Triglycerides Revisited To The Serial: Advances in Clinical Chemistry January 2017

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Triglycerides Revisited to the Serial
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DOI: 10.1016/bs.acc.2016.11.001
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From Paulo Ricardo Nazário Viecili, Brenda da Silva, Gabriela E. Hirsch, Fernando G. Porto, Mariana M.
Parisi, Alison R. Castanho, Michele Wender and Jonatas Z. Klafke, Triglycerides Revisited to the Serial.
In: Gregory S. Makowski, editor, Advances in Clinical Chemistry, Vol. 80, Burlington: Academic Press,
2017, pp. 1-44.
ISBN: 978-0-12-812075-0
© Copyright 2017 Elsevier Inc.
Academic Press
Author's personal copy
CHAPTER ONE
Triglycerides Revisited to
the Serial
Paulo Ricardo Nazário Viecili*,†,1,2, Brenda da Silva*,{,§,2,
Gabriela E. Hirsch*,§, Fernando G. Porto*,†, Mariana M. Parisi*,{,§,
Alison R. Castanho†, Michele Wender†, Jonatas Z. Klafke*,{,§,3
*Grupo Interdisciplinar de Saúde (GIS), Centro de Ensino e Pesquisa do Instituto de Cardiologia de Cruz Alta
(CEP-ICCA), Cruz Alta, Brazil
†
Programa de Resid^encia Medica do Hospital São Vicente de Paulo (HSVP), Cruz Alta, Brazil
{
Curso de Biomedicina, Universidade de Cruz Alta (UNICRUZ), Cruz Alta, Brazil
§
Grupo Multidisciplinar de Saúde (GMS), Universidade de Cruz Alta (UNICRUZ), Cruz Alta, Brazil
3
Corresponding author: e-mail address: jonzeni@hotmail.com
Contents
1. Introduction 2
2. TG Concept, Structure, and Function 3
3. TG Regulation 7
4. Genetics of the TGs 11
5. TGs and the Cardiovascular System 14
6. Treatment of Hypertriglyceridemia 22
6.1 Lifestyle Changes 22
6.2 Fibrates: Activators of Peroxisome Proliferator-Activated Receptor Alpha 23
6.3 Nicotinic Acid 25
6.4 Long-Chain Omega-3 FAs 25
6.5 Microsomal TG Transfer Protein Inhibitors 26
6.6 Monoclonal Antibodies PCSK9 and TGs: Clinical Evidence 26
6.7 Dyslipidemias and Dietary Flavonoids 28
6.8 Dyslipidemias and Dietary Garlic 29
6.9 Dyslipidemias and Dietary Nuts 29
7. Conclusions 30
References 30
Abstract
This review discusses the role of triglycerides (TGs) in the normal cardiovascular system
as well as in the development and clinical manifestation of cardiovascular diseases.
1
Grupo Multidisciplinar de Saúde (GMS), Programa de Pós-Graduação em Atenção Integral à Saúde
(PPGAIS), Universidade de Cruz Alta (UNICRUZ), Campus Universitário Dr. Ulysses Guimarães—
Rodovia Municipal Jacob Della Mea, Km 5.6—Parada Benito, 98020-290 Cruz Alta, RS, Brazil.
E-mail: vieciliprn@hotmail.com.
2
These authors contributed equally to this work.
Advances in Clinical Chemistry, Volume 80 # 2017 Elsevier Inc. 1

ISSN 0065-2423 All rights reserved.
http://dx.doi.org/10.1016/bs.acc.2016.11.001
2 Paulo Ricardo Nazário Viecili et al.
Regulation of TGs at the enzymatic and genetic level, in addition to their possible rel-
evance as preclinical and clinical biomarkers, is discussed, culminating with a description
of available and emerging treatments. Due to the high complexity of the subject and
the vast amount of material in the literature, the objective of this review was not to
exhaust the subject, but rather to compile the information to facilitate and improve
the understanding of those interested in this topic. The main publications on the topic
were sought out, especially those from the last 5 years. The data in the literature still give
reason to believe that there is room for doubt regarding the use of TG as disease bio-
markers; however, there is increasing evidence for the role of hypertriglyceridemia on
the atherosclerotic inflammatory process, cardiovascular outcomes, and mortality.
1. INTRODUCTION
Triglycerides (TGs) are nonpolar lipid molecules composed of a glyc-
erol molecule associated with three fatty acid (FA) molecules, and they rep-
resent the main form of lipid storage and energy in the human organism
[1,2]. They are synthesized primarily through the glycerol phosphate path-
way, and the traffic of TGs in specific tissues, such as muscle, liver, and adi-
pose tissue, depends on the nutritional state of the individual, and is a
biological process that is essential for life. An imbalance in this process
may lead to various metabolic disorders, such as obesity, lipotoxicity, or
hypertriglyceridemia. The elucidation of this process, at molecular and cel-
lular levels, has profound implications for the understanding of diseases
related to TGs, as well as for the development of new therapies [1,2].
The regulation of TG synthesis or hydrolysis is very complex and depends
on countless enzymes regulated by various hormones, with regulation occur-
ring at both transcriptional and posttranscriptional levels [3,4]. Studies on the
enzymes involved in TG biosynthesis began in the 1950s, when most of the
pathways were elucidated [4]. Lipoprotein lipase (LPL) has historically been
regarded as one of the key regulatory enzymes for TG hydrolysis present in
lipoprotein particles, while diacylglycerol acyltransferase (DGAT) is consid-
ered one of the key enzymes for TG synthesis [5]. Other enzymes, aside from
hormones and genes, have also been shown to play an important role in reg-
ulating TG synthesis [6]. In addition, the activity of these enzymes tends to be
regulated in a tissue-specific manner. For example, LPL activity is stimulated
by insulin in adipose tissue, while in muscle tissue it is stimulated by glucagon
[7,8].
Furthermore, various genes participate in TG regulation and exhibit
altered expression in certain pathologies [9]. It is currently known that these
genetic alterations (mutations and/or polymorphisms) are related to
Triglycerides Revisited 3
countless lipoprotein disorders, including disorders in TG carriers [10], and

may cause a predisposition or the characterization of lipid metabolism path-
ogenesis, as determined by extreme plasma TG levels [11]. Related to this
fact, various studies show that hypertriglyceridemia is an important risk fac-
tor for the development of cardiovascular diseases (CVDs), even after
adjusting for high-density lipoprotein (HDL) levels [12–14].
Moreover, most drug therapies currently available for treating disorders
related to TG imbalance affect TG lipolysis. However, hepatic lipogenesis
is also relevant in TG imbalances, and the genes involved in hepatic lipogen-
esis have been identified as important regulators of TG plasma levels as much
as those involved in the LPL pathway [6]. Among the medications available
today to treat TG disorders, we highlight statins, fibrates, omega-3 FAs, nia-
cin, and some elements of complementary and alternative medicine involved
in various mechanisms for controlling of TG synthesis and degradation [12].
Thus, this review will discuss the role of TGs in the normal cardiovas-
cular system and the whole organism, as well as in the development and clin-
ical manifestations of CVDs, taking into consideration TG regulation at an
enzymatic and genetic level, as well as clinical and preclinical biomarkers and
available treatments.
2. TG CONCEPT, STRUCTURE, AND FUNCTION

TGs are lipid molecules formed by glycerol derived from carbon
hydrates and/or gluconeogenic amino acids, bound to three FAs. These
FAs have a similar conformation in most TG molecules: there is a saturated
FA in position 1, an unsaturated FA in position 2, and a long-chain FA in
position 3 (see Fig. 1) [1]. TGs are the most abundant lipids in nature, and
their main characteristic is their essentially nonpolar nature, since the polar
regions of their precursors (glycerol hydroxyls and carboxyls of the FAs)
vanish when the ester bonds are formed. Animal fats and vegetable oils
are complexes formed by TGs, the difference between them being the spe-
cific FAs that compose them. TGs in animal fats are predominantly com-
posed of saturated FAs, lending them their solid appearance, while
unsaturated FAs predominate in vegetable oils, giving them their liquid con-
sistency. Both animal fats and vegetable oils can be digested in the organism
thanks to hydrolysis by lipases [15].
TGs are synthesized through two main pathways: the glycerol phos-
phate pathway and the monoacylglycerol (MAG) pathway. The glycerol
phosphate pathway is more common and is present in various cell types.
Glycerol
H2C O
Fatty acid
O
HC O
HO
H2C O
Triacylglycerol
O
H2C O Palmitic acid

O
Oleic acid
HC O
O
9 12 15
ω
H2C O α
Alpha-linolenic acid
Fig. 1 Structural representation of the molecules forming TGs: a glycerol molecule and
a fatty acid. Below is an illustration of the TG molecule originating from the ester bonds
between one glycerol and three FAs. The FAs depicted are palmitic acid, oleic acid, and
alpha-linolenic acid.
This pathway is based on the acylation of glycerol 3-phosphate through the

addition of FA groups, each of which is catalyzed by a different enzyme. In
contrast, the MAG pathway predominates in the small intestine and gen-
erates TGs based on MAG derived from dietary fat. The glycerol phos-
phate pathway occurs as follows: first, acylation of glycerol 3-phosphate
(addition of FA) occurs by the glycerol 3-phosphate acyltransferase, which
is present in the endoplasmic reticulum and mitochondria, forming
lysophosphatidic acid (LPA). Next, LPA receives an additional FA through
the action of 1-acylglycerol-3-phosphate acyltransferase, producing pho-
sphatidate, which then undergoes the action of phosphatidate phospha-
tase-1, a member of the lipin family. The diacylglycerol (DAG)
resulting from this process is converted into TGs by the DGAT enzyme
(see Fig. 2) [1,3,16,17].
To utilize dietary TGs, which constitute approximately 95% of
ingested fats, the most used pathway is the MAG pathway, which occurs
as follows: initially, TGs originating from the diet are digested by pancre-
atic lipase in the small intestine, specifically in the upper segment of the
jejunum. 2-Monoacylglycerol (2MAG) and free fatty acids (FFAs) result
from this degradation. If pancreatic lipase acts upon 2MAG again, glycerol
Fig. 2 Illustration of TG synthesis through glycerol phosphate. Glycerol 3-phosphate

receives its first fatty acid via GPAT, resulting in lysophosphatidic acid, which receives
its second fatty acid through the action of AGPAT, resulting in phosphatidate, which
undergoes the action of phosphatidate phosphatase-1, releasing phosphatidylinositol.
The DAG resulting from this reaction receives its third fatty acid via DGAT, finally
forming TG. AGPAT, 1-acylglycerol-3-phosphate acyltransferase; DGAT, diacylglycerol
acyltransferase; GPAT, glycerol 3-phosphate acyltransferase.
and FFAs are formed. These FFAs are absorbed by enterocytes and are
used to synthesize neutral fats. Then, the products of TG hydrolysis travel
through the enterocyte cytoplasm until reaching the endoplasmic reticu-
lum, where MAG binds covalently to acyl-CoA. Thereby, DAG is
formed through a reaction catalyzed by MAG acyltransferase, and its acyl-
ation by DGAT forms TG. TGs can also be synthesized by dephosphor-
ylation of phosphatidic acid and acylation of the resulting DAG (see
Fig. 3) [18–20].
TGs are an important form of energy storage in most organisms, as men-
tioned previously. They form based on the interaction between MAG and
FAs, and this reaction is catalyzed by acyltransferases and phosphatases in the
endoplasmic reticulum [21]. TGs are transported in the plasma by very low-
density lipoproteins (VLDLs) produced in the liver, chylomicrons (from the
Fig. 3 Illustration of TG synthesis from monoacylglycerol. TGs of dietary origin undergo

the action of pancreatic lipase, generating 2MAG and FFAs, which cross enterocyte
membranes. In the endoplasmic reticulum of enterocytes, MAG binds covalently to FFAs
through MGAT, forming DAG, which in turn receives another FFA by means of DGAT,
forming triacylglycerol. DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase; FFAs,
free fatty acids; MAG, monoacylglycerol; MGAT, monoacylglycerol acyltransferase.
diet), and metabolic remnants of these molecules [22]. They are stored in the
hydrophobic nucleus of cytosolic lipid droplets, which are basically intracel-
lular compartments of lipid reserves, which, in addition to their function as a
lipid stock, act as sites for TG synthesis [23]. After ingesting foods rich in fat,
TGs originating from the diet undergo intestinal hydrolysis, releasing FAs
and MAG, which are absorbed by enterocytes, then are resynthesized to
form TGs again [24].
TGs associate with apolipoprotein B-48 to form large chylomicrons,
which are released into the lymphatic system. Through the thoracic duct,
these molecules travel to the plasma and are rapidly metabolized by
LPL, yielding chylomicron remnants, which can be used by low-density
lipoprotein (LDL) receptors in the liver. The action that LPL exerts on
chylomicrons also releases FFAs, which are stored in adipose tissue or used
by other tissues as an energy substrate. The lipids derived from adipose tissue
lipolysis and those present in chylomicron remnants are concentrated in the
liver in the form of VLDLs, which are released into the plasma. In the
plasma, VLDL undergoes the action of LPL, forming IDLs, which are again
metabolized to obtain LDL. Most LDL is absorbed by the liver upon the
binding of apolipoprotein B-48 to LDL receptors (LDLRs). LDL particles
remaining in the plasma can be utilized by peripheral tissues to provide
nutrients, cholesterol, and fat-soluble vitamins [25].
3. TG REGULATION
TGs serve as an energy reserve in animals. They are synthesized pri-
marily in liver and adipose tissue, through a pathway that uses phosphatidic
acid as an intermediate, with glycerol 3-phosphate (which provides the glyc-
erol) and FAs as substrates. Glycerol 3-phosphate reacts with an acyl-CoA
molecule from the FA, forming phosphatidic acid, which produces DAG
after dephosphorylation [26,27]. After DAG is formed, another acyl-CoA
molecule reacts with DAG, forming the TG [26–28].
TGs are present in practically all cells of the organism in the form of lipid
droplets, which are covered with a monolayer of phospholipids and specific
proteins (such as adipose differentiation-related protein—ADRP) that reg-
ulate their formation, growth, and dissolution [29,30]. Due to the various
functions of TGs in the organism, higher organisms show various synthesis
pathways and mechanisms for their regulation [4]. There are distinct lipid
pools within individual cells, and it is believed that their synthesis involves
distinct biological pathways [31,32].
TG synthesis involves various enzymes, such as DGAT, sn-1,2(2,3)-
diacylglycerol transacylase (DAG transacylase), wax ester/DGAT, and
lecithin-DAG transacylase [33–36], the first two of which are the most
important in mammals [37]. The activity of the two enzymes differs in dif-
ferent organs depending on the need for TG synthesis. DGAT is seen more
often than DAG transacylase in organs with high rates of TG synthesis, such
as adipose tissue, the liver, mammary glands during lactation, small intestine
mucosa, and adrenals [37]. Furthermore, DAG molecules are also directly
involved in regulating TG synthesis, and the flow of DAG for TG synthesis
is strongly influenced by the activity of the enzyme phosphocholine
acetyltransferase (CTP) in a pathway that requires the intermediate
phosphatidylcholine [38].
Most enzymes involved in TG synthesis are integral cell membrane pro-
teins [3]. Acyl-CoA synthetase is the first enzyme in TG synthesis, playing a
critical role in regulating the entry of FAs into synthetic or oxidative path-
ways, depending on the physiological conditions at the time [3,39].
Mitochondrial GPAT, an enzyme involved in TG synthesis, is mainly

responsible for the acylation of glycerol 3-phosphate using acyl-CoA groups
from FAs, and its hepatic activity tends to decline during fasting [37,40].
Studies show that diet-induced changes in the concentration of GPAT
enzyme substrate change its reaction rate in vivo. The reduction in L-α-
glycerophosphate concentration, which occurs during extended fasting,
contributes to the reduced TG synthesis rate [41].
Present in almost all human adult tissues, DGAT is a key enzyme in TG
synthesis, and is responsible for the acylation of DAG in position 3, using
long- or medium-chain acyl-CoA. Its activity is high in tissues specialized
for TG biosynthesis, such as adipose tissue and the liver [5,37]. TGs synthe-
sized by this enzyme are stored in lipid droplets in the cytosol or secreted as
components of lipoproteins (liver and small intestine) [42,43]. Furthermore,
its activity depends on the availability of DAG molecules to accept acyl-CoA
[44,45], and is suggested to be a rate-limiting enzyme of TG synthesis [41].
In addition, mice deficient in DGAT1 have increased sensitivity to insulin
and leptin, and appear to be more resistant to obesity, due to alterations in
energy metabolism and glucose caused by the altered secretion of adipocyte-
derived factors, corroborating the importance of this enzyme in regulating
TG synthesis [43].
In contrast, the activity of DAG transacylase does not depend on acyl-
CoA molecules, and may be partially inhibited by lipase and esterase [34].
Phosphatidate phosphohydrolase (HPP-1) hydrolyzes phosphatidic acid to
form DAG only when it is associated with the endoplasmic reticulum [46].
Once synthesized in the liver or absorbed from the diet, TGs can partic-
ipate in the formation of VLDL particles or chylomicrons, or even be stored
in cytosolic lipid droplets in adipose tissue [13]. These particles also partic-
ipate in TG regulation, since the presence of TG remnants in the plasma is
also the result of the extensive hydrolysis of VLDL particles and chylomi-
crons, whose main function is to supply energy to peripheral tissues or, in
the case of adipose tissue, to store additional energy [47,48]. TG remnants
in TG-rich lipoproteins are then eliminated from the circulation by the liver
[47,48]. However, the regulation of the formation or hydrolysis of these par-
ticles is complex and involves transcriptional and posttranscriptional control
of enzymes that respond to specific hormones, such as the insulin/glucagon
relationship [3,4].
Insulin increases the activity of lipogenic enzymes. When fasted animals
are fed a diet rich in carbohydrates, the mRNA levels of FA synthase and
mitochondrial GPAT enzymes increase by approximately 20-fold [49,50].
Insulin also stimulates the synthesis and release of LPL, a key enzyme reg-
ulating TG hydrolysis from lipoprotein particles for later storage in the adi-
pocytes. These adipocytes then secrete LPL into the capillaries, which
digests the TGs from chylomicrons and VLDLs. As a result, FAs are released
that serve as a source of acyl-CoA to react with glycerol 3-phosphate from
glucose, again forming TGs that will be stored in adipose cells [6,26]. LPL is
one of the rate-limiting enzymes in TG hydrolysis, and its activation
depends on the presence of apolipoprotein CII, a component of lipoproteins
like VLDL, HDL, and chylomicrons. It is abundant in tissues where FA oxi-
dation is the main energy source, such as the heart and skeletal muscle
[51–55]. LPL is regulated differently in different tissues, and it is activated
in the muscle during fasting by glucagon and adrenaline, but not by insulin,
leaving the circulating TGs available for absorption and fat synthesis in adi-
pose tissue [7,8].
Individuals with defective LPL tend to exhibit high levels of blood TGs,
VLDLs, and chylomicrons, since these particles are not being metabolized
normally [26,56–58]. Furthermore, LPL regulation in adipose tissue and
muscle depends on the concentration of circulating VLDLs. In general, adi-
pose tissue tends to respond only to high blood concentrations of TGs, in
postprandial conditions for example. On the other hand, muscle tissue, car-
diac muscle, in particular, has a lower Km for these lipoproteins, being acti-
vated even by very low blood concentrations of VLDL [26], which explains
why LPL activity increases in muscle tissue during fasting and decreases in
adipose tissue upon glucagon stimulation [7,8].
Plasma glucose levels also interfere with TG synthesis, since this carbohy-
drate is a precursor of glycerol 3-phosphate, a substrate necessary for esterifi-
cation of FAs in TGs. Imaging studies have shown that an increase in glucose
uptake by adipose tissue is associated with a sharp decline in circulating
FAs [59]. Unlike insulin, glucagon is released during fasting and stimulates
lipolysis by phosphorylating hormone-sensitive lipase through protein kinase
A. This initiates a process of cleavage and release of FAs from TGs that is later
completed by other lipases, and these FAs can then be used as an energy
source [26]. Glucagon stimulates adenylate cyclase, increasing cAMP levels
and reducing the transcription of mitochondrial GMAT [49,50]. Increased
cAMP levels in adipose cells stimulate lipolysis, releasing FAs and glycerol into
the blood, which participate in energy production [26]. The amount of FAs
released in this process is also regulated, such that TG synthesis occurs together
with glyceroneogenesis [26]. Glyceroneogenesis consists of glyceride–glycerol
synthesis from sources other than glycerol and glucose, and this process has
been identified as an important carbon source in mammals, acting during

fasting [28].
Another important hormone in the regulation of the TG metabolism is
the peptide hormone leptin, which is expressed and secreted by adipocytes,
but acts via cerebral and peripheral receptors. It regulates lipid homeostasis in
various tissues, such as adipose, liver, muscle, and pancreatic tissue, promot-
ing FA catabolism and inhibiting TG accumulation [60–64]. Leptin reduces
FA and TG synthesis while simultaneously increasing lipid oxidation by
inhibiting the activity of acetyl-CoA carboxylase, a rate-limiting enzyme
in FA synthesis. This leads to a reduced malonyl CoA (inhibitor of carnitine
acyltransferase I and mitochondrial β-oxidation) concentration, thus block-
ing FA synthesis and favoring FA oxidation, resulting in lower intracellular
TG concentrations [51,65,66]. A number of studies have shown that the
overexpression of this hormone increases the mRNA expression of oxida-
tive enzymes and reduces the expression of enzymes such as FA synthase,
acetyl-CoA carboxylase, and mitochondrial GPAT in adipose tissue [63],
suggesting that leptin acts directly on peripheral tissues by inhibiting TG
synthesis [3].
Thyroid hormones also play an important role in regulating enzymes for
TG synthesis. For example, hypothyroidism increases microsomal GPAT
and DGAT activity and reduces mitochondrial GPAT and HPP-1 [67].
Most available drugs used for treating plasma TG imbalances regulate
lipolysis. However, hepatic TG lipogenesis is also important in this process,
and the genes involved in this pathway are important regulators of TGs, as
much as those regulated by the LPL pathway [6]. Several genes have been
identified that participate in TG regulation, such as the genes that participate
in TG lipolysis and elimination through LPL, the LPL gene itself, the apo-
lipoprotein A1-C3-A4-A5 (APOA1-C3-A4-A5) cluster, and the
angiopoietin-like 3 gene (ANGPTL3). Genes that directly or indirectly
influence hepatic lipogenesis also help regulate TGs, such as the glucokinase
regulatory gene (hexokinase 4) (GCKR), and the tribbles-1 gene (TRIB1),
among others [6]. This topic will be discussed next in greater depth later in
this review.
Thus, we can conclude that TG synthesis and metabolism are finely con-
trolled by enzymes, hormones, and genes, and that their regulation depends
on the nutritional state of the organism. Thus, the complete understanding
of these mechanisms is essential for understanding TG-related disorders,
whether resulting from endogenous or dietary problems, and also for the dis-
covery of new drugs and new therapeutic targets.
4. GENETICS OF THE TGs

Physiologically, various isoforms of the enzymes from the lipid syn-
thesis pathway can catalyze the same chemical reaction, even if, on occasion,
these isoenzymes are encoded by different genes. In addition, these enzymes
can be encoded by the same gene but undergo posttranslational modifica-
tions or alternative gene splicing, therefore exercising distinct functions.
In this regard, the genes and posttranslational modifications of the resulting
enzymes exert an important influence on TG metabolism [31,32].
With the technological advances in nucleotide and amino acid sequenc-
ing in recent decades, there has been enormous progress toward understand-
ing the genetic modifications of the enzymes involved in TG synthesis and
degradation, and their impact on the development of hypertriglyceridemia
[4]. Gene alterations, such as mutations and/or polymorphisms, in isolation
or in conjunction, may predispose or characterize the pathogenesis of dis-
eases involving the lipid metabolism, resulting in extreme TG plasma
levels [11].
A recent meta-analysis involving population studies on genetic associa-
tions showed the existence of over 100 genes involved in lipid plasma levels,
including TGs [68]. Furthermore, genetic alterations may be related to 40%–
60% of lipoprotein disorder cases, including disorders in chylomicrons and
VLDLs [10]. More importantly, some genetic variations that predispose
individuals to TG metabolism disorders may negatively influence their
response to treatment, so DNA screening in patients with hyper-
triglyceridemia may be an efficient strategy to guide individualized therapies
in the future [69].
A number of genes are involved in TG metabolism. Genes such as
apolipoprotein 5 (APOA5), apolipoprotein CII (APOC2), apolipoprotein E
(APOE), glycerol 3-phosphate dehydrogenase-1 (GPD1), glycosyl-
phosphatidylinositol-anchored high-density lipoprotein-binding 1
(GPIHBP1), lipase maturation factor 1 (LMF1), LPL, and angiopoietin-like
(Angptl) are associated with increased plasma TG levels, while rare variants
of the apolipoprotein C-III (APOC3) gene may be associated with reduced
TG levels. Individuals who are homozygous or compound heterozygous
for severe mutations in these genes present with the most severe cases of
hypertriglyceridemia, with TG levels greater than 1000 mg/mL and recurrent
pancreatitis. However, a large number of hypertriglyceridemia cases have not
yet been associated with genetic alterations [9].
The catabolism of TG-rich lipoproteins depends on LPL enzymatic

activity. LPL is capable of hydrolyzing the circulating TGs in chylomicrons
and VLDLs. The partial or total absence of LPL catalytic activity is the main
cause of hypertriglyceridemia in animals and humans [57,70]. LPL defi-
ciency is an autosomal recessive disorder caused by mutations that induce
the loss of LPL gene function, causing severe hypertriglyceridemia [71].
The LPL gene is located on chromosome 8p22, and consists of 10 exons.
Currently, over 100 variants of the LPL gene have been described, and the
majority of these variants are associated with the loss of catalytic function.
Patients with LPL deficiency may be homozygous or compound heterozy-
gous [71]. Functional variants, such as D9N, S291N, and S447X, and var-
iants in introns, such as HinaIII and PyuII, have been described in the LPL
gene. Of these polymorphisms, only S447x does not appear to be implicated
in elevated serum TG concentrations [72,73]. Interestingly, the molecular
basis of hyperlipidemia type 5 often includes a mutation resulting in loss
of LPL function [69].
LPL can be modulated in by ApoE in several ways. ApoE is a protein of
299 amino acids responsible for transporting cholesterol and TGs in the
bloodstream. Three isoforms of ApoE are encoded by three dominant
alleles: E2, E3, and E4. In relation to the ApoE variations, some studies sug-
gest that alleles E2 and E4 are related to increased serum TG levels, while
homozygotes for allele E3 tend to have normal TG levels [74–76].
The APOA1/C3/A4/A5 gene cluster in chromosome 11q23 plays an
important role in TG metabolism and LPL activity. APOC3 plays an essen-
tial role in regulating TG plasma levels. Rare mutations that affect the
APOC3 gene are associated with reduced TG plasma levels. Through
genetic sequencing, a recent study identified rare variants in the APOC3
gene sequence, and these variants had a significant effect on TG plasma
levels. Of the individuals in the study, 1 in 150 showed genetic alterations
in the APOC3 gene. Individuals with a mutation in the APOC3 gene
showed a 46% decrease in APOC3 protein expression, as well as a 39%
decrease in TG plasma levels when compared to individuals that did not
have these genetic alterations [77]. Corroborating this finding, an earlier
study showed that 5% of the cohort studied included individuals bearing
the null allele APOC3 R19X, and that these individuals had, in addition
to the genetic alteration, a favorable lipid profile and cardiovascular protec-
tion [78]. In addition, a missense mutation (A43T) in the APOC3 gene was
identified in individuals with reduced TG plasma levels [79].
The gene APO5 is located near the APOA4-C3-A1 cluster in chromo-

some 11, and encodes a protein with 366 amino acids named apo-A-V. Rare
mutations in the APO5 gene are related to premature protein truncation,
which causes a complete apo-A-V deficiency. Clinically, these patients
develop hypertriglyceridemia [80]. The rs662799 polymorphism in
APO5 has been associated with increased TG levels in both adults and chil-
dren [81,82]. In addition, a study that performed gene sequencing for
patients diagnosed with early acute myocardial infarction (AMI) showed that
rare variants in the APOA5 gene were responsible for a threefold increase in
the risk of AMI [83].
The mechanisms that regulate tissue-specific activity of LPL during the
fed-fast cycle are essential for TG metabolism. Recently, a group of proteins
named angiopoietin-like (Angptl8, Angptl3, Angptl4) proteins were
identified. These proteins are inhibitors of LPL activity. A deficiency in
them may cause hypotriglyceridemia, while overexpression may induce
hypertriglyceridemia [2].
A study performed in mice with extremely low TG levels showed a
mutation in the Angptl3 gene that resulted in loss of protein function. Muta-
tion of the Angptl3 gene and hypotriglyceridemia were correlated [84]. In
humans, individuals homozygous or heterozygous for mutations that induce
loss of function of ANGPTL3 develop combined hypolipidemia, character-
ized by a reduction in plasma levels of all classes of lipoproteins, such as
VLDL, LDL, and HDL [85,86]. Functional studies revealed that the mutant
alleles of ANGPTL3 and ANGPTL4 that are associated with low TG levels
interfere in the synthesis, secretion, or activity of the protein. In this regard,
1% of the entire population from the Dallas Heart Study and 4% of partic-
ipants with plasma TG in the lowest quartile had a rare mutation in
ANGPTL3, ANGPTL4, or ANGPTL5, and multiple mutant alleles at this
locus cumulatively contribute to variability in human plasma TG levels [87].
Recently, two new proteins were identified as essential for LPL function:
LMF and GPIHBP1. LMF1 is a chaperone responsible for the correct fold-
ing and maturation of nascent LPL in the endoplasmic reticulum into its
functional forms. Two nonsense mutants of this gene (p.Y439X and
W464X) were identified in two patients with severe hypertriglyceridemia,
leading to combined lipase deficiency [88,89]. A silent variant of the LMF1
gene has been considered pathogenic as determined by bioinformatic
approaches, and this variant may generate alterations in gene splicing. How-
ever, confirmation through functional studies is necessary [9].
LPL is present on the surface of endothelial cells in small capillaries of

tissues that require FAs as an energy source or for storage. In recent years,
it was discovered that GPIHBP1 transports LPL and is responsible for its
anchoring in capillary walls [90]. Thus, GPIHBP1 is essential for LPL
function on the surface of capillaries and for processing TG lipolysis [2].
Knockout mice for this protein show severe hypertriglyceridemia [90,91],
and humans with loss-of-function mutations show familial chylomicrone-
mia [92]. Mutations and deletions of the gene were also reported in patients
with severe hypertriglyceridemia [93–95].
In general terms, a study on patients with severe hypertriglyceridemia
identified rare genomic variations in genes involved with LPL function in
54% of patients. Mutations in LPL, APOC2, APOA5, and GPIHBP1 genes
were identified, and in 34% of the patients, LPL mutation was the only cause
of hypertriglyceridemia. Mutations in APOC2, APOA5, and GPIHBP1
were rare and cumulative in only 11% of patients [69]. Mutations in
APOC2, which encodes the essential cofactor for LPL activity apolipopro-
tein C-II, and in APOA5 have been reported in patients with severe hyp-
ertriglyceridemia [80,96].
GPD1 encodes the enzyme glycerol 3-phosphate dehydrogenase. The
availability of GPD1 is a regulatory factor of TG synthesis. It has been shown
that a mutation (c.361_1G>C) in the GPD1 gene is associated with mod-
erate to severe hypertriglyceridemia in childhood and adolescence that does
not persist into adulthood. This mutation results in an alternative splicing,
resulting in aberrant mRNA and producing a protein lacking the functional
site for substrate recognition. The functional consequences of this mutation,
when evaluated in vitro, were increased cellular TG concentration and
secretion [97].
Recent advances in molecular analysis methods allow for the identifica-
tion of rare genetic variants that may have significant effects on the risk of
developing hypertriglyceridemia as well as on the evolution of the disease.
In addition, genetic studies may aid in the development of therapies
for dyslipidemias as well as in the understanding of drug resistance
mechanisms [98].
5. TGs AND THE CARDIOVASCULAR SYSTEM

The prevalence of elevated circulating TG levels, hyper-
triglyceridemia, is on the rise worldwide, particularly in developed coun-
tries. In the United States, there has been an increase greater than
sevenfold in the average plasma TG concentration over the last 30 years [99].
Circulating TG levels <150 mg/dL are considered normal. Values between
150 and 199 mg/dL are considered high boundary values, and any above
200 mg/dL are classified as high, with those above 500 mg/dL considered
very high [100,101].
Hypertriglyceridemia is generally the result of an increase in one or more
TG-rich lipoproteins: chylomicrons, VLDL, or their remnants. The increase
occurs due to increased synthesis, reduced catabolism, or both, with the
underlying cause generally being the result of changes to metabolic factors,
such as apolipoprotein C-II, apolipoprotein C-III (apo C-III), cholesteryl
ester transfer protein (CETP), and LPL. However, hypertriglyceridemia
may also occur secondarily to other diseases (for example, diabetes mellitus,
hypothyroidism, kidney disease, nephrotic syndrome) [99,102]. Apo C-III,
which contributes to hypertriglyceridemia by inhibiting LPL activity, also
appears to be directly atherogenic by promoting proinflammatory effects
of vascular endothelial activation by binding inflammatory cells [103]. In
addition, other mechanisms for producing Apo C-III appear to be
upregulated in hyperglycemia, partly explaining the increased risk of coro-
nary artery disease (CAD) in poorly controlled diabetes mellitus type 2
[104,105].
There are also questions regarding which TG levels should be measured,
the high variability of TG concentrations in a single individual, and the asso-
ciation of TG levels with other atherogenic conditions such as low HDL
levels, obesity, and diabetes mellitus type 2 [99,106–109]. A human patho-
logical study found mass TG depositions in autopsied hearts of many indi-
viduals with advanced diabetes mellitus, all of which died of cardiac diseases,
regardless of intensive surgeries and medical treatments [110].
In reality, dietary choices and a lack of exercise are widely considered to
be the main contributors to the recent increase in circulating TG levels in
developed countries. Not surprisingly, environmental conditions, in partic-
ular, diets high in fat or with a high glycemic index where energy intake is
out of balance with energy use, are associated with hypertriglyceridemia,
and so is excess alcohol consumption [99,102].
TGs are attracting attention as risk markers, and are also linked to primary
and secondary prevention goals in groups of patients with metabolic syn-
drome, diabetes, and CAD [111,112]. There are a number of important rea-
sons to evaluate TG levels in patients, especially those with CVD [12].
Individuals with high TG levels are at greater risk of cardiovascular compli-
cations, particularly atherosclerosis [113]. TG concentrations above
150 mg/dL are observed almost twice as often in individuals with athero-
sclerosis [114]. For this reason, the broad evaluation and management of
CAD should include testing for hypertriglyceridemia and the associated
dyslipidemia [115].
Hypertriglyceridemia is a potential mediator of atherosclerosis, by mech-
anisms yet to be determined. A number of studies have attempted to explain
how TGs contribute to inflammation, atherosclerosis, plaque rupture, and
acute thrombus formation. A study on paired controls of patients
with CAD showed that 80%–82% of CAD patients had increased TG levels
while only 40%–48% of patients without CAD had elevated TGs
[111,112,116–118].
Atherosclerosis is an inflammatory disease affecting the arterial wall that
leads to myocardial, cerebral, and peripheral ischemic syndrome [119].
Inflammation and infections increase the production of a variety of cyto-
kines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1,
and IL-6, which alter lipid metabolism [120]. Many of the changes in plasma
lipids and lipoproteins that are seen during chronic inflammation and infec-
tions have also been observed after acute cytokine administration [121].
Several cytokines increase TG and VLDL serum levels (TNF-α, IL-1,
IL-2, IL-6, and others) [120]. The increase in serum TGs is due to increased
production and secretion of hepatic VLDLs caused by increased hepatic FA
synthesis and the reduced clearance of TG-rich lipoproteins that results.
Jointly, these changes cause an increase in the supply of FAs to the liver,
which stimulates hepatic TG synthesis [120]. A reduction in the clearance
of TG-enriched lipoproteins is due to a reduction in LPL, and a variety
of cytokines have been shown to reduce LPL synthesis in adipose and muscle
tissue [120].
Nonfasting postprandial hypertriglyceridemia has been associated with
an increased risk for atherosclerosis, and is now considered an important risk
factor for CVD when compared to the fasting state [120,122]. Plasma lipids
and lipoproteins are generally measured during fasting, and the treatment
guidelines for CVD prevention are based on these measurements. The
clinical practice guidelines for evaluating and treating hyperlipidemia as
provided by the Endocrine Society suggest the diagnosis of hyper-
triglyceridemia based on fasting serum levels, with a recommended fasting
duration of 12 h [123].
Hyperlipidemia, characterized by low HDL levels and high TG and LDL
levels, predisposes patients to atherosclerosis [124]. In postprandial insulin-
resistant states, TGs might be the most relevant factor in CVD risk. To assess
postprandial TGs, a precise and standardized methodology must be

identified. Currently, the lack of standardized measures for nonfasting TG
tests, the lack of specific references, and the variability of intervals for
postprandial lipid measurements have hampered its routine clinical
implementation [125].
The debate on the association regarding causality of hypertriglyceridemia
and CAD began in 1980, when analyses failed to identify TGs as an inde-
pendent risk factor. However, interest in this association reemerged in
the 1990s, when a number of studies showed that elevated TGs may indeed
be an independent risk factor for CAD [111]. The study by Framingham was
one of the first major studies to associate hypertriglyceridemia with CVDs,
particularly in women, and the next big question that needed to be answered
was if TGs represented an independent risk factor [126]. A meta-analysis of
the interaction data on emerging risk factors revealed TGs as a strong risk
factor for CVDs and cerebrovascular accidents (CVAs); however, after
adjusting for classic risk factors, researchers concluded that TG levels did
not provide any additional predictive value [83]. Some randomized con-
trolled trials arrived at a significant relationship between baseline TG levels
and CVA incidence, and the risk for cerebral events was increased by 5.5%
for each 10 mg/dL increase in baseline TG levels, reinforcing the need for a
clearer idea of the detrimental effect of increased TG in relation to CVA
[127,128].
The lack of a strong association between TG concentration and CVD
(after accounting for other risk factors such as high LDL and low HDL levels)
led clinicians to question if measuring TG levels has any use in patient’s car-
diovascular management. It is important to stress that in some studies,
patients with TG levels above 500 mg/dL are at increased risk of pancrea-
titis, providing a reason to measure TG levels in patients and treating indi-
viduals with high levels, regardless of cardiovascular risk [129–132]. Data
found in the literature reinforce the deleterious role of elevated TG
levels, either in isolation or when assessing the LDL/HDL relationship
[111,133,134].
In 2000, Cullen was attempting to demonstrate the association of TGs
with CAD, when he published data from an observational study spanning
8 years involving nearly 20,000 people aged 19–65, selected by their lipid
profile and cardiovascular risk factors at the beginning of the study and major
events, such as AMI and sudden death, were monitored over time. In this
study, it became evident that hypertriglyceridemia was an independent risk
factor for major coronary events even after adjusting for LDL and HDL, age,
systolic blood pressure, tobacco use, diabetes mellitus, family history of myo-
cardial infarction, and angina pectoris. This association remained in sub-
groups of participants who had higher LDL (163 mg/dL) or HDL
(40 mg/dL) levels. In this study, hypertriglyceridemia remained a potent risk
factor for CAD when combined with high LDL and low HDL levels and a
high LDL/HDL ratio (>5), showing a sixfold increase in the risk for cardio-
vascular events [133].
Reinforcing this, in a study of 495 patients with CAD, Luz et al. showed
that the relationship between lipids and CAD was stronger in terms of TGs
and the TG/HDL ratio than for total cholesterol, LDL, HDL, or non-HDL
cholesterol. In addition, TG levels >150 mg/dL and a TG/HDL ratio
>3.75 were not associated with early CAD in individuals with LDL
>160 mg/dL, showing that the TG/HDL ratio is especially important in
patients with relatively low LDL levels. Later, in a new study of 374 patients
who underwent coronary angiography due to suspected CAD, Luz et al.
assessed the relationship between lipids and extent of CAD (determined
by the Friesinger index). A statistically significant relationship was found
between extent of CAD and TG levels, as well as between extent of
CAD and TG/HDL ratio; however, there was no relationship when con-
sidering total cholesterol levels. In both studies, a high TG/HDL ratio was
the single and most potent indicator of extensive CAD among all lipid vari-
ables examined. These studies reinforce the involvement of hyper-
triglyceridemia and low HDL levels in atherosclerosis, stressing their role
in atherosclerotic plaque formation, endothelial dysfunction, and proc-
oagulation activity [135,136].
A prospective population-based study aimed at determining if the TG/
HDL ratio could predict coronary heart disease independently from total
cholesterol and other risk factors in the Iranian population, which has a high
prevalence of metabolic syndrome and low HDL levels. Monitoring over
11,316 person-years showed that total cholesterol, TG, and TG/HDL are
important risk factors for CAD in men after adjusting for age and risk factors.
The TG/HDL index indicates the relative size of LDL particles and, thus,
their resulting atherogenic potential. A high TG/HDL ratio indicates a
greater population of small, dense proatherogenic LDL particles. Total cho-
lesterol, HDL, and TGs were measured only once, and thus the potential
bias resulting from diluting the regression of TGs and measuring HDL can-
not be excluded. Second, the sample study is from the Caucasian eastern
region with a high prevalence of metabolic syndrome and low HDL levels,
and the capability of the TG/HDL ratio for predicting CAD in other
ethnicities with these characteristics has not been demonstrated. In conclu-

sion, the results suggest that the TG/HDL ratio should be considered when
evaluating CAD risk in populations with a high prevalence of metabolic
syndrome [137].
The PROVE IT-TIMI 22 study revealed that TG levels had a substantial
impact on cardiovascular outcomes in patients with acute coronary syn-
drome, independently from LDL [138]. Meta-analyses of prospective and
randomized studies likely provide stronger evidence for TG levels as an
independent risk factor. A meta-analysis of 29 prospective studies showed
that Western populations consistently show moderate and highly significant
associations between TG values and CAD risk [113]. One meta-analysis
including 35 studies suggested that fasting hypertriglyceridemia is associated
with increased risk of cardiovascular death, myocardial infarction, cardiovas-
cular events, and pancreatitis [139]. In addition, a more recent meta-analysis
that was even larger (330,566 individuals in 61 studies) reported a 22%
increase in atherosclerotic CVD risk for every 88 mg/dL increment in
TGs [140].
Thus, randomization data strongly suggest that hyperglyceridemia causes
atherosclerotic CVD; therefore reducing TG levels is more strongly rec-
ommended in treating hypertriglyceridemia to address the residual risk of
atherosclerotic CVD [112]. The most recent guidelines from the American
College of Cardiology and the American Heart Association make no specific
recommendations regarding treating high TG levels to reduce CVD risk,
although hypertriglyceridemia was associated with worse outcomes in per-
cutaneous coronary intervention or surgery [141]. They suggest that TG
levels higher than 500 mg/dL should prompt investigation of the secondary
causes of hyperlipidemia, but the guidelines do not show any additional
reduction of cardiovascular risk with the treatment of these elevated levels
[141]. One study investigated if patients with hypertriglyceridemia were
more prone to worse outcomes during cardiac catheterization, with the con-
clusion that hypertriglyceridemia was associated with worse outcomes from
percutaneous coronary intervention or surgery [142].
Based on this evidence, atherosclerosis, the most prevalent form of CVD,
has been the target of the majority of investigations on a direct role for TGs
in CVDs, strongly showing that TGs may directly influence specific aspects
of the development of atherosclerotic lesions. In patients with established
CAD, higher TG levels are independently associated with increased mortal-
ity, and even in patients with TG levels between 100 and 149 mg/dL, an
elevated risk of death was detected compared to patients with lower TG
levels, while severe hypertriglyceridemia indicates a population with a par-

ticularly increased risk of mortality [143].
Several hypotheses are based on the fact that TG-rich lipoproteins
(VLDL, chylomicrons) also contain significant quantities of cholesterol
and may promote the formation of foam cells, and thus cholesterol
contributes to the lesion [144–146]. Chylomicron remnants may also pro-
mote an increase in the inflammatory state of monocytes, thus increasing
their susceptibility to endothelial adhesion and invasion of the arterial wall
[147]. VLDL and chylomicron remnants are created through the partial
hydrolysis of their TGs by LPL. These particles have a greater percentage
of cholesterol and may acquire additional cholesterol by the transference
of HDL by CETP [148]. In hypertriglyceridemia, there is an increase in
VLDL synthesis, a slowing of clearance, and frequently an increase in rem-
nant particles [149].
It is worth stressing that nonfasting TG levels primarily reflect remnant
lipoproteins, particularly in hypertriglyceridemia, and these particles may be
atherogenic. There are prospective epidemiological studies that found sig-
nificant associations between nonfasting TG levels and the risk of adverse
cardiovascular events, and there is also strong evidence supporting the role
of cholesterol in remnant lipoproteins as a clinically significant risk factor for
CVD [150–154].
Although chylomicrons and, to a certain extent, LDLs are generally too
large to cross the endothelial layer and invade the arterial intima, the con-
version to remnants allows these particles to accumulate within the athero-
sclerotic lesions to deposit their cholesterol [155]. This would imply that
LPL levels, by increasing these remnants, are able to influence the develop-
ment of the atherosclerotic lesion, with studies on animals validating this
correlation [156–158]. Evidence for the importance of remnants in athero-
genesis is also available from individuals with hyperlipoproteinemia type III,
who exhibit reduced clearance of remnant lipoproteins and develop prema-
ture atherosclerosis [159]. Children and adolescents with persistently mod-
erate to high TG levels may have an increased risk of premature CVD as
adults [160].
The potential atherogenic effects of chylomicron remnants have also
been demonstrated in vivo. Thus, initial studies in rabbits showed that
the remnants of chylomicrons and LDL perfused in the carotid artery were
retained within the subendothelial space [161]. It is worth stressing that more
directly, LPL expression by the arterial endothelium and by macrophages on
the arterial wall acts on TGs of TG-rich lipoproteins to produce FFAs, both
on the surface and within the arterial wall, which are proinflammatory,
proatherogenic, and procoagulant [54,162]. In addition, various types of
TG-rich lipoproteins are directly atherogenic and their excess is more
readily demonstrated by high plasma TG levels [163,164]. The athe-
rogenicity of lipoprotein remnants, which are rich in TGs and cholesterol,
is more clearly seen in the classic disorder of excess remnants, named dys-
betalipoproteinemia, where both TG and cholesterol levels are increased,
increasing the risk of CAD [165].
Cholesterol retention was particularly high in the intima of hyper-
lipidemic Watanabe rabbits, especially in lipoproteins containing apoB-48
[161]. The fasting serum levels of apoB-48 were significantly higher in
patients with CAD in comparison to patients without it [166,167]. Further-
more, apoB-48 is significantly increased in patients with early atherosclero-
sis, participating in the initial stages of lesion progression [167]. Consistent
with these results, apoB-48 levels in fasting conditions were also significantly
correlated with thickness of the intima-media layer in normolipidemic
individuals [168].
It is important to stress that the association of plasma ApoB-48 levels
(reflecting the postprandial lipoproteins) with the presence of carotid plaques
in diabetes mellitus type 2, as well as the strong association between
nonfasting TG levels and the increased risk of CAD, are epidemiological
data that strongly support the basic science for postprandial atherogenesis
[169,170]. However, the international standardization of the tests and the
definition of normal reference values are necessary to extend the use of
apoB-48 determinations in clinical practice.
Oxidative stress is an important aspect to be considered, which has been
previously reported in hypertriglyceridemia [171–173]. Some evidence of
oxidative damage was demonstrated in hypertriglyceridemic individuals,
independently of the cholesterol concentrations. Our research group,
through a study involving 127 individuals, showed that there is a relationship
between oxidative stress and TG level. This is due to the fact that the oxi-
dative biomarkers studied (advanced oxidation protein products and
ischemia-modified albumin) are positively correlated with TG stratification
level, which did not occur when they were stratified by total cholesterol
levels [174]. Regardless of cholesterol levels, individuals with TG levels
above 150 mg/dL showed higher oxidative biomarkers when compared
to normotriglyceridemic individuals. After adjustments, the multivariate
logistic regression analysis showed this effect to be independent of age, gen-
der, hypertension, diabetes mellitus, tobacco use, physical inactivity, body
mass index, abdominal circumference, LDL and HDL levels, and total cho-
lesterol concentrations [174].
Undoubtedly, there is still much to be discovered regarding TGs. How-
ever, the need to reduce the circulating concentrations of this lipid molecule
has become increasingly evident. The benefits of TG reduction notably end
up positively influencing cardiovascular event outcome and mortality [111].
6. TREATMENT OF HYPERTRIGLYCERIDEMIA
6.1 Lifestyle Changes
One of the first measures taken to reduce TGs is a change in lifestyle, empha-
sizing physical activity and nutrition, considering that the best results can be
achieved through nonpharmacological treatment [112,175]. With regard to
diet, reducing sugar intake is strongly encouraged, since in excess it stimu-
lates hepatic FA synthesis and the accumulation of TGs [112]. It is also
important to reduce fat intake, since fats trigger the production of chylomi-
crons and consequently increase TGs [112]. Regarding physical activity, we
stress its direct effect on reducing TG levels, likely due to increased beta-
oxidation and, consequently, lipolysis [112]. A number of guidelines recom-
mend the addition of fibrates, niacin, or long-chain omega-3 FAs if elevated
TG or non-HDL cholesterol levels persist despite the use of high-intensity
statin therapy [176].
Mendelian randomization data strongly suggest that hypertri-
glyceridemia causes atherosclerotic CVD, and so TG level-lowering treat-
ment in HTG is now more strongly recommended to address the residual
atherosclerotic CVD risk than has been the case in previously published
guidelines. Fibrates are the best-established agents for lowering TG level
and are generally used as first-line treatment of TG levels greater than
500 mg/dL. Statins are the best-established agents for preventing atheroscle-
rotic CVD, and so are usually used as a first-line treatment of TG levels lower
than 500 mg/dL [112].
The use of statins will not be discussed since there are vast amounts of
published material regarding their use in treating hypercholesterolemia,
and which is outside the scope of this review. However, we did opt to
include more recent information on the use of fibrates, niacin, long-chain
omega-3 FAs, and possible new therapies such as microsomal TG transfer
protein inhibitors, PCSK9 inhibitors, herbal medicines such as flavonoids,
and foods such as garlic and nuts.
6.2 Fibrates: Activators of Peroxisome Proliferator-Activated

Receptor Alpha
After statins, the drugs that most stand out are the fibrates, given that they
yield some of the best results for reducing TG levels, and they also reduce
total cholesterol and LDL-C, while increasing HDL-C levels [3,177].
Fibrates exert their action by stimulating the peroxisome proliferator-
activated nuclear receptors alpha (PPAR-α), consequently leading to the
increased production and action of LPL and a reduction in apoprotein CIII
(Apo CIII), mechanisms that stimulate lipolysis of VLDL-cholesterol
(VLDL-c) and chylomicron TGs [178].
In terms of preventing and treating atherosclerotic diseases, PPAR-α
plays a critical role due to the fact that its activation inhibits various phases
in the development and progression of atherosclerosis [5,179]. Downstream
effects of PPAR-α include a decrease in the expression of adhesion mole-
cules such as MCP-1, a reduction in the inflammatory process by reducing
bonding and decreasing activation of monocytes and T cells, and it also reg-
ulates the expression of adhesion molecules, such as ICAM-1, VCAM-1,
and P-selectin, promoting the efflux of subendothelial cholesterol and
directly stimulating the formation of foam cells [180].
Atherosclerosis is characterized not only as a pathology related to lipid
storage but also as a chronic inflammatory disease. In response to an athero-
genic stimulus, endothelial cells secrete proinflammatory cytokines, which
may subsequently promote the fixation, adhesion, and migration of mono-
nuclear cells from the endothelium to the subendothelial intima. Further-
more, these cytokines potently induce the differentiation of monocytes
into macrophages loaded with lipids or foam cells, resulting in amplification
of the local inflammatory response in the lesion and in the potential for
plaque rupture [173,7]. We also stress interferon-γ (IFN-γ); IL-1, IL-2,
IL-6, and IL-18; and TNF-α as the most well-known proinflammatory
mediators of importance involved in atherogenesis. Studies show that
PPAR-α agonists significantly impede production of IFN-γ, IL-2, and
TNF-α [181].
In short, PPAR-α stimulation may exert a potent antiinflammatory
effect by antagonizing the generation of proinflammatory cytokines, consid-
ering that the recruitment of macrophages and T-lymphocytes is a key factor
for the development of the atherosclerotic process, and given that monocyte
chemotactic protein-1 (MCP-1) is a fundamental chemokine in the devel-
opment of atherosclerosis and cardiovascular syndromes. The latter, through
its chemotactic activity, induces the diapedesis of monocytes from the lumen
into the subendothelial space, promoting the atherosclerotic lesion forma-

tion [182]. In human endothelial cells exposed to high glucose concentra-
tions, medications such as fenofibrate and clofibrate negatively regulated the
expression of MCP-1 [180]. In studies on rabbits with plaque in their fem-
oral arteries being fed a high-fat diet, it was found that fenofibrate may
reduce P-selectin levels in the plaques. These results suggest that PPAR-
α can function as a negative regulator of transendothelial adhesion [183].
In studies on mice with mixed dyslipidemia, it was found that the
administration of fenofibrate alleviated the atherosclerotic lesions induced
by macrophages acting as foam cells [184]. Fenofibrate prevents cardiovas-
cular events in patients with diabetes type 2 and moderate kidney disease
in the long term [185,12]. An experimental study performed with Wistar
male rats (250–300 g) found that in the group with myocardial infarction,
receiving 100 mg of clofibrate for 3 days promoted an antiinflammatory
cellular environment, improving the hemodynamics around the infarction
[179]. The data also show that clofibrate has a protective effect on the heart,
as evidenced by a smaller infarction area, and this evidence is correlated
with the ability of clofibrate to reduce IL-6 production and consequently
reduce proinflammatory activity, preserving the viability of the cardiac
musculature [179].
Clinical trials using the coronary angiography to evaluate carotid intima-
media thickness and average luminal diameter have shown that fibrates are
capable of reducing the progression of atheromatous plaques, and are used as
a monotherapy [186,13]. Meta-analyses of the effects of fibrates show a con-
sistent but small reduction in cardiovascular events of 10%–11% with the use
of these drugs [187,188]. The effect is restricted to a reduction in nonfatal
myocardial infarction or rates of coronary intervention, with no benefits
in terms of death rates by CVD, fatal myocardial infarction, or CVA
[189]. Fibrates do appear to reduce the risk of cardiovascular events in
patients with hypertriglyceridemia, especially if associated with low
HDL-C levels [112].
In this regard, it is important to mention a recent meta-analysis that
showed the effect of fibrates on cardiovascular risk is greater in patients with
high TG levels. This meta-analysis of 4671 patients with atherogenic dys-
lipidemia found a significant difference in the magnitude of the effect of
fibrates between dyslipidemia subgroups (low HDL-c in isolation, high
TG levels alone, or both). A greater effect was found in patients with high
TG levels. Similarly, another meta-analysis showed that the benefit was
greater in individuals that had hypertriglyceridemia and low HDL-C [190].
6.3 Nicotinic Acid

Nicotinic acid reduces plasma TG concentrations by inhibiting DGAT to
reduce TG synthesis in hepatocytes. This leads to a reduction in FA release
from adipose tissue. Niacin is capable of reducing TGs with effects varying
from around 5% to 40%, and it also reduces LDL-C and lipoprotein(a) and
increases HDL-C. Despite the favorable effects on lipid markers, prospective
studies failed to show an improvement in CVD risk [175]. There is evidence
that combining niacin and statins may reduce atherosclerosis and cardiovas-
cular events, and high-dose treatment significantly reduces carotid athero-
sclerosis over 12 months in patients treated with statin with low HDL-C
and/or diabetes type 2 with coronary disease, or carotid or peripheral ath-
erosclerosis [177]. However, there are a lack of studies on niacin as a mon-
otherapy, and there are also various critiques concerning its impact on
cardiovascular risk reduction. Higher doses of niacin can cause undesirable
effects, resulting in the diminished interest in this drug.
6.4 Long-Chain Omega-3 FAs

Omega-3 polyunsaturated fatty acids (PUFAs) are found in fish oil and have
been shown to mitigate the risk of CVD [191]. Omega-3 FAs are essential
FAs because they cannot be synthesized de novo and must be consumed
from dietary sources such as marine fish [192]. PUFAs reduce fatal and non-
fatal myocardial infarction, stroke, CAD, sudden cardiac death, and overall
mortality [193]. They also have beneficial effects for reducing mortality after
myocardial infarction. Omega-3 FAs lower plasma TGs. In patients with
severe hypertriglyceridemia who are unresponsive to statins, they augment
TG reduction [194,195].
Long-chain omega-3 FAs are associated with reductions in plasma TG
levels of approximately 25%–34% and modest elevations in HDL-C of
approximately 1%–3% [196]. Additionally, elevations in LDL-C levels have
been observed (approximately 5%–11%) [196]. However, 4%–8% reduc-
tions in non-HDL-C have also been observed [197,198]. Higher long-chain
omega-3 FA doses and higher baseline TG levels have been associated with
greater TG reductions [199]. In a meta-analysis of 36 placebo-controlled,
crossover trials, long-chain omega-3 FAs (at an average dose of approxi-
mately 4 g/day) reduced TG levels by 34% in patients with baseline TG
levels of >2.0 mmol/L (>177 mg/dL), whereas in patients with baseline
TG levels of <2.0 mmol/L (<177 mg/dL), TG levels were reduced by
an average of 25% [196].
Three forms of long-chain omega-3 FAs have been approved as prescrip-

tion formulations: eicosapentaenoic acid (EPA) ethyl esters (Vascepa) [200];
a combination of ethyl esters of omega-3 FAs, EPA and docosahexaenoic
acid (DHA) being the most prevalent (Omacor [also known as Lovaza]
[201], Omtryg, and some generics); and a mixture of long-chain omega-3
FAs in FFA form, the most abundant of which being EPA, DHA, and doco-
sapentaenoic acid (DPA) (Epanova) [202]. The last of these formulations,
Epanova, is not dependent on pancreatic enzyme activity for absorption,
and therefore, this formulation does not need to be taken with a high-fat
meal. This, at least in theory, may have benefits, as a low-fat diet is rec-
ommended by all guidelines for managing severe hypertriglyceridemia
[123,176,203–207].
6.5 Microsomal TG Transfer Protein Inhibitors

Microsomal triglyceride transfer protein (MTP) is observed in the lumen of
the endoplasmic reticulum. It is responsible for the transfer of TGs and other
lipids from their site of synthesis in the endoplasmic reticulum into the
lumen during the assembly of VLDLs [208,209]. VLDLs produced by
the liver are the major sources of LDLs in plasma. MTP inhibitors have
the potential for use as plasma lipid-lowering drugs. Specific MTP inhibitors
reduced LDL levels by 70%–80% and TG levels by 30%–40% [18].
Lomitapide treatment, in a single-arm, open-label, phase III study, was
proven effective in reducing LDL-C levels by 50.9% and ApoB levels by
55.6% in patients with homozygous familial hypercholesterolemia.
Major adverse events included elevated liver aminotransferase levels and
the accumulation of hepatic fat [210]. SLx-4090 (Nano Terra, Brighton,
MA, USA) is an orally administered MTP inhibitor which was designed
to act selectively on the enterocytes lining the GI tract. It prevents the for-
mation of chylomicrons, which transport TG and cholesterol into the sys-
temic circulation. SLx-4090 can reduce LDL-C and postprandial TG levels
[211–213].
6.6 Monoclonal Antibodies PCSK9 and TGs: Clinical Evidence

The discovery that proprotein convertase subtilisin/kexin type 9 (PCSK9)
represents a key regulatory pathway for hepatic LDLR degradation sheds
light on newly uncovered issues regarding LDL-C homeostasis. Indeed,
as confirmed by phase II and III clinical trials, targeting PCSK9 with mono-
clonal antibodies represents the newest and most promising pharmacological
tool for treating hypercholesterolemia and atherogenic dyslipidemia, and

this new class also decreases TG levels [214].
Evidence in human studies on the direct involvement of PCSK9 in apoB
production has been provided by study conducted on a family with
autosomal-dominant hypercholesterolemia carrying an S127R mutation
in PCSK9 [215]. This particular gain-of-function PCSK9 mutation dramat-
ically increased the apoB production rate by threefold compared to matched
control subjects or patients with LDLR mutation [216]. Then the increased
apoB resulted in an overproduction of VLDL, IDL, and LDL. This particular
phenotype is different from that observed in subjects carrying mutations in
LDLR or apoB, suggesting a dual role of PCSK9 in both LDLR expression
and apoB secretion. Nevertheless, it cannot be excluded that VLDL produc-
tion increases in response to a lack of nascent VLDL reuptake by the LDLR
degraded by PCSK9 [217].
Finally, the observed positive correlation between PCSK9 and IDL, the
TG-rich LDL subfraction [218], raises the possibility of a significant contri-
bution of IDL to the observed linear relationship between PCSK9 and TGs.
There is scarce clinical evidence on the role of PCSK9 in postprandial hyp-
ertriglyceridemia. The oral fat load in healthy volunteers or patients carrying
the R104C-V114A loss-of-function PCSK9 mutation did not alter plasma
levels of PCSK9 [218]. The same study was also performed in obese subjects
where, in the postprandial period, PCSK9 was significantly associated with
the area under the curve for apo B48 and inversely correlated with the TG–
apoB48 fractional catabolic rate [219]. These data suggest that PCSK9 might
influence the catabolism of TGs and apoB48-containing chylomicrons dur-
ing the postprandial state in obese individuals [219].
During the past 3 years, monoclonal antibodies toward PCSK9 have
emerged as a new class of drugs that very effectively lower LDL cholesterol
levels [220]. Evolocumab is a fully human monoclonal antibody in this cat-
egory, which typically reduces LDL cholesterol levels by 60% when admin-
istered at the doses that were studied in phase III trials [221–226]. A recent
study showed that the patients receiving evolocumab, when compared with
patients receiving standard therapy, saw changes in related atherogenic lipid
measures similar to those observed for LDL cholesterol, with a 52% reduc-
tion in non-HDL cholesterol, a 47.3% reduction in apolipoprotein B, a
36.1% reduction in total cholesterol, a 12.6% reduction in TGs, and a
25.5% reduction in lipoprotein(a) [227].
Although PCSK9 monoclonal antibodies may reduce TG levels, the
drug was not developed for this purpose, and there is also no evidence that
this treatment can affect CAD or mortality. In cases of homozygous familial

hypertriglyceridemia, this drug is being considered an option despite being
administered intravenously and its current side effects [214].
6.7 Dyslipidemias and Dietary Flavonoids

Flavonoids may improve dyslipidemias by modulating lipid absorption and
lipogenesis [228]. Flavonoid-rich foods or beverages and/or purified flavo-
noids have been shown to lower plasma TG and/or total cholesterol and
LDL cholesterol (or increase HDL cholesterol) in circulation in both
humans with MS and rodent models [229–235].
Flavonoids could be decreasing lipid absorption at the gastrointestinal
level. However, flavonoids can also modulate the activity of different
enzymes involved in lipid metabolism and the expression of transcription
factors involved in TG and cholesterol synthesis, for example, sterol regu-
latory element-binding proteins SREBP-1 and SREBP-2. A grape-seed
proanthocyanidin extract was found to reduce TG in normolipidemic rat
[236,237] and mice, and in high-fat-fed rats [238], in association with the
downregulation of hepatic SREBP-1. Additionally, it suppressed the over-
expression induced by a high-fat diet of enzymes involved in lipogenesis: Fat
acid synthase and ATP-citrate lyase isoform [239]; microsomal transfer pro-
tein, the key controller of very LDL assembly; and diglyceride acyltransferase
[240]. Similarly, other flavonoid extracts, such as licorice, and purified fla-
vonoids, such as baicalin, decreased liver SREBP-1, acetyl-CoA carboxyl-
ase, and fat acid expression [241,242] and activity in rats fed a high-fat diet.
EGCG administration to high-fat-fed mice decreased body and liver weight
and TG, and plasma cholesterol levels [228].
In LDLR-null mice with diet-induced insulin resistance, the flavanone
naringenin accelerated hepatic fat acid oxidation and prevented TG accumu-
lation in the liver, effects associated with an increased expression of PPAR-
coactivator-1, carnitine acyltransferase I, and acyl-CoA oxidase, molecules
involved in FA oxidation. Naringenin also reverts the increased expression
of SREBP-1 in liver and muscle of rats, diminishing the SREBP-1c-
stimulated lipogenesis [243]. In a 6-month treatment, naringenin lowered
total hepatic cholesterol and cholesteryl ester [243]. The effects of adminis-
trating a cranberry extract enriched in flavonoids were evaluated in
both nonobese and obese C57/BL6 mice. At the end of the treatment, non-
obese mice showed a reduced expression of the following hepatic key
enzymes involved in cholesterol synthesis: HMG coenzyme A reductase,
HMG-coenzyme A synthase, farnesyl diphosphate synthase, and squalene

synthase. On the other hand, in obese mice, cranberry extract administration
improved the lipid profile and reduced visceral fat mass. These effects are
likely mediated by the activation of the adiponectin/AMPK (5-AMP-
activated protein kinase) pathway, which accelerates fat acid utilization in
the muscle and decreases fat storage in the adipocytes [243,244].
Although there are several in vivo studies demonstrating that flavonoid-
rich foods may improve dyslipidemias and lipogenesis, on the other hand,
there are fewer large clinical studies demonstrating the effects in humans.
6.8 Dyslipidemias and Dietary Garlic

A number of studies have pointed out the potential of Allium sativum (garlic)
for reducing lipid levels, as it reduces TG and cholesterol levels. In vitro
studies on primary cultured rat hepatocytes showed that garlic extract
inhibits FA and TG synthesis [79,245]. In addition, the study by Adoga
[230,246] using Wistar rats fed a sucrose-rich diet with or without the addi-
tion of garlic showed that garlic reduces TG biosynthesis by reducing
NADPH concentration in tissues, increasing the hydrolysis of these lipids,
increasing pancreatic lipase activity, and deactivating enzymes involved in
lipid synthesis, by interacting with the thiol groups of these enzymes.
Aside from the effect of the extract as a whole, according to Liu et al. [79]
a number of compounds present in garlic play a role in reducing TGs,
namely: S-allyl cysteine, S-propyl cysteine, and S-ethyl cysteine. These
compounds are capable of inhibiting FA synthesis in primary cultured rat
hepatocytes, thus reducing the synthesis of new FAs and, consequently,
TG biosynthesis. It was also reported that in rats, garlic reduces the hepatic
TG concentration and the administration of garlic along with a fat-rich diet
over 4 months reduced lipid deposition in the aorta and in atheromatous
lesions in rabbits [247]. However, although these effects of garlic are encour-
aging, there are insufficient studies with humans to confirm the results, thus
opening the possibility for further research.
6.9 Dyslipidemias and Dietary Nuts

In the past decade, the importance of nut consumption on several chronic
conditions has been investigated. Nuts are rich in PUFAs and monounsat-
urated fatty acids (MUFAs), with the exception of walnuts, which are higher
in PUFAs [248,249]. Nuts also contain bioactive compounds such as phy-
tosterols, tocopherols, and polyphenols [249].
Many clinical trials have shown that nuts decrease total and LDL choles-
terol, but their impact on HDL cholesterol and TGs, components of the
metabolic syndrome, is less certain.
In a meta-analysis of 13 clinical trials, serum HDL cholesterol and
TG concentrations were not significantly affected by walnut consumption
[250]. These findings are consistent with other analysis of 25 trials evalu-
ating the relation between different types of nuts and blood lipids in
normolipidemic and hypercholesterolemic subjects. The daily consump-
tion of nuts had only significant effect on hypertriglyceridemia individuals,
with reduction by 20.6 mg/dL (10.2%) [251]. Because individuals with
metabolic syndrome are usually hypertriglyceridemic, nut consumption
could be expected to have favorable effects on TGs, probably because
the metabolic characteristics of these individuals differ from those of the
general population. Nut consumption was also shown to have beneficial
effects on the lipid components of metabolic syndrome in the PREDI-
MED trial [252].
7. CONCLUSIONS
The effects of TGs and their excess in organisms are increasingly being
discovered. Efforts to reduce TG levels, including the correction of the sec-
ondary cause of hypertriglyceridemia, changes in eating habits, and physical
activity, along with the use of statins, fibrates, nicotinic acid, and omega-3
FAs, continue to be the main alternatives. In some cases, the concomitant
use of two or more of these treatment modes is necessary. New treatment
options are promising and are being generated, but they lack definitive
results. Randomized clinical trials aimed at testing the effects of new ther-
apies on cardiovascular event outcomes are underway.
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Paulo Ricardo Nazário Viecili Brenda da Silva

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Advances in Clinical Chemistry, Volume 80 # 2017 Elsevier Inc. 1

countless lipoprotein disorders, including disorders in TG carriers [10], and

2. TG CONCEPT, STRUCTURE, AND FUNCTION

H2C O Palmitic acid

This pathway is based on the acylation of glycerol 3-phosphate through the

Fig. 2 Illustration of TG synthesis through glycerol phosphate. Glycerol 3-phosphate

Fig. 3 Illustration of TG synthesis from monoacylglycerol. TGs of dietary origin undergo

Mitochondrial GPAT, an enzyme involved in TG synthesis, is mainly

been identified as an important carbon source in mammals, acting during

4. GENETICS OF THE TGs

The catabolism of TG-rich lipoproteins depends on LPL enzymatic

The gene APO5 is located near the APOA4-C3-A1 cluster in chromo-

LPL is present on the surface of endothelial cells in small capillaries of

5. TGs AND THE CARDIOVASCULAR SYSTEM

postprandial TGs, a precise and standardized methodology must be

ethnicities with these characteristics has not been demonstrated. In conclu-

levels, while severe hypertriglyceridemia indicates a population with a par-

6.2 Fibrates: Activators of Peroxisome Proliferator-Activated

into the subendothelial space, promoting the atherosclerotic lesion forma-

6.3 Nicotinic Acid

6.4 Long-Chain Omega-3 FAs

Three forms of long-chain omega-3 FAs have been approved as prescrip-

6.5 Microsomal TG Transfer Protein Inhibitors

6.6 Monoclonal Antibodies PCSK9 and TGs: Clinical Evidence

tool for treating hypercholesterolemia and atherogenic dyslipidemia, and

this treatment can affect CAD or mortality. In cases of homozygous familial

6.7 Dyslipidemias and Dietary Flavonoids

HMG-coenzyme A synthase, farnesyl diphosphate synthase, and squalene

6.8 Dyslipidemias and Dietary Garlic

6.9 Dyslipidemias and Dietary Nuts

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mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1, Am. J. Hum.

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[184] N. Hennuyer, A. Tailleux, G. Torpier, H. Mezdour, J.C. Fruchart, B. Staels, et al.,

the management of dyslipidaemias of the European Society of Cardiology (ESC) and

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