferase; LDL: low-density lipoproteins; LDLR: LDL receptor; LPL: lipoprotein lipase; PLTP: plasma phospholipid transfer protein; SR-B1: scavenger receptor
class B member 1; VLDL: very-low-density lipoproteins.

that EPA/DHA supplementation does not change HDL-C levels in
humans, although it could be demonstrated that HDL composition
was significantly changed upon supplementation [114]. A down-
regulation of several HDL-associated proteins involved in inflammation
was observed with both fatty-acids supplements, but to a greater extent
with EPA. Furthermore, apoM abundance in HDL was increased after
EPA/DHA supplementation. ApoM forms a complex with S1P that has
anti-atherosclerotic functions [115], which suggests that dietary fatty
acid supplementation influences HDL composition and its function.
The effects of soy proteins on fasting apoA-I concentrations are
rather inconsistent. Although most studies did not find any effects of
soy protein supplementation [113], one study showed that soy-
containing products did increase apoA-I concentrations, while another
study demonstrated the opposite, with apoA-I levels decreasing after
soy supplementation [116]. Further studies are needed to clarify the un-
derlying mechanisms of these differential effects, and especially the ef-
fects of soy protein supplementation on HDL composition and
functionality.
A recent randomized two-way crossover clinical trial supported the
notion that dietary interventions can significantly alter HDL composi-
tion. This trial investigated the effects of a short-term Mediterranean
or fast food diet on HDL composition and function [117]. The subjects re-
ceived both diets for 4 days, with a 4-day wash-out period in between.
In total 170 HDL-associated lipid species were analysed of which 41
were differentially affected by the diet. Saturated fatty acids and odd
chain fatty acids were enriched by the fast food diet, while very-long
chain fatty acids and unsaturated fatty acids were enriched after the
Mediterranean diet. This clearly demonstrates that the HDL lipidome
can be remodeled within 4 days of diet change [117].
Besides the described food supplementations, drink consumption
can also influence apoA-I levels. Several studies have shown that coffee
or tea drinking does not influence fasting apoA-I levels [113]. However,
a very consistent and striking improvement of both fasting and
postprandial apoA-I concentrations have been found after alcohol
consumption [118,119]. As demonstrated by an increased cholesterol
efflux capacity, HDL functionality was also improved in one of these
studies [120].
4.1.1.2.1.2. Micronutrients. Theobromine, a supplement found in cocoa
has been shown to increase serum HDL-C concentrations in a 4-week
randomized controlled trial [121]. Interestingly, it has been shown
that the potency of theobromine depends on the baseline lipoprotein
profile of the studied subjects, as theobromine was not effective in sub-
jects with low HDL-C levels and high VLDL triglyceride levels [122,123].
However, one of these studies could not fully confirm the beneficial ef-
fects of theobromine on HDL levels, although non-significant trends
were observed [123]. The underlying mechanism by which theobro-
mine affects HDL has been postulated to be mediated by the inhibition
of phosphodiesterases, resulting in the degradation of cAMP and
increased ABCA1 activity [122]. The effects of theobromine are indepen-
dent of intestinal apoA-I production [124]. Whether theobromine also
affects HDL function remains to be determined.
Vitamins have also been shown to influence HDL concentration and
composition. For example, in mice vitamin C and E supplementation re-
duces the phospholipid content in HDL by decreasing PLTP activity

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S. Nazir, V. Jankowski, G. Bender et al.
[125]. Besides lipid remodelling, these vitamins also promoted HDL
protein modifications by increasing paraoxonase 1 (PON1) and apoD,
which correlated with improved HDL antioxidant activity [125]. The
effect of PON1 on oxidation has been confirmed by studies in which
PON1 deficiency is associated with decreased HDL antioxidant activity,
whereas the addition of PON1 increases the antioxidant activity
of HDL [126]. This may be one of the main underlying reasons
why PON1 deficient mice are more susceptible to the development of
atherosclerosis [126].
Taken together, various dietary interventions have been proven to
be beneficial for HDL concentrations, but also especially for HDL compo-
sition and functionality, although many inconsistencies remain to be
further elucidated. From a preventive point of view these strategies
are difficult to successfully implement as it remains challenging to trig-
ger people to comply with strict dietary regimes.
4.1.1.2.2. Drugs
4.1.1.2.2.1. Niacin. Niacin or nicotinic acid has been used widely to raise
HDL-C levels, by 15–25% [127], although, the underlying mechanism of
action is not fully understood. The Arterial Biology for the Investigation
of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study
clearly demonstrated benefit by showing that niacin stabilized carotid
intima-media thickening, on top of statin use [128]. In a follow-up
study, ARBITER 6-HDL and LDL Treatment Strategies in Atherosclerosis
(ARBITER 6-HALTS), niacin was shown to be superior to ezetimibe in re-
ducing carotid intima-media thickening in patients [129]. These out-
comes led to the worldwide and widespread use of niacin to increase
HDL-C for several years [127,130], until two major and more recent clin-
ical trials cast doubt on the efficacy and especially also the safety of
niacin.
The Atherothrombosis Intervention in Metabolic Syndrome with
Low HDL/High Triglycerides: Impact on Global Health Outcomes
(AIM-HIGH) trial was the first double-blind, randomized, multi-center
trial to assess whether addition of extended-release niacin to statin-
treated patients reduces atherogenic dyslipidemia and cardiovascular
risk [131]. Although niacin treatment resulted in improvement of mul-
tiple lipid parameters, the primary endpoints, including cardiovascular
risk, were not met and the trial was terminated after 3-years of
follow-up on the basis of futility. The Second Heart Protection Study –
Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-
THRIVE) was another large double-blind, randomized, multi-center
trial studying the effect of niacin in combination with laropiprant, in
statin-treated patients [132]. Laropiprant is a prostaglandin (a type of
eicosanoid – physiologically active lipid compound) D2 receptor antag-
onist which is suggested to reduce previously observed side effects of
niacin, such as flushing. Similar to AIM-HIGH, this study revealed favor-
able effects on lipid parameters, but no significant reduction was ob-
served in major vascular events. Subjects treated with niacin also had
significantly increased adverse effects, including gastrointestinal prob-
lems, infection, bleeding and a trend towards increased risk of death.
Based on these studies, niacin was withdrawn from several markets, al-
though the use of niacin is still extensively being investigated in various
pathologies.
4.1.1.2.2.2. Fibrates. Fibrates, PPARα agonists, have been evaluated in
several clinical outcome trials [133–137]. However, the results of
these studies were variable [138], possibly because different types of
fibrates (e.g. gemfibrozil, bezafibrate, fenofibrate) were used and differ-
ent patient groups (with or without diabetes) were investigated. Al-
though the association of fibrate use with CVD mortality was limited
in most studies, disproportionately large benefits have been observed
in patients with high plasma triglyceride and low HDL-C levels at the
start of the study. This observation triggered the initiation of a new clin-
ical trial called Pemafibrate to Reduce Cardiovascular OutcoMes by Re-
ducing Triglycerides IN patiENts With diabetes (PROMINENT) [139].
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Advanced Drug Delivery Reviews 159 (2020) 94–119
This trial has started recruiting patients to test this PPARα agonist in
about 10,000 statin-treated patients with diabetes and high triglycer-
ide/low HDL-C plasma levels. First results from this study are expected
in 2022 and are eagerly anticipated to determine whether fibrates
have an greater therapeutic potential in this sub-group of patients.
This ongoing trial will also provide more information whether
pemafibrate, a next generation, more potent and selective PPARα mod-
ulator [140] has less adverse side effects, such as gastrointestinal issues,
skin rash, muscle pain and in some cases liver dysfunction following
chronic use, than the currently available PPARα agonists [141,142]. It
would be highly interestingly to also assess whether pemafibrate has ef-
fects on HDL composition, besides HDL-C. It has previously been shown
that fenofibrate affects HDL composition in rabbits, by decreasing satu-
rated fatty acids and increasing unsaturated fatty acids, which could
thereby also influence HDL functions like the cholesterol efflux capacity
[143]. Further studies in a human setting would be needed to confirm
the effects of fibrates on HDL composition.
The activation of PPARα is the main mechanism of action of fibrates
or fibric acid [144]. This modulates several processes, including increas-
ing the oxidation of free fatty acids in the liver and reducing the hepatic
synthesis of triglycerides [138]. Additionally, PPARα increases expres-
sion of lipoprotein lipase (LPL), which hydrolyzes triglycerides and
phospholipids in VLDL, chylomicrons and HDL [145] and reduces
circulating triglyceride levels. Fibrates also increase HDL-C levels and in-
crease the synthesis of apoA-I, apoA-II and ABCA1 [146,147]. Interest-
ingly, in contrast to these human observations, fibrates do not exert
similar effects on apoA-I synthesis in rodents [148]. These differential
effects of PPARα are likely due to species-specific regulation of apoA-I,
as there are 3 nucleotides difference between rat and human ApoA1
promotor sites, rendering the PPARα-response element in the ApoA1
promotor non-functional in rats [149]. These differences complicate
studies of the underlying molecular mechanisms.
4.1.1.2.2.3. CETP inhibitors. CETP regulates lipoprotein cholesterol/tri-
glyceride ratios, as discussed above. There is a negative correlation be-
tween CETP activity and plasma HDL-C levels, making CETP inhibition
an interesting therapeutic target. There have been several clinical stud-
ies focusing on the effects of CETP inhibition on HDL levels and assessing
the therapeutic potential of these agents in CVDs [29,138].
One of the first trials, ILLUMINATE, assessed the effects of the CETP
inhibitor, torcetrapib. It was terminated prematurely due to an unex-
pected increase in mortality rates due to sepsis [150]. Subsequent stud-
ies discovered that torcetrapib has a significant effect on the renin-
angiotensin-aldosterone system (RAAS), resulting in hypertension and
hypokalemia which possibly contributed to the detrimental outcome
[151]. The sepsis-related mortality of torcetrapib could not be attributed
to any direct effects on lipopolysaccharide binding protein (LBP), nor to
inhibition of the interaction of CETP with LPS [152]. Therefore, it could
be speculated that on top of the aldosterone elevation, changes in
plasma lipoprotein metabolism and composition may have contributed
to the increase in sepsis. Based on these results, other trials turned their
focus to novel CETP inhibitors such as dalcetrapib (dal-OUTCOMES) and
evacetrapib (ACCELERATE). These studies did not show any of the pre-
viously observed adverse side-effects, but were also terminated early
due to futility [153,154]. The recently published trial of anacetrapib (RE-
VEAL), demonstrated for the first time that CETP inhibition can have
beneficial effects on clinical outcomes [155]. Anacetrapib increased
HDL-C plasma levels by more than 2-fold, while decreasing LDL-C levels
by more than 20%, resulting in a decreased occurrence of first major cor-
onary events by 9% without any safety concerns. Although these results
seem promising, the clinical benefit is rather modest and perhaps more
related to the small decrease in LDL-C plasma levels. Therefore, the
pharmacological development of anacetrapib has been stopped, which
at least at this moment is the end of clinical trials focussing on this
class of drugs for CVD-therapy [156]. A potential explanation for this
S. Nazir, V. Jankowski, G. Bender et al.
futility of CETP inhibition in CVD is provided by a recent Mendelian
randomization analyses [157]. In this study, 102,837 participants
from 14 studies were analysed and the observed associations were ex-
ternally validated in 189,539 participants from 48 studies. Considered
alone, a CETP score was associated with higher levels of HDL-C, lower
LDL-C and a corresponding lower risk of major CV events. However,
when combined with a 3-hydroxy-3-methylglutaryl-CoA reductase
(HMGCR) score, the CETP score was still associated with a similar reduc-
tion in LDL-C, but an attenuated non-significant risk of major CV events.
These results indicate that a monotherapy of CETP inhibition, without
statin treatment, may have more pronounced beneficial effects. This hy-
pothesis could be tested in future clinical trials in statin-intolerant
patients.
In addition to the REVEAL-trial, the dal-ACUTE randomized trial,
which investigated the effects of the CETP inhibitor dalcetrapib on
markers of HDL function, fuelled the debate that future studies should
focus on modulating HDL functionality rather than HDL-C levels [158].
This study showed that CETP inhibition resulted in approximately 30%
increase in HDL-C levels, while the apoA-I content and total cholesterol
efflux capacity were only increased by 10%, clearly supporting the con-
cept of dissociation between increased HDL-C levels and improvements
in HDL function. Recently, it was also shown that elderly subjects have
remarkably high cholesterol efflux capacity, compared to middle-aged
individuals, although the implications of this for therapeutic approaches
and clinical trials remains to be determined [159].
4.1.1.2.3. Direct targeting of apoA-I and HDL. Changing HDL levels and
composition can also be done in a more direct manner. For example,
the endogenous synthesis of apoA-I is increased to some extent with
a small molecule called apabetalon or RVX-208 or RVX000222, which
inhibits the bromodomain and extra terminal (BET), resulting in an
epigenetic modulation of the genes responsible for apoA-I synthesis.
A Phase II clinical trial showed that RVX-208 was associated with in-
creased plasma apoA-I and HDL-C levels in statin-treated patients
with coronary artery disease [160]. These beneficial effects were con-
firmed in a Phase IIb trail (ASSURE) which employed serial intravas-
cular ultrasound measures of coronary atheroma in 281 patients
treated with RVX-208 or placebo for 26 weeks [161]. RVX-208 treat-
ment modulated plaque vulnerability favourably, though interest-
ingly only changes in HDL particle concentration could be observed
upon treatment, not in HDL-C or apoA-I. Although RVX-208 treat-
ment of non-human primates demonstrated striking increases in
serum apoA-I and HDL-C levels (60% and 97%, respectively) [162],
the observed increases in human trial were on average below 10%
[160]. Although the treatment protocols differed, this significant dif-
ference in effect on lipid levels indicates that there may be an as yet
unknown species-dependent mechanism of action of RVX-208. Cur-
rently, there is an ongoing Phase III study, investigating the effects
of apabetalone (RVX000222) on major adverse cardiac events
(BETonMACE) [163,164]. These results are eagerly awaited to evalu-
ate the potential of this therapeutic approach.
Another strategy to increase apoA-I levels is to infuse artificially syn-
thesized apoA-I mimetic peptides. These can be designed to mimic the
lipid binding properties of apoA-I and improve their stability relative
to the parent apolipoprotein [165,166]. Several pre-clinical studies
have shown that apoA-I mimetic peptides have anti-inflammatory, an-
tioxidant and antitumor activities [167,168]. One drawback until now is
that most of these apoA-I mimetic peptides are designed to enhance
only one or two specific functions of apoA-I rather than the full spec-
trum of physiological relevant functions. One of these mimetic peptides
that showed great promise in pre-clinical studies is the peptide 5A,
which induces cholesterol efflux via ABCA1 and ABCG1, thereby reduc-
ing atherosclerosis in mice [169]. Furthermore, 5A inhibits acute inflam-
mation and oxidative stress in human endothelial cells and rabbit
carotid arteries [170]. Future clinical trials should determine the poten-
tial of this apoA-I mimetic peptide in humans.
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Advanced Drug Delivery Reviews 159 (2020) 94–119
Pre-clinical studies of another mimetic peptide called 4F, showed
that this peptide was only able to inhibit early atherogenesis, but was
ineffective against more mature lesions [171]. 4F peptide was tested in
humans for the first time in a randomized clinical trial that assessed
the efficacy and safety of orally administrated D-4F peptide in high-
risk coronary heart disease patients. Treatment with D-4F resulted in
HDL with improved anti-inflammatory properties, suggesting that D-
4F might be a potential therapeutic agent to improve HDL function
[172]. However, large clinical trials have not been performed to evaluate
the effect of these mimetic peptides on major adverse cardiovascular
events, though based on the pre-clinical work it seems that 4F could
only be effective in an early stage of atherosclerosis development
which is difficult to test in a human setting as patients are often only
identified in the later stages of the disease.
Direct infusion of reconstituted HDL is another therapeutic ap-
proach. To date monomeric apoA-I which is present in the HDL fraction
of most humans and the dimeric form of apoA-I (apoA-IMilano) which
has an enhanced cholesterol efflux potential have been formulated as
reconstituted HDL for use in clinical trials [138].
In a randomized clinical trial, infusions of reconstituted HDL contain-
ing monomeric apoA-I (CSL-111), significantly improved plaque char-
acteristics although there were no changes in atheroma volume [173].
The successor of CSL-111, which has an enhanced ability to accept cho-
lesterol from ABCA1, is called CSL-112 [174]. In a dose-ranging Phase IIb
trial (AEGIS-I), infusions of CSL-112 were well tolerated, without any se-
rious safety concerns, and acutely enhanced cholesterol efflux [175].
Currently, a large-scale Phase III trial of patients with acute coronary
syndrome is being undertaken to evaluate the ability of CSL-112 to re-
duce major adverse cardiovascular events [176].
CER-001 is another reconstituted HDL preparation that contains apoA-
I and sphingomyelin. Pre-clinical studies have demonstrated that CER-
001 stimulates reverse cholesterol transport and induces atherosclerosis
regression in mice [177]. Recently, the results of a Phase II double-blind,
randomized, multicenter trial (CARAT) was published, in which the effect
of CER-001 infusion on coronary atherosclerosis progression was evalu-
ated in statin-treated acute coronary syndrome patients [178]. Unfortu-
nately, the lipid profile in these patients did not change and regression
of coronary atherosclerosis was not influenced by CER-001 infusion.
Another study using a recombinant apoA-IMilano/phospholipid com-
plex (ETC-216) showed significant regression of coronary atherosclero-
sis, demonstrating great promise for this approach [179]. It has been
demonstrated that plaque regression after ETC-216 treatment in a rab-
bit model, was associated with a shift towards a more stable lesion phe-
notype after four days [180]. A follow-up study confirmed that these
beneficial effects are long lasting [181]. However, the clinical develop-
ment of ETC-216 was halted after a serious adverse reaction occurred
early during an follow-up clinical trial in one patient. During infusion
the patient developed a severe reaction consisting of flushing, chills, hy-
potension and ultimately multi-organ failure. This all pointed to a sys-
temic inflammatory reaction which would suggest a contamination of
the infused product, which was indeed the case as small quantities of re-
sidual host cell proteins that elicit immune responses were found in
ETC-216. Hereafter, a similar complex containing apoA-IMilano was in-
troduced as MDCO-216. This formulation did not induce any adverse
immunostimulation in healthy volunteers or patients with stable coro-
nary artery disease [182]. However, in a double-blind, randomized clin-
ical trial of acute coronary syndrome patients, infusion of MDCO-216
did not promote atherosclerotic lesion regression [183].
Several direct targeting approaches have been developed and are
being tested. Especially in the approaches where reconstituted HDL is
being used, a major focus has been to increase HDL function by, for ex-
ample, developing agents that have an enhanced cholesterol efflux ca-
pacity or that contain specific proteins that improve HDL function,
such as sphingomyelin or apoA-IMilano. As the importance of HDL func-
tion is being more recognized, future approaches of HDL therapy should
focus on this aspect.
S. Nazir, V. Jankowski, G. Bender et al.
4.1.2. Diabetes mellitus
Diabetes Mellitus (DM) is a disease involving inappropriately el-
evated blood glucose levels. The main subtypes of DM are type 1
(T1DM), caused by defective insulin secretion, and type 2 (T2DM),
caused by defective insulin function [184]. T1DM generally presents
at a very young age, while T2DM is occurs in adolescents and adults
that have prolonged hyperglycemia due to lifestyle problems. As
the pathogenesis of the two types of DM is different, different
therapeutical approaches are required. Both types of DM are associ-
ated with a high risk of developing chronic complications, such as
retinopathy, nephropathy, neuropathy, endothelial dysfunction,
and atherosclerosis.
4.1.2.1. Effects of HDL on the pathogenesis of diabetes mellitus. During the
course of T2DM, plasma triglycerides and LDL-C increase, while HDL-C
decrease [185]. A meta-analysis evaluated the association of HDL-C
and risk of diabetic nephropathy in T1DM patients, demonstrating
that higher HDL-C levels indeed result in a reduced risk of diabetic com-
plications [186]. In contrast, a recent retrospective population-based co-
hort study involving 2113 patients with T2DM demonstrated that the
levels of HDL-C are non-protective in T2DM patients [187].
HDL particles also undergo structural and functional modifications
in DM, resulting in loss and HDL function [185] (Fig. 6). For example, el-
evated levels of oxidative stress lead to oxidative modification of apoA-I
in HDL and thereby contributes to the generation of dysfunctional HDL
in DM [188,189]. These modifications have also been shown to result in
decreased cholesterol efflux capacity [190], and impaired antioxidant
properties in T1DM [191]. Moreover, PON1 expression is decreased dur-
ing T1DM and T2DM development, which possibly contributes to the
observed cardiovascular complications [192,193]. This is supported by
the observation that elevated levels of HDL-associated PON1 were ob-
served in a subset of people with T1DM that are protected from vascular
complications [192]. Additionally, advanced glycation end products
(AGEs) which are elevated in DM and contribute to diabetic complica-
tions have also been shown to modify apoA-I and impair its
cardioprotective functions [194]. In line with this, macrophages treated
with albumin isolated from T2DM patients have significantly impaired
cholesterol efflux and intracellular lipid accumulation, compared to
cells treated with non-diabetic albumin, further demonstrating an im-
portant role of glycation in lipid handling [195]. Lipid accumulation
has also been demonstrated to play a role in diabetic nephropathy, as
evidenced in streptozotocin-induced diabetes in mice with significantly
reduced renal expression of ABCA1, ABCG1 and SR-B1. As these changes
in ABCA1, ABCG1 and SR-B1 preceded the development of nephropathy
in these mice, it follows that defective cholesterol efflux may be the
cause of intracellular accumulation of lipids in renal cells and the devel-
opment of diabetic nephropathy [196]. In T2DM the distribution of HDL
particles is also affected, with a shift from large HDL particles enriched
in cholesteryl esters to smaller, denser triglyceride-rich HDL particles,
thereby also affecting the HDL function [197].
Besides the effects that diabetes has on HDL composition and func-
tion, apoA-I and HDL also have anti-diabetic properties [198]. For exam-
ple, it has been demonstrated that apoA-I increases insulin secretion
from pancreatic beta-cells in an ABCA1-dependent manner, while HDL
does the same in an ABCG1-dependent manner [199]. Furthermore, it
has been shown that overexpression of apoA-I in mice increases insulin
sensitivity, while apoA-I deficiency impaired glucose tolerance
[200,201]. In line with these findings, Torcetrapib and dalcetrapib (in-
hibitors of CETP activity) increase plasma HDL-C and apoA-I and im-
prove glycaemic control in patients with T2DM [202,203]. Glucose
uptake by skeletal muscle cells is also increased by apoA-I, in an
ABCA1 and SR-B1 dependent manner [204].
All in all, it seems that diabetes impacts on HDL function, while
vice versa HDL function also impacts on diabetes, clearly demon-
strating that HDL functionality is an important determinant for its ef-
fects on DM.
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4.1.2.2. Clinical potential of apoA-I and HDL in diabetes mellitus. In a recent
systematic review and network meta-analysis of patients with T2DM,
the impact of dietary interventions on the blood lipid profile was
assessed, with a Mediterranean diet raising HDL-C and decreasing TG
levels compared to control diet. This indicates that a Mediterranean
diet can be used to manage diabetic dyslipidaemia [205].
Besides dietary interventions, fibrates have also been tested in the
context of DM. Initially, the Action to Control Cardiovascular Risk in Di-
abetes (ACCORD) lipid study did not show major beneficial effect of
adding a fibrate on top of a statin, compared to statin alone, on cardio-
vascular outcomes and mortality in T2DM patients, although diabetic
retinopathy progression was reduced [206]. However, a beneficial effect
in CV-events was shown in a pre-specified sub-group of patients with
dyslipidemia. This triggered a follow-up study (ACCORDION) in which
a secondary analysis was performed in a pre-specified sub-group of par-
ticipants with dyslipidemia, demonstrating that fibrates reduce mortal-
ity rates in dyslipidemic patients [207]. In addition, a multicenter
randomized controlled study showed that in T2DM patients, adminis-
tration of ezetimibe/rosuvastatin combination therapy significantly re-
duces the apoB/A-I ratio and improves the lipid profile compared to
patients receiving rosuvastatin monotherapy [208].
rHDL infusions also have beneficial effects in DM patients, by im-
proving endothelial function and nitric oxide availability, compared to
controls [209]. In line with this, a small randomized clinical trial demon-
strated that a single infusion of rHDL in patients with T2DM decreased
plasma glucose levels and increased plasma insulin levels [210]. Fur-
thermore, focusing on diagnosis instead of therapy, it has been shown
that both oxLDL/LDL and oxLDL/HDL are potent biomarkers for T2DM
[211] and can be used for discriminating the presence of macrovascular
disease in diabetic patients [212].
All in all, the therapeutic efficiency of improving HDL function in the
context of DM based on above results would be an interesting research
focus for the future.
4.1.3. Liver disease
The liver plays a vital role in the synthesis, secretion, catabolism, and
storage of lipids and lipoproteins. The two main types of fatty liver dis-
ease are nonalcoholic fatty liver disease (NAFLD) and alcoholic liver dis-
ease (ALD). NAFLD includes simple steatosis (SS) and the more severe
nonalcoholic steatohepatitis (NASH), which is characterized by inflam-
mation and fibrosis, while ALD can lead to fibrosis, hepatic steatosis and
cirrhosis [213].
4.1.3.1. Effects of HDL on the pathogenesis of liver disease. Several studies
have shown that moderate, regular consumption of alcohol leads to fa-
vorable changes in HDL lipids and apolipoproteins [214]. Moderate con-
sumption of alcohol also affects HDL function by improving their anti-
inflammatory and anti-oxidant properties [214]. Although very little is
known about the HDL composition and function in patients with SS
and NASH, it has been shown that NAFLD is associated with an altered
HDL proteome, such as decreased plasminogen and antithrombin III
levels [215], and an increased number of small HDL particles [216].
HDL isolated from NAFLD patients also showed a reduced cholesterol ef-
flux capacity [217] and the HDL of patients with liver cirrhosis are
enriched with triglycerides, free cholesterol and phospholipids [218].
Furthermore, enzymes that are involved in HDL maturation and metab-
olism, such as CETP and LCAT, are significantly decreased in patients
with cirrhosis, resulting in a shift towards the larger HDL2 subclass as
well as diminished cholesterol efflux capacity [219]. These composi-
tional and functional changes were in addition to decreased HDL-C
levels with deterioration of liver function in cirrhotic patients [220].
HDL-C levels are inversely associated with the development of other
liver diseases. For example, HDL-C levels are increased in the early
stages of Primary Biliary Cirrhosis (PBC) and decline with disease pro-
gression [221], which is mediated by increased circulating hepatic lipase
activity and HDL catabolism. Hepatitis C virus (HCV) and Hepatitis B
S. Nazir, V. Jankowski, G. Bender et al.
virus (HBV) related infections that mainly affect the liver are also asso-
ciated with low serum HDL-C levels. The interaction of lipids and lipo-
proteins with liver diseases has also recently been reviewed in [222].
4.1.3.2. Clinical potential of HDL in liver disease. As outlined above, there is
a clear link between HDL and liver disease. However, very few studies
have focussed on the clinical potential of HDL in this disease. For exam-
ple, niacin has been shown to beneficially affect NASH/NAFLD which has
recently been elegantly reviewed by Kashyap et al. [223]. In short, both
in-vitro (primary hepatocytes and human hepatoblastoma cell lines)
and in-vivo (rat model of NAFLD) studies have demonstrated that niacin
decreases hepatic fat deposits, inflammation, steatosis and fibrosis,
which are all major complications associated with NASH/NAFLD
[224,225]. Clearly, more studies are needed to elucidate whether HDL
targeting has any clinical potential in liver disease. As HDL composition
also plays an important role, it would be important that these studies
not only increase HDL-C levels but also regulate HDL composition and
thereby its function.
4.1.4. Cancer
Chronic inflammation has been linked to steps that promote
tumorgenesis, including cellular transformation, survival, proliferation,
angiogenesis and metastasis [226]. The majority of cancers are linked
to somatic mutations and environmental factors, such as smoking,
whereas diet also plays an important role [227]. Accumulating evidence
also suggests that apoA-I and HDL play a role in cancer development
and disease progression.
4.1.4.1. Effects of HDL on the pathogenesis of cancer. As cancer is a very
heterogeneous disease, it is challenging to describe disease-specific ef-
fects of HDL. Therefore, selected cancer types, for which a clear effect
of HDL has been demonstrated, will be highlighted in this section. This
does not exclude that HDL is not involved in other subtypes.
Recently, RNA sequencing analysis of hepatocellular carcinomas
(HCC) revealed that apoA-I mRNA levels were significantly reduced in
diseased tissue compared to healthy liver tissue [228]. This coincided
with reduced protein levels of apoA-I in cancerous liver tissue and
serum of HCC patients [229], suggesting a tumor suppressor role of
apoA-I and HDL. Other studies have confirmed this negative association
between apoA-I and HDL serum levels with parameters cancer develop-
ment, summarized in [229]. Although the majority of studies have
shown a clear inverse association of apoA-I with the development of
cancer, positive correlations have also been reported. For example,
apoA-I levels are upregulated in the serum of patients with early stage
gastric adenocarcinoma and retinoblastoma [230,231]. These discrep-
ancies highlight the difficulty of determining a precise role for apoA-I
and HDL in cancer. Furthermore, it is not known whether alterations
in HDL and apoA-I levels could be either a cause or consequence of the
carcinogenesis.
Several studies have confirmed that cancer cells require large
amounts of cholesterol to maintain their high degree of proliferation.
This means that cancer cells and tissues over-express specific compo-
nents involved in cholesterol transport, especially SR-B1 [232]. There-
fore it is plausible that HDL is the major source of cholesterol for
cancer cells. If this is the case, HDL functionality would also be an impor-
tant determinant in regulating the upregulated cholesterol homeostasis.
One study that highlights the importance of HDL functionality in cancer,
has shown that HDL completely inhibits the oxidative stress-induced
proliferation of prostate cancer cells [233]. The exact role that HDL func-
tion plays in cancer should therefore be one of the main focus points of
future research, especially in light of the important role of HDL function-
ality in other diseases.
4.1.4.2. Clinical potential of apoA-I and HDL in cancer. In-vitro studies
using recombinant apoA-I or apoA-I mimetic peptides have demon-
strated that apoA-I can decrease the proliferative, survival and
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migratory behaviour of various carcinoma cells (reviewed in: [229]).
Animal cancer models have confirmed these effects by showing that
apoA-I inhibits the growth of tumors and their metastatic progression
(reviewed in: [229]). For example, a genetic approach was used to test
the role of apoA-I in a melanoma model. ApoA-I deficient mice showed
an increased tumor burden and reduced survival, while conversely
transgenic overexpression of human apoA-I reduced the malignant bur-
den and metastases, thereby increasing survival [234]. These effects
were mainly attributable to immunomodulatory properties of apoA-I,
by which tumor-associated macrophages were re-programmed from a
pro-tumor M2 to an anti-tumor M1 phenotype. In line with this, an-
other study demonstrated that apoA-I mimetic peptides inhibited
tumor development in a mouse model of ovarian cancer [235]. Although
apoA-I and HDL have shown promising results in preclinical studies, it is
challenging to apply such therapies to the highly diverse and variable
pool of cancer patients. Therefore, feasibility remains a matter of debate
and more research into the underlying mechanisms, and especially
large clinical trials, would be needed to explore the possibility of using
apoA-I and/or HDL as anticancer agent.
Another interesting approach that is currently being explored within
the cancer field is the use of HDL as drug delivery platform [236–238].
Such systems are believed to provide tumor-selectivity and site-
specificity, while reducing off-target effects [239]. As noted above, can-
cer cells overexpress SR-B1 and reconstituted HDL nanoparticles are
being produced to specifically target this receptor in cancer cells [240].
The main advantage of such a delivery system is that apoA-I and HDL
are naturally occurring and infusions will not result in immune re-
sponses as has been shown in the CVD-focussed studies described
above. Taken together, apoA-I and/or HDL seems to be an interesting ap-
proach for cancer, either being used as direct effectors or as delivery
platforms. Future research should first address the question of the ex-
tent to which HDL plays a causal role in the development of different
types of cancer.
4.2. Infectious diseases
Infectious diseases are disorders caused by organisms including bac-
teria, viruses, fungi or parasites. A wide diversity of infectious diseases
exists and the way of transmission, signs and symptoms vary depending
on the organism causing the infection.
4.2.1. Bacterial, viral and parasitic infections
4.2.1.1. Effects of HDL on the pathogenesis of infectious diseases. Bacterial
infections caused by Gram-negative bacteria modulate HDL composi-
tion and size by reducing the apoA-I and phospholipid content and in-
creasing SAA [241]. Endotoxemia also induces changes in enzymes
that are important for HDL remodelling, such as CETP and LCAT [241].
HDL also plays an important role in more severe infections causing sep-
sis, which will be discussed in detail later.
HDL also interacts with Gram-positive bacteria, by binding directly
to lipoteichoic acid (LTA) [242] and attenuating inflammation and cell
death in-vitro [243]. These beneficial effects have also been validated
in mice, where apoA-I attenuated LTA-induced acute lung injury and cy-
tokine production [243]. These observations support the hypothesis
that raising plasma HDL levels may be a viable therapeutic approach
for the treatment/prevention of infectious diseases.
However, recently it became clear that this relationship is not
straightforward [244]. In two well-characterized and large-scale cohorts
from Copenhagen, it has been demonstrated that HDL-C levels are asso-
ciated with infection-related hospitalization [245]. Interestingly, this as-
sociated followed a U-shaped pattern where low and very high HDL-C
levels were associated with increased infection risk. Supporting this
finding, SNPs in the genes encoding for CETP and hepatic lipase (LIPC)
were associated with a reduced risk for infections (especially bacterial
infections). It remains challenging to explain the intriguing association
S. Nazir, V. Jankowski, G. Bender et al.
between high HDL-C and increased infectious risk [244]. As inflamma-
tion results in changes in the composition of HDL, including the accu-
mulation of SAA, it is possible that such compositional changes may be
responsible for the observed association. Furthermore, PTMs may
occur in inflammatory environments, as described above, which again
induce changes in HDL composition and function. All in all, this again
highlights the need to further investigate the exact role of HDL function
in bacterial infections.
The interaction between HDL and parasitic infections mainly relates
to the ability of apoL-1 to limit Trypanosoma brucei and Leishmania in-
fections [242]. ApoL-1 is part of the trypanosome lytic factor-1 (TLF-1)
complex, that mediates uptake by parasites. After uptake, apoL-1 enters
lysosomes where the acidic pH causes a conformational change
resulting in lysosomal swelling that kills the trypanosome [246,247].
Due to these specific effects of apoL-1, it could be speculated that ap-
proaches to increase the apoL-1 content in HDL could have beneficial
outcomes in parasitic infections.
Changes in plasma HDL-C levels also occur during viral infections,
such as human immunodeficiency virus (HIV). HIV infected patients
have significantly decreased HDL levels, which align with upregulated
inflammasome-related gene expression and serum levels of IL-6 and
CRP [248]. These negative correlations demonstrate that HDL might af-
fect the progression of HIV infection by modulating the inflammatory
state, although determining whether changes in HDL are cause or con-
sequence remains to be determined. On the other hand, the pro-
inflammatory state in these patients also increases apoA-I and HDL
levels following antiretroviral therapy depending on the extent of in-
flammation at baseline [249]. In a small retrospective study, it was
shown that HIV infection also corresponded with a decrease in the anti-
oxidant and anti-inflammatory functions of HDL [250]. The importance
of HDL function has also been confirmed in another study, demonstrat-
ing that antiretroviral treatment was associated with higher HDL anti-
oxidant function and PON-1 activity [251].
4.2.1.2. Clinical potential of apoA-I and HDL in infectious diseases. Several
pre-clinical studies have investigated the effect of apoA-I mimetic pep-
tides in infectious diseases or related processes. For example, the 4F mi-
metic peptide inhibits the expression of pro-inflammatory mediators in
LPS-treated cells in-vitro by neutralizing LPS [252]. These beneficial ef-
fects have been confirmed in-vivo in endotoxemic rats, where 4F treat-
ment results in the attenuation of acute lung injury and increases
survival rates [253]. Future studies are warranted to translate these
findings into the clinical setting.
Regarding parasitic infections, it has been demonstrated that a re-
combinant apoL-1-nanobody binds to trypanosomes and lyses them
in-vivo [254]. Treatment of mice infected with Trypanosoma brucei
brucei with this apoL-1 nanobody resulted in a striking clearance of
the parasite from the circulation, indicating the therapeutic potential
of this approach [254].
Although, HDL clearly plays a potentially important role in infectious
diseases, the clinical potential of apoA-I and HDL in these diseases is un-
explored. Therefore, it would be worthwhile for future studies to focus
on the clinical potential of increasing HDL functionality in these diseases
as an interesting new approach for treatment or possibly prevention.
4.2.2. Sepsis
LPS, also known as lipoglycan or endotoxin, is found in the outer
membrane of gram-negative bacteria and is considered to be the
major cause of sepsis. LPS binds to LBP, an acute phase protein, which
transfers LPS from the bacterial wall to membrane-bound CD14. Subse-
quently, the LPS-CD14 complex binds and signals through TLR4 on
immune cells to activate the transcription factor NF-κB and mitogen-
activated protein kinases (MAPKs), such as p38 and c-Jun NH2-
terminal kinase (JNK) [255,256]. This activation regulates the expres-
sion of several endogenous mediators of inflammation such as IL-8,
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IL-1ß, TNF-α, VCAM-1 and ICAM-1 that are known to be involved in
the progression of septic shock.
4.2.2.1. Effects of HDL on the pathogenesis of sepsis. Interestingly it has
been shown that HDL, especially apoA-I, can neutralize LPS [257] by in-
creasing its biliary excretion and clearance by the liver, thereby
protecting against septic shock (Fig. 5) [258]. Further support of LPS-
lipoprotein interactions comes from a biosensor study demonstrating
that the majority of LPS is associated with HDL [259]. This interaction is
mediated by lipid transfer proteins such as CETP, PLTP and LBP, which
transfer LPS to lipoproteins [260]. However the exact contributions of
these transfer proteins to this process remain unclear. Although CETP
binds weakly to LPS compared to LBP [152], mice overexpressing
human CETP have improved survival when exposed to experimental sys-
temic inflammation [261]. Furthermore, it has been shown in hamsters,
that endotoxin and pro-inflammatory cytokines such as TNF-α and IL-1
decrease serum CETP activity, as well as CETP mRNA levels and protein
expression in several tissues including the heart, muscle and adipose tis-
sue [262]. This increases circulating HDL levels, which is beneficial for the
clearance of endotoxins, even though the pro-inflammatory environ-
ment will reduce its endotoxin clearing potential. Decreased CETP activ-
ity during inflammation has also been reported in sepsis patients
[241,263]. In line with this, Mendelian randomization studies have con-
firmed a causal role for CETP in sepsis, as a missense variant in CETP re-
duced HDL-C levels and decreased sepsis survival [264].
In humans clear associations have been made between HDL and the
development of sepsis. Clinical studies have highlighted that HDL-C
levels decline during sepsis [265,266] and that this is associated with in-
creased mortality and adverse clinical outcomes [267,268]. Reduced
levels of HDL-associated S1P in patients with sepsis are associated
organ failure [269]. Low levels of S1P are associated with cardiac dys-
function in mice with sepsis [270]. Additionally, it has been shown
that HDL levels decreases, HDL size increases due to association with
SAA and HDL function is compromised during the acute phase reaction
in sepsis patients [271,272]. This was confirmed in a pilot study of older
patients where isolated HDL had impaired cholesterol efflux capacity
and a pro-inflammatory profile, compared to healthy controls [273].
Therefore HDL function also seems to play an important role in the path-
ogenesis of sepsis.
The above associations do not prove that a causal relationship exists
between HDL and sepsis in humans. However, a causal role of apoA-I in
protection against sepsis has been confirmed in mouse models of sepsis
where apoA-I deficiency robustly increased production of inflammatory
cytokines, while overexpression of apoA-I increased survival rates com-
pared to control mice [274]. Treatment of septic mice with HDL signifi-
cantly reduced the release of IL-8, IL-6 and TNF-α [275,276],
demonstrating a potential role of HDL as therapeutic target for
endotoxemia.
A potentially causal relationship between HDL and sepsis in humans
has recently been demonstrated in a prospective study of >400,000 par-
ticipants that examined the association of lipid levels and the risk of in-
fectious hospitalizations and 28-day sepsis mortality [277]. A 1 mmol/l
increase in HDL-C levels associated with a hazard risk for infectious dis-
ease of 0.84. More importantly, Mendelian randomization using HDL-C-
related genetic variants further demonstrated a causal relationship be-
tween raised HDL-C and reduced risk of infectious hospitalization and
there was a significant inverse relation existed between HDL-C and
28-day sepsis mortality [277]. Together these results demonstrate that
HDL-C is causally related to sepsis. Future studies should investigate
whether this causal relationship also exists between HDL function and
sepsis as this is most likely even a more important parameter for disease
outcome.
4.2.2.2. Clinical potential of apoA-I and HDL in sepsis. Based on the above
described relationship of HDL and sepsis with the reductions of HDL
concentration and HDL dysfunction, there seems to be a great potential
S. Nazir, V. Jankowski, G. Bender et al.
Fig. 5. Mechanism of action by which HDL protects against sepsis. In sepsis, lipopolysaccharide (LPS) binds to LPS-binding protein (LBP) and interacts with the CD14 receptor, initiating
inflammatory cytokine signalling via TLR4. HDL can inhibit these inflammatory processes via two pathways, (i) inhibition of the inflammatory signalling or (ii) binding and capturing the
LPS-LBP complex resulting in excretion via the liver.
for HDL-based therapies in sepsis. Until now, all studies focused on a di-
rect targeting approach using apoA-I mimetic peptides or reconstituted
HDL infusions.
Fig. 6. Diabetes alters HDL composition and function. In diabetes, high levels of oxidative
stress, advanced glycation end products (AGE) and reactive oxygen species (ROS),
induce direct or indirect via PON-1 and myeloperoxidase (MPO) compositional changes
in HDL particles, rendering them dysfunctional. Thereby HDL is less effective in
extracting cholesterol from cells.
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Several studies have investigated the potential therapeutic effect of
the apoA-I mimetic peptide 4F in a rat model of sepsis (cecal ligation
and puncture (CLP)). Administration of 4F, 6 h after CLP surgery, signif-
icantly decreased plasma IL-6 concentrations, improved cardiac func-
tion and reduced mortality [278]. In another study which used the
same experimental setup, further beneficial effects of 4F treatment
were observed for kidney, vascular and lung function [279]. Together
these studies demonstrate that 4F has beneficial effects on sepsis-
related injury and by using a therapeutically relevant model (treatment
after sepsis induction) these studies highlight the therapeutic potential.
Reconstituted HDL has also been used to study sepsis in animal
models [275,280–284]. For example, reconstituted HDL infusion limited
organ injury during endotoxic shock in rodents [282]. The main limitation
of these studies is the timing of the infusion. Infusion of reconstituted HDL
before initiation of sepsis is of limited relevance in a clinical setting. Re-
cently, infusion of CSL-111 2 h after induction of sepsis in mice reduced
inflammation in plasma, liver and lungs [283]. This suggests that
reconstituted HDL has therapeutic potential in septic conditions.
To date, no randomized human study using apoA-I mimetic peptides
or reconstituted HDL has been performed in septic patients. However, in
a randomized, placebo-controlled study in volunteers infused with
reconstituted HDL as pre-treatment followed by an endotoxin challenge
there was reduced release of pro-inflammatory cytokines and downreg-
ulation of CD14 in monocytes [276]. Although the group size was ex-
tremely small (n = 8), this study highlights the therapeutic potential
of HDL in human endotoxemia and stresses the need for randomized
studies with greater power.
S. Nazir, V. Jankowski, G. Bender et al.
4.3. Auto-immune diseases
4.3.1. Rheumatoid arthritis
Rheumatoid Arthritis (RA) is a chronic inflammatory disease charac-
terized by symmetrical synovitis and mediated by autoimmune mecha-
nisms, leading to bone destruction with progressive pain [285]. RA is
also associated with inflammation and affected patients have a signifi-
cantly increased risk of CVD [286,287]. A meta-analysis has demon-
strated that the risk of CVD mortality in patients with RA is increased
by a striking 50%, compared to healthy controls [287].
4.3.1.1. Effects of HDL on the pathogenesis of rheumatoid arthritis. Clinical
studies showed that RA patients have decreased serum HDL-C and
apoA-I levels compared to healthy controls [288–291]. In particular,
atheroprotective small sized HDL particles are reduced in patients
with RA [292]. However, as such modifications are mirrored by in-
creased LDL-C and total cholesterol levels, the actual clinical significance
of HDL-C variations remains unclear [293]. Therefore, elucidation of the
exact role of HDL-C in RA and especially the question as to whether low
HDL-C levels are a consequence of the disease or a causal mediator re-
mains an active field of research. A recent study explored the causal ef-
fect of HDL on collagen induced arthritis (CIA) in mice, and
demonstrated that HDL decreased the expression of pro-inflammatory
cytokines and the development of RA [294]. These beneficial effects
have been confirmed by another study, where apoA-I and reconstituted
HDL attenuated arthritis in rats, likely by reducing TLR2 expression in
macrophages [295]. Although these studies suggest that HDL can have
causal effects, it should be kept in mind that these models might not re-
flect the complex mechanisms that underlie alterations in lipid metab-
olism in RA patients. Supporting a role for HDL-C in RA in humans is
the observation from the Copenhagen General Population Study and
the Copenhagen City Heart Study that the hazard ratio for RA is 1.51
when comparing low vs. high HDL cholesterol levels, although this
only resulted in a non-significant statistical trend [296].
Interestingly, the composition and functional characteristics of HDL
are also significantly altered in RA. HDL isolated from RA patients
shows profound modifications, including increased SAA and reduced
PON-1 levels, resulting in a pro-inflammatory HDL particle [297].
These modifications also result in functional changes, as HDL isolated
from patients with RA have a reduced ability to protect LDL from oxida-
tion and possibly facilitate LDL oxidation [298]. Furthermore, HDL from
RA patients have a reduced capacity to act as cholesterol acceptors, in-
dependent of HDL-C levels [299]. ABCG1-mediated cholesterol efflux
is also impaired in RA patients and inversely correlates with disease ac-
tivity [299]. Furthermore, anti-apoA-I autoantibodies are detectable in
the serum of RA patients and predict acute cardiovascular events
[300]. Together, modifications of HDL composition in RA impair the
anti-inflammatory, antioxidant and cholesterol efflux-promoting ca-
pacity, highlighting that HDL function plays an important role in the
progression of RA.
4.3.1.2. Clinical potential of apoA-I and HDL in rheumatoid arthritis. Several
treatments for RA influence HDL levels and functionality. For instance, a
meta-analysis of 3552 patients demonstrated that baricitinub, a selec-
tive inhibitor of JAK1/2 signalling in RA, increases HDL-C levels in a
dose dependent manner [301]. However, a similar increase was also ob-
served in LDL-C levels, and no changes in CV risk were observed. There-
fore the exact contribution of specific HDL-associated lipid changes in
RA and the relationship with CV risk remains to be determined. More-
over, the treatment of RA patients with methotrexate reduces the in-
flammation and disease activity and restores the function of HDL back
to normal [302]. Decreases in RA disease activity over time were also as-
sociated with increases in PON-1 and apoA-I levels and decreases in the
HDL inflammatory index and levels of MPO, clearly demonstrating res-
toration of normal HDL function. HDL function can even be further im-
proved by combining methotrexate treatment with the TNF-α
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antagonist infliximab [303]. The importance of HDL function in RA has
also been demonstrated in the Abatacept Versus Adalimumab Compar-
ison in Biologic-Naïve RA Subjects with Background Methotrexate
(AMPLE) study [304] where decreased CRP levels were associated
with improved HDL function and composition. Additionally, improve-
ment in disease activity was associated with higher PON1 activity and
lower HDL-SAA content, highlighting that this treatment regime re-
models the HDL proteome. Collectively, these outcomes indicate that
HDL composition and function play important roles in RA and should
be the focus of future research to optimize HDL-based treatment
approaches.
4.3.2. Systemic lupus erythematosus
Systemic Lupus Erythematous (SLE) is a systemic autoimmune dis-
ease of multifactorial origin, in which environmental and genetic factors
induce immune disorders [293]. Typically, SLE coincides with the pro-
duction of type I interferon and is characterized by dysregulation of T-
and B-cells. SLE is associated with an increased cardiovascular risk and
accelerated atherosclerosis [305].
4.3.2.1. Effects of HDL on the pathogenesis of systemic lupus erythematosus.
Patients with SLE show changes in their serum lipids and lipoproteins
similar to those observed in patients with RA [306–308]. The systemic
inflammation, oxidative stress and autoimmunity in SLE patients also
induces compositional changes leading to the formation of pro-
inflammatory and dysfunctional HDL [309]. Accumulating evidence
suggests that changes in HDL composition and function are responsible
for the 7–50 fold increased risk of coronary artery disease in SLE patients
[309–311]. Carotid intimal-medial thickening was also observed in chil-
dren and adolescents with SLE, demonstrating the early onset of athero-
sclerosis in these patients [312]. Furthermore, almost half of the SLE
patients have pro-inflammatory HDL, which correlates with increased
oxidized LDL and carotid plaque formation and carotid intimal-medial
thickening [313]. Similar to HDL found in RA patients, HDL from SLE pa-
tients also has increased levels of SAA and decreased levels of PON-1
[314]. Interestingly, anti-apoA-I antibodies are also correlated with dis-
ease activity in SLE patients [315]. The ABCA1- and ABCG1-mediated
cholesterol efflux capacity of HDL is also significantly reduced in SLE pa-
tients [299].
4.3.2.2. Clinical potential of apoA-I and HDL in systemic lupus erythemato-
sus. Although the above studies indicate that SLE has an adverse effect
on HDL function, there are at present no clear indications that apoA-I
or HDL can causally or directly affect the development of SLE. However,
dysfunctional HDL might be an important biomarker for the identifica-
tion of CVD risk in SLE patients. The therapeutic potential of hypolipid-
emic treatment in SLE has been confirmed by treating SLE patients with
pravastatin plus ezetimibe, which improved the ratio of LDL-C and HDL-
C levels [316]. However, whether direct HDL-targeted approaches, such
as infusion of apoA-I or reconstituted HDL, has beneficial effects in SLE
patients still needs to be determined.
4.3.3. Psoriasis
Psoriasis is a chronic inflammatory skin disease related to immune
inheritance. However, to date, the true cause of the disease remain un-
clear [317]. Nowadays, psoriasis is considered to be a multisystem dis-
ease that may be related to other diseases, including rheumatological,
cardiovascular and psychiatric complications [317].
4.3.3.1. Effects of HDL on the pathogenesis of psoriasis. Several studies that
have compared serum lipid levels in patients with psoriasis to healthy
controls, demonstrate a trend towards increased serum triglyceride
levels, with a concomitant decrease in HDL levels [318–320].
This change in lipid profile has been shown to increase MI risk in pa-
tients with psoriasis [318,320–322]. More generally, a meta-analysis of
14 studies reported a 1.37-fold increased risk for cardiovascular
S. Nazir, V. Jankowski, G. Bender et al.
mortality in patients with psoriasis, compared to the general, healthy
population [323]. Additionally, IL-10 showed a strong inverse correla-
tion with HDL-C in psoriasis patients. In a small randomized, placebo-
controlled clinical trial it could be shown that there is also a direct causal
role for IL-10 in psoriasis, as administration of recombinant human IL-
10 to psoriatic arthritis patients sharply decreased HDL-C levels [324].
After discontinuation of the IL-10 therapy, HDL-C levels recovered and
returned to baseline. Thereby, IL-10 seems to play an important role in
the so called Disappearing HDL Syndrome, which is characterized by se-
vere HDL deficiency in non-critically ill patients [324].
Besides these changes in HDL levels, patients with psoriasis also
have significant changes in HDL composition and functionality as
reflected by decreased cholesterol efflux capacity together with de-
creased anti-inflammatory properties and decreased anti-oxidant prop-
erties [325]. In line with this, patients with psoriasis have low PON-1
activity, which is also inversely correlated with the psoriasis area and
severity index [326]. HDL-associated proteins also undergo changes in
psoriasis, as apoA-I and apoM are significantly reduced, while SAA in-
creased. To corroborate these findings, and to show the therapeutic po-
tential of HDL, anti-psoriatic therapy has been shown to restore both
HDL composition and function [327–329].
4.3.3.2. Clinical potential of apoA-I and HDL in psoriasis. It is clear that HDL
composition and function play a role in psoriasis. However, as is the case
for SLE, it remains to be determined whether changes in HDL function
have a causal role in disease development or is only a consequence
of disease status. It is at this point unclear whether more direct
HDL-targeted approaches would benefit psoriasis patients. More
pre-clinical research is needed to establish whether HDL levels and/or
functionality do indeed have a causal role in this pathology, after
which therapeutic approaches can be tested to improve the HDL func-
tion and perhaps impair the development of psoriasis.
4.3.4. Inflammatory bowel disease
Inflammatory bowel disease (IBD), mainly consisting of Crohn's dis-
ease and ulcerative colitis, is a chronic and relapsing inflammatory dis-
ease of the gastrointestinal tract [330]. There is not one single
pathogenic mechanism underlying IBD, but various host and environ-
mental triggers can dysregulate the mucosal immune response to gut
microbiota, fuelling disease development [331,332]. The absence of a
specific trigger makes research into IBD complex and careful elucidation
of a wide array of causal contributors is essential.
4.3.4.1. Effects of HDL on the pathogenesis of inflammatory bowel disease.
In a mouse model of colitis, apoA-I and HDL suppresses intestinal in-
flammation. This is exemplified in apoA-I-deficient mice with increased
mucosal damage coinciding with increased intestinal MPO activity and
TNF expression [333]. In line with this, mice overexpressing human
apoA-I showed less severe symptoms in the same colitis model. HDL-
induced autophagy that inhibits cytokine expression could be a plausi-
ble mechanism underlying these effects [333]. Similar trends have also
been observed in patients with Crohn's disease and ulcerative colitis
in whom total cholesterol and HDL-C levels were significantly lower,
while LDL-C was elevated, compared to controls [334]. Further
supporting a role for HDL-C in IBD is the observation that in The Copen-
hagen General Population Study and the Copenhagen City Heart Study
the hazard ratio for Crohn's disease and ulcerative colitis is 3.22 and
1.94, respectively, when comparing low vs. high HDL cholesterol levels
[296]. Interestingly, low HDL-C levels in childhood seem to prime these
individuals for IBD. In a Finnish study low HDL-C was inversely corre-
lated with IBD after 34 years of follow-up [335], stressing the need for
preventive measures.
Crohn's disease is also associated with accelerated atherosclerosis. In
a small cohort of 60 Crohn's disease patients and 122 matching controls,
carotid intimal-medial thickness, which is indicative of accelerated ath-
erosclerosis, was significantly increased [336]. HDL may have played a
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Advanced Drug Delivery Reviews 159 (2020) 94–119
role in this, as the level was profoundly reduced during disease exacer-
bation. Furthermore, HDL isolated from Crohn's disease patients has a
reduced ability to attenuate oxidation [336]. Altogether, it is clear that
HDL plays an important role in IBD, though it is not yet clearly eluci-
dated whether HDL-changes are causal or a consequence of disease
status.
4.3.4.2. Clinical potential of apoA-I and HDL in inflammatory bowel disease.
It has been shown that the circulating apoA-I mimetic peptide 4F selec-
tively targets the small intestine, where it is transported into the intes-
tinal lumen followed by reabsorption by the intestinal mucosa [337].
This mimetic peptide also reduced the levels of pro-inflammatory
fatty acid metabolites in enterocytes [338]. Recently, it has been
confirmed that 4F treatment has beneficial effects on IBD in mice, by
mitigating disease development and reducing the levels of pro-
inflammatory mediators in tissues and plasma [339]. The mechanism
underlying these effects include inhibition of LPS responses in macro-
phages and the intestinal epithelium, and direct clearance of pro-
inflammatory lipids from intestinal tissue and plasma. The beneficial
effects of apoA-I mimetic peptides on IBD have been confirmed in an-
other study in which mice with colitis were treated with the 5A peptide
[340] which reduced intestinal inflammation, intestinal MPO levels and
plasma pro-inflammatory cytokine levels. Combined in-vitro and in-
vivo approaches demonstrated that inhibition of monocyte infiltration
and activation by 5A was the main underlying mechanism [340]. All in
all, apoA-I mimetic peptide treatment seems to be a potential novel
treatment for IBD. As HDL functionality is also disturbed in IBD, future
studies should also focus on therapeutic approaches in which HDL func-
tionality and composition are restored. Such approaches might have a
greater therapeutic effect and value than raising apoA-I levels.
4.4. Neurological disease
Interest in lipoprotein metabolism in the brain gained interest after
it was demonstrated that apoE was connected with the development
of several neurological disorders [341]. The brain is highly enriched in
cholesterol and accounts for ~25% of total body cholesterol. Net transfer
of cholesterol from the periphery into the central nervous system (CNS)
is restricted as the blood-brain barrier (BBB) limits the movement of
plasma lipoproteins into the brain [342]. Here we will describe the
role of HDL on two main neurodegenerative disorders, Alzheimer's dis-
ease (AD) which is the leading cause of senile dementia and Parkinson's
disease (PD) which mainly affects movement and is characterized by
tremors.
4.4.1. Effects of HDL on the pathogenesis of neurological disease
For AD, several studies have demonstrated a clear negative associa-
tion between plasma HDL-C levels and risk of AD. For example, a small
prospective cohort study of 1,130 individuals in Manhattan revealed
that high HDL-C levels are associated with a decreased risk of AD
[343]. In line with this, a study of Japanese-American men indicated
that the levels of apoA-I and HDL-C were inversely associated with the
risk of AD and dementia [344]. In AD patients without dementia, this
beneficial effect of HDL-C has also been observed, as high HDL-C levels
correlate with an improved verbal memory [345]. Furthermore, another
study with subjects from the Sydney Memory and Aging Study (MAS)
stated that elderly individuals with mild cognitive impairment had
lower levels of apoA-I and apoH and higher levels of apoJ. Interestingly,
among the apolipoproteins, apoA-I was the most significant predictor of
cognitive decline [346], highlighting the importance of HDL composi-
tion in AD. Although these studies demonstrate clear associations,
they were undertaken in small cohorts so some caution is warranted
in interpretation and larger studies would be needed to confirm these
results.
Recently, two large genome-wide meta-analyses of AD found that li-
poprotein metabolism and genes that encode for HDL biogenesis/
S. Nazir, V. Jankowski, G. Bender et al.
metabolism and HDL apolipoproteins, such as APOE, ABCA1, APOC1,
APOM, APOA2, PON1, CLU, LCAT, CETP, and APOA-I [347,348], suggesting
that besides HDL-C levels HDL composition also plays an important
role in AD. This was confirmed in a recent prospective case-cohort study
of older adults with dementia. Higher levels of apoE in HDL were asso-
ciated with lower dementia risk, but only when HDL did not contain
apoC-III [349]. Likewise, higher levels of apoE in whole plasma and in
HDL were linked to better cognitive function on the Alzheimer's Disease
Assessment Scale-Cognitive Subscale (ADAS-Cog) [350]. Combined,
these studies clearly show that HDL-C, but especially HDL composition
are associated with AD. Further studies are needed to elucidate the un-
derlying mechanisms of these effects and to determine whether these
effects play a causal role or a consequence of disease state.
Several studies have shown that apoA-I levels were significantly de-
creased in the cerebral spinal fluid and in plasma of patients with PD,
particularly in the early stage of disease development suggesting
apoA-I may be a suitable biomarker for PD [351,352]. Supporting the no-
tion that HDL composition also plays a role in PD it has been shown that
the activity of plasma PON1 decreases in PD patients [353]. Several stud-
ies have also reported that individuals with polymorphisms in the PON1
gene that are associated with decreased enzyme activity, have an in-
creased risk of developing PD [354,355]. Although a causal role for
apoA-I or HDL in PD remains to be elucidated, these associations indi-
cate that there is an important link in which HDL composition could
be an important determinant.
4.4.2. Clinical potential of apoA-I and HDL in neurological disease
Although HDL-based therapeutic strategies have not been tested for
AD in clinical trials, numerous pre-clinical studies have been performed
in mouse models of AD. For example, in a mouse model of AD, genetic
overexpression of human apoA-I that increases plasma HDL levels pre-
vents the development of age-related cognitive deficits [356]. Further-
more, intravenous administration of rHDL reduced soluble brain
amyloid beta (Aβ) levels, microgliosis and memory deficits in mice
[357,358]. Though these studies show potential beneficial effects of
HDL treatment, further studies are needed to confirm and validate
these results in clinical settings.
Niacin is another promising way to influence AD. In a cohort study
dietary intake of niacin reduced the risk of AD and cognitive decline
[359], though these studies lacked direct measurement of blood niacin
levels. Niacin could also play a beneficial role in PD, which is character-
ized by neuroinflammation [360]. Niacin has a high affinity for the
hydrocarboxylic acid receptor 2 (HCAR2 or GPR109A) [361] which is
highly expressed on macrophages, through which niacin can induce
anti-inflammatory responses. In a clinical trial it was confirmed that
low doses of niacin in PD patients induced a shift in macrophage polar-
ization, from the pro-inflammatory M1 towards the anti-inflammatory
M2 phenotype in a HCAR2 dependent manner [362], clearly demon-
strating the potential of niacin treatment in this neuropathology.
4.5. Chronic kidney disease
Chronic kidney disease (CKD) describes the gradual loss of kidney
function. Early stages of CKD has few symptoms and is often unrecog-
nized. However, in more advanced stages accumulation of dangerous
levels of fluid, electrolytes and waste products can cause serious compli-
cations and increase the risk of kidney failure, CVD and death.
4.5.1. Effects of HDL on the pathogenesis of chronic kidney disease
Mildly impaired estimated glomerular filtration rate (eGFR) is asso-
ciated with low HDL-C levels [363]. A recent longitudinal cohort study in
almost 2 million participants demonstrated that individuals with low
HDL-C levels had a higher risk for CKD development and progression
[364]. Interestingly, similar to the described U-shape association be-
tween HDL-C and infectious diseases, a similar shaped association exists
between HDL-C and CKD as participants with high HDL-C levels had an
109
Advanced Drug Delivery Reviews 159 (2020) 94–119
increased risk for CKD. Two other recent studies confirmed this U-
shaped association between HDL-C levels and CKD and also demon-
strated that a similar association exists between HDL-C and the risk
for total and CVD-related mortality [365,366].
However, a Mendelian randomization study that investigated 68
SNPs that are associated with HDL-C did not show any association
with kidney function [367]. This suggests that HDL-C is likely not the
most important determinant of kidney function, but do not exclude
the possibility that HDL composition and function might be involved.
Indeed, the HDL in hemodialysis patients has increased SAA, surfac-
tant protein B, albumin and apoC-III levels [368,369]. The enrichment of
HDL with SAA and surfactant protein B is associated with cardiac events
and all-cause mortality, independent of HDL-C [369]. Impaired cholesterol
efflux capacity of HDL from hemodialysis patients and a more pro-
inflammatory macrophage response to patient HDL has also been de-
scribed [370]. Further supporting the fact that HDL functionality is im-
paired in CKD is the observation that HDL isolated from CKD patients
contain high levels of symmetric dimethylarginine and reduce the pro-
duction of nitric oxide in endothelial cells [371]. Such abnormal HDL func-
tion in CKD patients is also a plausible explanation for the observation that
eGFR modifies the association between HDL-C and CVD risk [372]. Further
supporting a role for HDL composition in CKD is the observation that
APOL1 variants have been associated with an increased CKD risk in
African Americans and Hispanics [373]. Additionally, acquired LCAT defi-
ciency is a major cause of low plasma HDL levels in patients with CKD
[374]. In patients from the Ludwigshafen Risk and Cardiovascular Health
study, participants with normal kidney function (eGFR>90 ml/ml/
1.73m2) showed a clear inverse association between HDL-C and CVD-
related mortality [372]. However, in patients with mild or advanced re-
duced kidney function, higher HDL-C was no longer associated with re-
duced CVD risk. The role of HDL in CKD has recently been reviewed in
[375]. All in all, there are strong indications that HDL composition and
function is a more important predictor of CKD than HDL-C.
4.5.2. Clinical potential of apoA-I and HDL in chronic kidney disease
HDL is clearly associated with CKD and CKD-related CVD risk. Though
it seems clear that CKD influences HDL-C and HDL function, it remains to
be determined whether there is a causal role for HDL in CKD development
and progression. At this point, studies that address this question are still
missing and should be a focus point for future research. Based on the de-
scribed associations, it seems that efforts should be put into the elucida-
tion of the role of HDL function in this context and approaches that
have the potential to modify HDL composition and thereby function.
4.6. Other diseases
Many other diseases are associated with changed HDL levels and
composition. Although indications for a causal role of HDL in these pa-
thologies is still missing, it has become clear that HDL composition
and function is changed during disease development. For example, de-
creased HDL-C levels have been observed in patients with Sjögren's syn-
drome, Kawasaki disease, and ankylosing spondylitis [376–378].
Furthermore, a recently conducted meta-analysis suggested abnormal-
ities in serum lipid levels in patients with periodontal disease (PD), in-
cluding reduced HDL levels and elevated LDL levels [379]. These
patients also show a clear increased risk for the development of CVD,
in particular atherosclerosis [380]. Another study, demonstrated that
in Behçet's disease patients, HDL concentrations are decreased, and
there is a shift in HDL subpopulation distribution from HDL2 to HDL3
[381]. The potential causal role of HDL in these diseases as well as the
therapeutic potential of HDL-targeting remains to be determined.
5. Discussion and conclusions
HDL has already long been known as a key player in the lipid metab-
olism. Over the past decades it has become clear that HDL has diverse
S. Nazir, V. Jankowski, G. Bender et al.
functions that affect physiological and pathological processes. Although
it was originally believed that the level of HDL-C was the most impor-
tant determinant of these processes, emerging evidence indicates that
the composition and thereby function of HDL is perhaps the most im-
portant factor. In this review the effects of HDL in various inflammatory
and infectious diseases has been discussed, especially focusing on the
importance of HDL function, together with an overview of the clinical
potential.
In recent years, there has been a lively debate about the effectiveness
and feasibility of many of the discussed therapeutic strategies. This was
mainly fueled by an meta-analysis of 40 clinical trials in CVD, which
showed that niacin, fibrates and CETP inhibitors have not been effective
in decreasing all-cause mortality, coronary heart disease mortality,
myocardial infarction or stroke in patients treated with statins [4]. Al-
though anacetrapib has shown benefits, there has been a change in
the conceptual framework that future therapies should focus on manip-
ulating HDL function rather than HDL-C levels.
As HDL may lose its functionality in many inflammatory and patho-
logical conditions, the main therapeutic outcome should be the im-
provement of HDL function, rather than simply raising its plasma
concentration. Although there are controversial data and opinions
about the effectiveness of reconstituted HDL and apoA-I mimetic pep-
tides, this approach seems one of the most promising areas for targeting
improvements in HDL function. Clinical evidence for the use of
reconstituted HDL is still limited and difficult to interpret as each
study has focussed on different patients and conditions, and there is
no consistency in the composition of the different reconstituted HDL
particles. Accumulating evidence also suggests that the phospholipid
component of rHDL plays an important, and previously overlooked,
role in HDL functionality as highlighted in [382]. Additional and more
elaborate clinical trials are still needed to reliably evaluate the full po-
tential of this therapeutic approach.
Additionally, it would be worthwhile to investigate whether existing
therapies improve HDL functionality in addition to increasing HDL-C
plasma levels. Most clinical studies have not focussed on functionality,
or this has only been evaluated as a secondary finding. Once again,
this emphasizes the need for evaluation of HDL functionality as a pri-
mary objective in future clinical studies, as also highlighted in recent
other reviews [383,384].
The necessity to focus on HDL function does not only hold
true for therapeutic strategies, but also for diagnostic purposes.
HDL-C levels per se do not necessary reflect the potential of HDL
to exert beneficial effects, stressing the importance of HDL-
composition/function testing in every clinical setting. Therefore,
future studies should not only focus on raising HDL-C levels, but
especially concentrate on improving HDL function to provide use-
ful diagnostic and therapeutic approaches for cardiovascular and
many other diseases [385].
Sources of funding
This work is supported by a grant from the Interdisciplinary Center
for Clinical Research within the faculty of Medicine at the RWTH Aachen
University, the DZHK (German Centre for Cardiovascular Research) and
the BMBF (German Ministry of Education and Research), and NWO-
ZonMw Veni (91619053) to E.P.C.v.d.V; by the DFG (SFB/TRR219-TP-
C09) to S.Z. and (SFB/TRR219-TP-S03) to V.J.
Declaration of Competing Interest
None.
Acknowledgements
All illustrations are made with the help from [386].
110
Advanced Drug Delivery Reviews 159 (2020) 94–119
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