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Contents lists available at ScienceDirect

Digestive and Liver Disease

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

Review Article

Nonalcoholic fatty liver disease: A precursor of the metabolic

syndrome
Amedeo Lonardo a,∗ , Stefano Ballestri b , Giulio Marchesini c , Paul Angulo d , Paola Loria a
a
AUSL Modena and University of Modena and Reggio Emilia, Department of Biomedical, Metabolic and Neural Sciences, Division of Internal Medicine,
NOCSAE – Baggiovara, Modena, Italy
b
AUSL Modena, Department of Internal Medicine, Division of Internal Medicine, Hospital of Pavullo, Pavullo nel Frignano, Italy
c
“Alma Mater Studiorum” University, Unit of Metabolic Diseases and Clinical Dietetics, Bologna, Italy
d
University of Kentucky, Division of Digestive Diseases & Nutrition, Section of Hepatology, Medical Center, Lexington, KY, USA

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

Article history: The conventional paradigm of nonalcoholic fatty liver disease representing the “hepatic manifestation of
Received 30 April 2014 the metabolic syndrome” is outdated. We identified and summarized longitudinal studies that, suppor-
Accepted 21 September 2014 ting the association of nonalcoholic fatty liver disease with either type 2 diabetes mellitus or metabolic
Available online xxx
syndrome, suggest that nonalcoholic fatty liver disease precedes the development of both conditions.
Online Medical databases were searched, relevant articles were identified, their references were further
Keywords:
assessed and tabulated data were checked.
Dissociation
Although several cross-sectional studies linked nonalcoholic fatty liver disease to either diabetes and
Insulin resistance
Natural history
other components of the metabolic syndrome, we focused on 28 longitudinal studies which provided
Pathogenesis evidence for nonalcoholic fatty liver disease as a risk factor for the future development of diabetes.
Moreover, additional 19 longitudinal reported that nonalcoholic fatty liver disease precedes and is a risk
factor for the future development of the metabolic syndrome.
Finally, molecular and genetic studies are discussed supporting the view that aetiology of steatosis
and lipid intra-hepatocytic compartmentation are a major determinant of whether fatty liver is/is not
associated with insulin resistance and metabolic syndrome.
Data support the novel paradigm of nonalcoholic fatty liver disease as a strong determinant for the
development of the metabolic syndrome, which has potentially relevant clinical implications for diag-
nosing, preventing and treating metabolic syndrome.
© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Introduction frequently associated with the constellation of clinico-laboratory

Steatosis and steatohepatitis, in the absence of competing aeti-
ologies such as high alcohol intake, hepatitis C virus (HCV) infection,
drugs and other endocrine disorders, are both part of the nonalco-
holic fatty liver disease (NAFLD) spectrum [1–3]. NAFLD may either
occur in the absence of fatty changes – and is often alluded to either
as “cryptogenic” or nonalcoholic steatohepatitis (NASH)-cirrhosis
[4,5] – or encompass hepatic and extra-hepatic complications, from
hepatocellular carcinoma to atherosclerosis [6]. NAFLD is presently
recognized as one the most common causes of altered liver tests,
of end-stage liver disease requiring liver transplantation, and is
∗ Corresponding author at: Division of Internal Medicine, NOCSAE – Baggiovara,
Via Giardini 1135, 4100 Modena, Italy. Tel.: +39 0593961807; fax: +39 0593961322.
E-mail addresses: a.lonardo@libero.it, a.lonardo@ausl.mo.it (A. Lonardo).
features that comprise the metabolic syndrome [7–9].
The metabolic syndrome is a cluster of cardio-metabolic condi-
tions, generally triggered by an expansion of the adipose visceral
tissue [10], which include insulin resistance – with or without
impaired glucose metabolism and type 2 diabetes (T2D) – athero-
genic dyslipidemia [low high density lipoprotein (HDL)-cholesterol
and high triglycerides], and high blood pressure [11]. The present
definition of metabolic syndrome, at variance with one of its earliest
proposals [12], does not include hepatic steatosis despite evidence
supporting this association [13]. The existence and the utility of
metabolic syndrome as a separate entity has been challenged by
some experts [14]. Moreover, it remains controversial whether the
presence of the full-blown syndrome really adds to the cardiovas-
cular risk dictated by its individual components, particularly T2D
[15,16]. Nevertheless, the single traits of the metabolic syndrome
tend to aggregate in the same individuals and, more importantly,
the presence of each of them often anticipates the appearance of

http://dx.doi.org/10.1016/j.dld.2014.09.020
1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Lonardo A, et al. Nonalcoholic fatty liver disease: A precursor of the metabolic syndrome. Dig Liver
Dis (2014), http://dx.doi.org/10.1016/j.dld.2014.09.020
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Table 1
Nonalcoholic fatty liver disease and metabolic syndrome – the original spectrum of similarities.

Steatosis Metabolic syndrome

Epidemiology
Prevalence in the general population Up to 25% of adults Epidemic in the elderly
Prevalence grows with age Yes Strongly age-dependent
Males more affected Yes (adults, children) Yes

Anthropometry
Association with central obesity Abdominal adiposity is an independent predictor Visceral fat is correlated with Insulin response and dyslipidemia

Metabolism – Association with

Hyperinsulinemia Documented Pathogenic mainstay
Hypertension In drinkers and non-drinkers Yes
Obesity Yes Yes
Hypertriglyceridemia Yes Yes
Low HDL Cholesterol Circumstantial Evidence Yes

Clinical features
Systemic disease Yes Yes
Accelerated atherogenesis Circumstantial Evidence Yes
Response to diet and/or exercise In the obese Yes

Experimental pathology
Animal Models (rat) Atherogenic diet induces steatosis Hypertensive animals have hyperinsulinemia and hypertriglyceridemia

Adapted from Lonardo [20].

additional components over time [17]. This, together with the pos-
sible progression to organ failure and of the development of some
cancer types, including primary liver cancer [9,11,18,19], makes
metabolic syndrome a relevant condition in clinical practice and a
major public health concern worldwide.
In 1999, European researchers [20–22] provided biological, clin-
ical and epidemiological evidence for the theory that NAFLD should
be regarded as the hepatic manifestation of the metabolic syn-
drome (Table 1) [20]. Since then, a “chicken and egg” scientific
debate has arisen, concerning the primacy of metabolic syndrome
(and insulin resistance) over NAFLD or, conversely, of NAFLD
over the metabolic syndrome [23]. Moreover, while most studies
acknowledge NAFLD to be a risk factor for T2D [24], the notion that
NAFLD anticipates the future development of components of the
metabolic syndrome other than T2D is far less accepted, although
it has been suggested by few authors [23,25,26] mainly based on
their expert opinion.
In our systematic review of the literature, we discuss all avail-
able data supporting the view that NAFLD, rather than being
a mere “manifestation of the metabolic syndrome” is indeed a
necessary precursor of the future development of metabolic syn-
drome in humans. To this end, further to identifying all relevant
cross-sectional studies, we specifically address the evidence from
prospective studies showing that NAFLD is an independent risk fac-
tor for the future development of both T2D and other components
of the metabolic syndrome. Methodological limitations of such data
are briefly analysed. Finally, we discuss how some examples of
dissociation of NAFLD from metabolic syndrome – seemingly con-
tradicting our thesis – eventually confirm the general paradigm of
NAFLD being a precursor of the metabolic syndrome.
2. Research strategy
The PubMed data base was manually searched for the follow-
ing terms: “Metabolic syndrome”; “Type 2 Diabetes”; “Obesity”;
“Dyslipidemia” “Hyperlipidemia”; “Insulin resistance”; “Predictor”;
“Fatty liver”; “Follow-up”; “Association” and “Dissociation”. The
research was updated at the 28th of April 2014. Further biblio-
graphic updates were performed whenever needed during the
revision process.
All of the identified articles and their references were further
checked in duplicate in order to identify appropriate articles. Per-
tinent studies were identified as a result of the agreement two
investigators, who also tabulated the methods and chief findings
of the selected material.
The accuracy of the tabulated data was independently per-
formed by all authors.
3. Association of NAFLD with other conditions
3.1. Type 2 diabetes
Many cross-sectional studies demonstrate that NAFLD is asso-
ciated with insulin resistance/pre-diabetes/T2D [27–39]. Despite
a variable follow-up range, data appear consistent in disclosing
that the “NAFLD pathway” to T2D follows a route characterized
by insulin resistance developing at various anatomic sites, notably
including hepatic insulin resistance. Interestingly, the NAFLD-
T2D association occurs irrespective of potential confounders and
particularly obesity and moderate alcohol drinking, suggesting
that NAFLD may closely mirror the development of fatty pan-
creas disease [40] and thus reflect tissue lipotoxicity. Moreover, a
quantitative relationship links fasting plasma glucose with NAFLD
prevalence: the higher the former, the higher the latter [29].
However, widely acknowledged predictors of T2D in non-NAFLD
populations (such as high fasting glucose and low HDL-cholesterol
and adiponectin, mirroring insulin resistance) and low physical
activity also predict T2D in NAFLD suggesting that NAFLD prob-
ably amplifies the physiological determinants of T2D. Finally, most
findings appear to be confirmed irrespective of ethnicity (e.g.
T2D-prone Asians vs. Caucasians) and of the diagnostic technique
followed to capture NAFLD, spanning from the most invasive or
accurate tests (liver histology, magnetic resonance imaging) to the
most insensitive (liver tests), via the most widely performed ultra-
sonography scanning.
However, the above studies [27–39] are cross-sectional. Accord-
ingly, they do not rule out the possibility that primarily impaired
gluco-regulation may eventually result in the development of
NAFLD. In order to clarify this issue, in Supplementary Table S-1
the studies showing NAFLD as a risk factor for the future devel-
opment of T2D were summarized. Eleven out of 12 studies were
conducted in Far East, most of them from Korea. With such a
limitation, they confirm that NAFLD is an independent risk factor
for the development of T2D, although confirmation from Western
countries appears necessary. Moreover, the diagnostic technique
used to detect NAFLD may lead to different results. For instance,

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Table 2
Nonalcoholic fatty liver disease and metabolic syndrome – the expanded spectrum of similarities.

NAFLD Metabolic syndrome

Increasing serum uric acid levels Are associated with increased prevalence and histological
severity of NAFLD [66–68]
High fructose consumption Is associated with increased prevalence of NAFLD and
increased NASH severity [83,84] owing to enhanced
lipogenesis, hepatic fibrosis, inflammation, endoplasmic
reticulum stress and lipoapoptosis [85]
TSH Clinical/subclinical hypothyroidism and elevated TSH,
though in the normal range, are associated with increased
prevalence and histological severity of NAFLD [89–92]
Bile acids Participate in the pathogenesis of NAFLD through
regulating hepatic nutrients and energy homeostasis;
stimulating GLP-1 secretion in the small intestine and
energy expenditure in brown adipose tissue and skeletal
muscle [98]. UDCA’s role in NASH management, however,
remains controversial [99,100]
Increased physical exercise Protects from NAFLD, independent of weight loss
[104–108] and improves histological steatosis [109]
Light to moderate alcohol consumption Is associated with a reduced prevalence of NAFLD and
NASH [3,117–120]
Caffeine Seemingly protects from NAFLD and liver fibrosis
[133–136] without decreasing the risk of NASH [134,135].
Beneficial liver outcomes are mediated by antioxidant,
antifibrogenic, antinflammatory, insulin sensitizing,
lipolytic, cyto, and genoprotective activity [137–142]
Smoking Risk factor for the development of NAFLD and its fibrotic
progression [146–148]
Altered sleep physiology Shorter sleep duration and severe obesity-related
obstructive sleep apnoea are independently associated
with development and histological severity of NAFLD
[150–152]
Brown adipose tissue Subjects maintaining active brown adipose tissue are
protected from NAFLD [157]
Intestinal microbiota May promote NASH by several mechanisms including
improved energetic efficiency; increased gut permeability
and production of lipopolysaccharides with activation of
the innate immune system; altered bile acids pool;
reduced bioavailability of dietary choline and increased
endogenous ethanol production [162–172]
Vitamin D deficiency Is associated with NAFLD development and the severity of
hepatic histological changes [189–192]
Are associated with increased prevalence and incidence of
metabolic syndrome [69–82]
Increases the risk of developing metabolic syndrome and
its components [86–88]
There is a close dose-dependent relationship between
increasing TSH and incident/prevalent metabolic
syndrome in various ethnicities and across different
age-groups [93–97]
Are powerful regulators of metabolism and induce
increased thermogenesis, protect from diet induced
obesity, hepatic lipid accumulation, and increased plasma
triglyceride and glucose levels via activation of Bile acids
receptors (FXR and TGR5) [101–103]
Protects from the development of and cures established
metabolic syndrome [110–116]
Seemingly protects from the development of at least some
components of the metabolic syndrome. Conversely, heavy
drinking increases the risk of metabolic syndrome
[121–132]
Reported to be a protective factor from metabolic
syndrome, maybe through a lipolytic effects of caffeine on
adipocytes [143–145].
Positively and reversibly associated in a dose-dependent
manner with the risk of metabolic syndrome [149]
Altered sleeping time duration and continuity are
associated with increased risk for the metabolic syndrome
[150,153–156]
The presence of brown adipose tissue is inversely related
to BMI. Brown adipose tissue activity plays a role in
constitutional leanness without affecting glucose
metabolism [158–161]
Plays a significant role in the development of metabolic
syndrome via increased energy harvesting, metabolic
endotoxinemia; control of lipid and glucose metabolism
via the composition of bile-acid pools and the modulation
of FXR and TGR5 signalling; modulation of intestinal
microbial composition by innate immune system;
“brain-gut enteric microbiota axis” [170,173–188]
May increase the risk for metabolic syndrome, type 2
diabetes, insulin resistance, obesity, hypertension and
cardiometabolic outcomes [193–198]

List of abbreviations: BMI, body mass index; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcholic steatohep-
atitis; TGR5, membrane-type G-protein-coupled receptor for bile acids; TSH, thyroid stimulating hormone; UDCA, ursodeoxycholic acid.

the less specific gamma-glutamyltransferase (GGT) values more
accurately predict the development of T2D than aminotransferase
levels. Similarly, the ultrasonographic severity of NAFLD is associ-
ated with increasing risks of T2D and, notably, NASH (more than
simple steatosis) appears to be more closely associated with T2D.
However, such a conclusion was challenged by a subsequent meta-
analysis by Musso et al. showing that the risk of developing T2D is
increased to a similar extent in both steatosis and NASH [41].
3.2. Other components of metabolic syndrome
Data reporting NAFLD as a risk factor for either some indi-
vidual components of metabolic syndrome [arterial hypertension
[42,43] and dyslipidemia [44]] or the full-blown syndrome are
less established than NAFLD progression to T2D. Many cross-
sectional studies support the view that NAFLD is associated with
the metabolic syndrome [13,22,45–64].
Data universally confirm the strong NAFLD-metabolic syndrome
association in humans. In addition, although each component of
metabolic syndrome [including serum uric acid, not included in
the diagnostic criteria but clearly a component of the syndrome
from a pathophysiological point of view [8]] is independently asso-
ciated with NAFLD, a few features (visceral obesity, dyslipidemia
and insulin resistance/T2D) are more closely related to NAFLD.
The association of NAFLD with the metabolic syndrome appears
to be stronger in lean than in obese individuals, especially in
women. NAFLD specifically anticipates the presence of metabolic
disorders and independently predicts insulin resistance, identify-
ing those individuals with insulin resistance who may be missed by
metabolic syndrome criteria in certain populations. The frequency
of metabolic syndrome significantly increases with quintiles of ALT
and GGT, even within the normal range of these enzymes [51].
Moreover, T2D and hypertriglyceridemia are more commonly asso-
ciated with raised hepato-biliary enzymes, and particularly GGT
[65], an association which appears to be independently mediated
by insulin resistance. In turn, the presence of metabolic syndrome
is associated with the development of fibrosis or NASH.
Again, association in cross-sectional studies does not provide
evidence as to which condition comes first. In order to address this
issue, studies supporting the view that NAFLD precedes the devel-
opment of metabolic syndrome are summarized in Supplementary
Table S-2.

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Collectively, they suggest that NAFLD, either diagnosed via sur-
rogate indices or by ultrasonography, antedates the presence of
several components of metabolic syndrome, not only of T2D. This
association is largely regulated by the presence of insulin resis-
tance. However, in 13 out of 15 such studies, NAFLD was diagnosed
on surrogate laboratory indices, on ultrasonographic findings in
two and in none by the gold standard liver biopsy technique. More-
over, the diagnostic criteria tended to be heterogeneous and given
that enlarged waist circumference is both a main pathogenic key
for NAFLD and is central for the diagnosis of metabolic syndrome, it
is virtually impossible to rule out the possibility that visceral obe-
sity links the development of both NAFLD and metabolic syndrome.
Finally, no specific traits of the metabolic syndrome (dysglicemia,
dyslipidemia, high blood pressure and central obesity) are manda-
tory for the development of the full-blown metabolic syndrome
(Supplementary Table S-2).
4. Does NAFLD precede metabolic syndrome? Insulin
resistance as a major player
Compared to our “historical” perception (Table 1), present
understanding of the epidemiological, clinical and pathogenic simi-
larities between NAFLD and the metabolic syndrome has expanded
to a substantial extent. Accordingly, it presently embraces a large
number of risk/protective factors and biological mediators, i.e.,
serum uric acid, fructose, TSH, bile acids, physical exercise, alco-
hol, caffeine, smoking, altered sleep physiology, brown adipose
tissue, intestinal microbiota and vitamin D deficiency (Table 2)
[66–198]. Associations of these factors with NAFLD may mirror
different pathophysiological mechanisms underlying the natural
course leading from NAFLD to metabolic syndrome.
Phylogenetically evolved to promote survival, insulin resistance
will lead to the deleterious manifestations of the metabolic syn-
drome whenever inappropriately activated by unhealthy lifestyles
[199]. Clinically, insulin resistance is defined as the critical
connector linking stress, visceral adiposity, and decreased cardio-
respiratory fitness with increased cardiovascular disease [14].
Biologically, elevated fasting glucose will result from hepatic
insulin resistance, whereas increased free fatty acids (FFA) con-
centrations are the expression of peripheral insulin resistance
[200]. At molecular level, insulin resistance invariably results from
the interaction of cell membrane receptors with either excess
nutrients or inflammatory cytokines. Such an interaction will
trigger JNK and IKK, protein kinase C, S6K, mTOR, and ERK. All
these pathways are involved in the amplification of inflamma-
tion, phosphorylation of insulin receptor substrates 1 and 2, stress
of endoplasmic reticulum, production of reactive oxygen species
and mitochondrial dysfunction [201]. Once triggered, this vicious
circle of systemic metabolic dysfunction of insulin and leptin
action tends to self-perpetuate [202]. Impaired intracellular insulin
signalling will eventually result in perturbed Glut-4-mediated
glucose uptake with preserved/potentiated MAP kinase-mediated
mitogenesis/cell survival pathways [200].
First proposed, as early as 1988, as the underlying factor in
the metabolic syndrome [203], insulin resistance undoubtedly
plays a major role in the pathophysiology of the metabolic syn-
drome [204]. The expansion of visceral adipose tissue will result
in the liver being overflowed with FFA, thus leading to steato-
sis. A fatty liver, in turn, is the prerequisite for the development
of highly atherogenic dyslipoproteinemia featuring low HDL-
cholesterol, hypertriglyceridemia and increased small and dense
low-density lipoprotein (LDL) particles, as well as for fasting hyper-
glycemia, which stimulates the pancreas to compensatory insulin
over-secretion. Collectively, increased FFA concentrations, hyper-
glycemia and hyper-insulinemia may directly (or indirectly via
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sympathetic over-activation) promote arterial hypertension and
ectopic deposition of fat in extra-adipose tissues. More importantly,
the described metabolic derangements are intimately associated
with increased production of fibrinogen, PAI-1, TNF-alpha, IL-6 and
decreased adiponectin levels. A subclinical pro-inflammatory pro-
atherogenic state will ensue, which is a major biological feature of
insulin resistance and a typical hallmark of the metabolic syndrome
[204].
While most individuals with NAFLD have insulin resistance
[13,205], only a minority of those with NAFLD exhibit the full-
blown metabolic syndrome [206]. This finding most likely results
from fatty liver being a precursor [207] and a necessary prerequisite
to the development of progressive metabolic disease [23,208–210].
Adipose tissue is the only physiologic reservoir of fatty acids, and
the accumulation of fat in the extra-adipose tissues may be tissue-
damaging and eventually lead to organ dysfunction (a concept
alluded to as “lipotoxicity”). Data from a mouse model support the
view of fatty liver being a protective mechanism which prevents
progressive liver damage in NAFLD [211] suggesting that esterifica-
tion into triglycerides might well be a mechanism which detoxifies
histologically damaging FFA in the liver. Further evidence for the
concept that fatty liver is an adaptive phenomenon derives from its
occurrence in animal species other than humans suggesting that
steatosis is evolutionarily “useful” [212–215].
Characterization of the role of PKC␧ is probably the most exciting
progress in our understanding of the molecular pathogenesis of the
connection linking liver steatosis with hepatic insulin resistance.
In obese humans, fatty substrates such as diacylglycerol account
for 64% of the variability of insulin sensitivity via the activation
of PKC␧ [216], which impairs insulin signalling as shown in rats
using antisense oligonucleotides [217]. Of outstanding interest, the
intracellular compartmentation of diacylglycerol dictates whether
or not PKC␧ will translocate to the plasma membrane so promoting
hepatic insulin resistance [218]. Stated otherwise, various classes of
lipids (such as mono-, di- and tri-acylglycerol) sequestered within
lipid droplets/Endoplasmic reticulum fraction are deemed to be
innocuous as far as the development of hepatic insulin resistance
is concerned in the CGI-58 knockdown mouse model [219].
In humans, however, most cases of NAFLD are strongly
associated with insulin resistance. In agreement, diacylglycerol
acyltransferase 2 (DGAT2), the enzyme catalysing the final step
in the biosynthesis of triglycerides, may link glycemia and triglyc-
eridemia [220]. These data are fully consistent with the view that
the development of a fatty liver occurs upstream in the chain of
metabolic events eventually leading to the development of the
metabolic syndrome [210] and help understand the mechanistic
reason why subjects with NAFLD were 1.6 times more likely to
develop T2D than NAFLD-free persons in a recent 3-year follow-
up Japanese study [221]. Of clinical interest, a growing number
of components of the metabolic syndrome are associated with an
increased risk of hepatic fibrosis in the individual patient [222]
thus enabling the identification of those who should undergo liver
biopsy [223]. In particular, data have shown that a vicious cir-
cle links T2D and liver disease, with NAFLD contributing to the
future development of T2D and the latter triggering progressive
liver injury [40]. Fatty pancreas develops in the setting of metabolic
syndrome, carrying amazing similarities to NAFLD in terms of organ
inflammation, end-stage organ failure, susceptibility to cancer and
post-surgical complications [224].
Lipid droplets display a unique protein repertoire including
Adipophilin and TIP47 which, further to fatty adipocytes, are
expressed in lipid droplets of hepatic stellate cells. Perilipin, once
deemed to be characteristic of lipid droplets in the adipocytes and
steroidogenic cells, is expressed de novo in liver cells of steatotic
liver in humans [225]. The finding that the distribution of perilipin
is predominantly perivenous in the liver lobule [225] may suggest
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Fig. 1. Primacy of nonalcoholic fatty liver disease over metabolic syndrome. Based on epidemiological and biological data discussed in the text, the cartoon schematically
illustrates the theory of nonalcoholic fatty liver disease being the precursor of metabolic syndrome. Although not included in current diagnostic criteria of metabolic
syndrome, uric acid is definitely a trait of the metabolic syndrome constellation from a pathophysiological point of view and a determinant of development and progression
of nonalcoholic fatty liver disease, as discussed in Table 2. The key-role of lipid droplets in potentially protecting fatty liver from developing insulin resistance is highlighted
based on recently published data [218,219].

a specific role of this protein in the four-step model of histoge-
netic events originally proposed by Wanless to account for NASH
pathogenesis and its progression to cirrhosis via hepatic venular
obstruction [226]. Perilipin has been confirmed by following stud-
ies as one of the most prominent upregulated genes in NAFLD [227].
In summary, alterations in the regulation of lipid droplets phys-
iology and metabolism influence the risk of developing metabolic
diseases such as T2D and NAFLD [227]. Fig. 1 illustrates the hypoth-
esis that NAFLD is a precursor of the metabolic syndrome via insulin
resistance resulting from PKC␧ activation which conceivably occurs
in most cases of NAFLD in humans.
If the “general rule” is that steatosis and insulin resistance are
associated, are there any examples of such two conditions being
dissociated from each other?
5. Dissociation of NAFLD from insulin resistance and the
metabolic syndrome
The first clinical evidence for conditions where high-grade
steatosis occurs without insulin resistance or low-grade liver fat
content is nonetheless associated with insulin resistance was
reported in 2006. This conclusion was reached by comparing insulin
resistance (assessed by HOMA-IR) and steatosis grade in three nat-
urally occurring different conditions displaying a variable extent
of steatosis: familial hypobetalipoprotenemia (FHBL), NAFLD and
steatosis (evaluated histologically) associated with HCV infection
[228]. In 2010 Amaro et al. measuring insulin resistance with the
hyperinsulinemic-euglycemic clamp procedure coupled with glu-
cose tracer infusion and liver fat content with magnetic resonance
(MR) spectroscopy, confirmed the results in FHBL individuals [229].
Of interest, circumstantial evidence suggests that FHBL is associ-
ated with progressive liver disease only in those patients featuring
components of the metabolic syndrome [230].
Consistent with the potential occurrence of steatosis dissoci-
ated from insulin resistance, Kantartzis et al. reported that single
nucleotide polymorphisms in the diacylglycerol acyltransferase 2
(DGAT2) gene accounted for variability in liver fat content rather
than for insulin resistance. These results confirm and extend
to humans the finding that DGAT2 mediates the dissociation
between fatty liver and insulin resistance [231]. The same group
of researchers reported that the patatin-like phospholipase 3 gene
(PNPLA3) is a key factor in determining whether fatty liver is associ-
ated or not with metabolic derangements such as insulin resistance
[232].
Finally, PNPLA3 gene polymorphisms have recently been associ-
ated with those NAFLD cases occurring in the absence of metabolic
syndrome [233], indirectly suggesting that genetic conditions
which promote the development of fatty changes in the liver may
occur independently of insulin resistance.
A detailed survey of those studies demonstrating a dissocia-
tion of fatty liver and T2D in both experimental conditions and
humans has recently been published by Sun et al. [234]. Collec-
tively, findings from both genetically engineered animal models
and humans with genetic conditions confirm the view that the aeti-
ology of steatosis is a major determinant of whether steatosis is
associated (such as seen in most cases of NAFLD observed in clin-
ical practice) or dissociated from insulin resistance and features
of the metabolic syndrome (such as seen in NAFLD occurring in
carriers of PNPLA3 gene polymorphisms and in FHBL individuals)
[228,233,234]. As schematically depicted in Fig. 1, compartmenta-
tion of intrahepatocytic lipids may potentially account for the end
result of NAFLD being either associated or dissociated from insulin
resistance [218,219] and therefore from the risk of developing
the metabolic syndrome. Once fully characterized in humans, the
sub-cellular mechanisms of dissociation of steatosis from insulin
resistance may become a preferential target for the prevention and
management of insulin resistance and the metabolic syndrome.
6. Conclusions
A systematic review of the literature shows that the presence of
NAFLD is intimately linked with the metabolic syndrome, including

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T2D. Moreover, NAFLD is a strong determinant for the future devel-
opment of the metabolic syndrome. This is likely to occur as a
result of its being a key factor associated with insulin resistance
in naturally occurring conditions in humans. Exceptions to such
a theory are found in some genetic polymorphisms where the
steatosis-insulin resistance-metabolic syndrome triad is dissoci-
ated in humans. The molecular biology of events dictating NAFLD
being associated with or dissociated from insulin resistance is
increasingly being elucidated.
On these grounds, the diagnostic importance of NAFLD as a cri-
terion for the presence, as well as for risk of future development
of metabolic syndrome, needs to be emphasized. From a thera-
peutic point of view, those pathogenic-based interventions aimed
at reversing NAFLD are likely to be a rational approach in the
prevention and treatment of hepatic insulin resistance, metabolic
syndrome and related complications.
Conflict of interest
None declared.
Acknowledgement
This article is devoted to the memory of late Professor Paola
Loria, M.D. The authors are grateful to Dr Leon Adams for invaluable
advice and thank Elisa Gibertini for kind assistance as a graphic
artist.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.dld.2014.09.020.
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