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Diabetes & Metabolism 40 (2014) 95–107

Review

Adiponectin: A multitasking player in the field of liver diseases

T.E. Silva ∗ , G. Colombo , L.L. Schiavon
Division of Gastroenterology, Federal University of Santa Catarina Campus, Universitário Reitor João David Ferreira Lima,
Trindade Florianópolis, SC, Brazil 88040970
Received 25 September 2013; received in revised form 19 November 2013; accepted 21 November 2013

Abstract
Adiponectin is the most abundant adipokine synthesized by adipose tissue and has been shown to be a key component in the relationship
between adiposity, insulin resistance and inflammation. It circulates in plasma at physiological concentrations that represent 0.05% of all plasma
proteins. Adiponectin has trimeric, hexameric and multimeric forms that bind to receptors AdipoR1, AdipoR2 and T-cadherin especially in liver,
muscle and endothelial cells. Adiponectin is considered a potent modulator of lipid and glucose metabolism with antidiabetic, antiatherogenic and
anti-inflammatory properties, and plays an important role in the pathogenesis of metabolic diseases. The hepatoprotective effects of adiponectin,
especially in non-alcoholic fatty liver disease (NAFLD), have been widely investigated, and its antisteatotic, anti-inflammatory and antifibrogenic
effects have already been described. Adiponectin levels are reduced in individuals with fatty liver disease independently of body mass index, insulin
resistance and other adipokines, and are inversely related to the severity of steatosis and necroinflammation, suggesting an important role in the
relationship between adipose tissue, the liver and insulin sensitivity. Adiponectin has also been found to be reduced in cases of hepatitis B and C
infection, and in cholestatic and autoimmune diseases, but is increased in patients with cirrhosis of different aetiologies. In addition, an important
role for the liver in the regulation of adiponectin secretion by adipocytes, mediated by bile acids, has recently been proposed. The present report
describes the importance of adiponectin in hepatic diseases as well as some future perspectives of the role of adiponectin as a biomarker and
therapeutic target in liver diseases.
© 2013 Elsevier Masson SAS. All rights reserved.

Keywords: Adiponectin; Liver disease; Cirrhosis; Non-alcoholic fatty liver disease; Bile acids

1. Introduction The progression of liver diseases and fibrogenetic processes is

caused by the excess accumulation of extracellular matrix prod-
Liver diseases are among the 10 main causes of mortality ucts in the liver, the result of persistent activation of inflammation
worldwide and the fifth most common cause of death in the and tissue-repair mechanisms [4]. Among the features of liver
UK, after heart disease, stroke, respiratory diseases and can- fibrogenesis, the importance of metabolic factors, especially
cer [1]. Viral hepatitis is the main cause of liver disease, with those related to obesity, is becoming increasingly accepted. Adi-
an estimated 180 million individuals infected by hepatitis C pose tissue is not only a deposit for lipids, but also a recognized
virus (HCV) [2] and 350 million infected by hepatitis B virus and important source of hormones that influence body adiposity,
(HBV) worldwide [3]. In addition, as a result of increasing glucose homoeostasis, inflammation and cardiovascular disease
rates of obesity in populations all over the world, non-alcoholic [5]. Adipocytes secrete several types of adipokines, including
steatohepatitis (NASH) due to non-alcoholic fatty liver dis- leptin [6], adiponectin [7], adipsin [8], resistin [9], visfatin [10],
ease (NAFLD) is becoming a major public-health problem [1]. tumour necrosis factor-alpha (TNF-␣) [11] and plasminogen
Together with abusive alcohol consumption, these diseases are activator inhibitor type 1 (PAI-1) [12].
important risk factors for the development of cirrhosis and hepa- Since its discovery, adiponectin has proved to be a key compo-
tocellular carcinoma (HCC) [1]. nent in the relationship between adiposity and insulin resistance
(IR) [5]. The hepatoprotective effects of adiponectin in NAFLD
have been widely investigated, and several recent studies eval-
∗ Corresponding author. Rua Eliseu Guilherme, 160 Coqueiros Florianopolis,
uating the relationship between adiponectin levels and other
SC, Brazil 88080825. Tel.: +55 48 91014068; fax: +55 48 33343588.
E-mail addresses: telma.gastro@gmail.com, dratelma.gastro@gmail.com
liver diseases, such as chronic viral hepatitis, liver cirrhosis and
(T.E. Silva). autoimmune liver diseases, have also been published. In addition

1262-3636/$ – see front matter © 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.diabet.2013.11.004
96 T.E. Silva et al. / Diabetes & Metabolism 40 (2014) 95–107

to its influence in the progression of those diseases, the evidence Despite its abundant presence in plasma, adiponectin is cleared
also suggests an important role of the liver and bile acids in the rapidly with a half-life of around 75 min [28]. It interacts
regulation of adiponectin synthesis and release by adipocytes. with an adaptor protein containing a pleckstrin homology
The physiological actions of adiponectin and its role in chronic domain (APPL1) [29], and provokes activation of AMPK
liver diseases are discussed here. and peroxisome proliferator-activated receptor-alpha (PPAR-␣).
Adiponectin also provokes several signalling molecules in most
2. Biological actions of adiponectin tissues, including skeletal muscle, liver, heart, endothelium,
adipocytes and brain [18,30–33], thereby increasing glucose
Adiponectin, identified by four independent groups in 1995 uptake in muscle, decreasing hepatic glucose production (gluco-
and initially called apM1, ACRP30, AdipoQ and GBP28 neogenesis), and increasing fatty acid oxidation in muscles and
[7,13–15], is a 28-kDa protein composed of 274 amino acids the liver [30,34]. This leads to lowered IR as a result of decreased
[13] and encoded by the ADIPOQ gene, located on the long triglycerides in muscles and liver [35]. Adiponectin also inhibits
arm of human chromosome 3, locus 3q27 [16]. It comprises an endothelial NF-␬B signalling and proinflammatory cytokines
amino-terminal signal sequence, a variable region, a collagen- such as IL-6 and TNF-␣, while stimulating anti-inflammatory
like domain (cAd) and a carboxyl-terminal globular domain cytokines such as IL-10 [19,21,36]. Thus, adiponectin is consid-
(gAd) [13]. Adiponectin in the circulation has two isoforms: ered a powerful metabolic modulator of glucose and lipids with
full-length adiponectin (fAd); and a globular fragment (a pro- antiatherogenic, antidiabetic and anti-inflammatory properties,
teolytically cleaved fragment consisting of gAd) [17,18]. The and plays a role in the regulation of glucose and lipid homoeosta-
globular fragment is present in small amounts in plasma and sis (Fig. 1). This means it is important in the pathogenesis of
increases free fatty acid oxidation in muscle tissue, an impor- metabolic diseases [37].
tant mechanism for the control of energy homoeostasis [17], Adiponectin secretion varies with circadian rhythm [38]
while fAd has the capacity to group globular domains into and is influenced by hormones such as prolactin [39], growth
three isoforms: trimeric (low molecular weight); hexameric hormone [39], testosterone [40] and osteocalcin [41] as well
(middle molecular weight); and multimeric (high-molecular- as by beta-adrenergic agonists [42] and glucocorticoid treat-
weight) [18,19]. Each oligomeric form has distinct biological ments [43]. Women have higher levels of adiponectin than
properties and activates different cellular signalling pathways in men possibly because of the effects of sex hormones, their
several tissues [19]. The monomeric (30-KDa) form appears to greater subcutaneous fat accumulation and higher percentage
be confined to adipocytes and has not been observed in circu- of body fat. This leads to increased sensitivity to insulin and
lation [20], while only the trimeric form activates adenosine lipogenesis [44]. Testosterone selectively reduces the high-
monophosphate-activated kinase protein (AMPK) in skeletal molecular-weight form of adiponectin by inhibiting its secretion
muscle, reduces interleukin (IL)-6 secretion and stimulates IL- by adipocytes [45].
10 secretion [18,19]. Surprisingly, the hexameric and multimeric Adiponectin secretion is inversely correlated with body mass
isoforms both activate the nuclear factor-kappa B (NF-␬B) path- index (BMI) [46], with higher adiponectin levels in non-obese
way, which mediates IL-6 induction [21,22]. Although IL-6 is than obese people [46,47]. Elevated levels were observed in
usually associated with IR, some reports have paradoxically patients with anorexia nervosa [48]. Adiponectin is thought to
suggested that IL-6 contributes to improved insulin sensitivity have protective effects against the metabolic syndromes and type
[22,23]. One of the proposed mechanisms is a transient rise in 2 diabetes mellitus (DM2) [49,50]. Increased adiponectin lev-
IL-6 levels, leading to insulin receptor substrate (IRS)-2 upre- els after bariatric surgery suggest that its expression is subject to
gulation and enhanced insulin signalling in the liver, possibly feedback inhibition in obesity [51,52]. As obese individuals have
by an as yet unidentified adiponectin receptor [22]. Multimeric more body fat, adipocyte hypertrophy and macrophage infil-
adiponectin is the active form of the protein in the mediation of tration of adipose tissue activates proinflammatory cytokines
several of its activities, especially insulin sensitivity [24]. Cen- (TNF-␣, IL-6, IL-10) and nitric oxide [53,54]. These alterations
tral nervous system (CNS) activities of adiponectin are attributed can lead to a reduction in the expression of adiponectin mRNA
to the trimeric and hexameric forms [25]. and adiponectin release from adipocytes [46]. Adiponectin and
The effects of adiponectin are mediated by membrane recep- TNF-␣ are mutually inhibited, and the expression of adiponectin
tors/proteins called AdipoR1, which is abundantly expressed is suppressed by IL-6 [36,55]. The latter is characterized by a
in skeletal muscle, and AdipoR2, which is predominantly decrease in insulin-sensitizing and anti-inflammatory adipocy-
expressed in the liver [26]. AdipoR1 has a high affinity for glob- tokines such as adiponectin, with an increase in proinflammatory
ular fragments and a low affinity for fAd, whereas AdipoR2 has adipocytokines such as TNF-␣, IL and resistin [56]. This may
an intermediate affinity for both fAd and gAd [26]. Adiponectin explain why obese people have lower circulating levels of
also binds to T-cadherin, a receptor for hexameric and high- adiponectin despite the fact that adipose tissue is responsible for
molecular-weight forms of adiponectin expressed in endothelial its synthesis [46]. Adipocytokine dysregulation plays a crucial
and smooth muscle cells [27], and the underlying factor for some role in metabolic syndromes [57].
of the antiatherogenic and vasoprotective actions of adiponectin The association between high adiponectin levels and low
[5]. DM2 risk was confirmed in a meta-analysis by Li et al. [58].
Adiponectin circulates through plasma at physiological con- Adiponectin levels are significantly reduced in patients with
centrations that represent 0.05% of total serum protein [13]. DM2 and increased after treatment with insulin-sensitizing
 T.E. Silva et al. / Diabetes & Metabolism 40 (2014) 95–107 97

Fig. 1. Adiponectin isoforms and their main biological actions.

agents (thiazolidinediones). These agents stimulate synthe- multitude of metabolic processes such as atherosclerosis, IR and
sis of adiponectin by activating the synthesizing peroxisome diabetes [61], and as an important player in NAFLD and its pro-
proliferator-activated receptor-gamma (PPAR-␥) agonist, thus gression to NASH [62]. Adiponectin is a potent stimulator of
boosting insulin sensitivity [59]. Recently, the importance of the ceramidase activity and enhances ceramide catabolism [63].
fibroblast growth factor (FGF) 21–adiponectin–ceramide axis Individuals with higher concentrations of adiponectin also
in the control of energy expenditure and insulin action was present with lower cardiovascular risk [64,65]. Low plasma
highlighted [60]. So too has the role of sphingolipids such as adiponectin levels are associated with progression of subclini-
ceramides and glucosylceramides as an important class of bioac- cal coronary atherosclerosis in type 1 diabetic and non-diabetic
tive lipids, the accumulation of which has been implicated in a subjects independently of other cardiovascular risk factors [65],
98 T.E. Silva et al. / Diabetes & Metabolism 40 (2014) 95–107

whereas mutations of the adiponectin gene related to low hor- of hepatic dysfunction in asymptomatic people [90,91]. In
mone levels have been identified and associated with DM2 [66] women, a negative correlation between adiponectin and GGT
and NAFLD [67]. was observed [91,92] as well as a positive correlation between
GGT and homeostasis model assessment-estimated insulin
3. Adiponectin levels in selected liver diseases resistance (HOMA–IR) [92].
Thus, the liver represents an important target wherein
Several studies have reported that the disruption of adipocy- adiponectin participates in the control of various events such
tokines affects liver disease. Indeed, leptin and TNF-␣ levels as metabolism, inflammation and fibrosis. The adipokine also
are significantly higher, while adiponectin and ghrelin levels appears to exert distinctive effects in different liver diseases and
are lower, in patients with NASH compared with controls [68]. appears to be significantly influenced by liver function. The fol-
Other studies have shown obesity to be an independent risk fac- lowing is a discussion of the relevance of adiponectin in the
tor for fibrosis in chronic liver diseases such as NASH [69], most important liver diseases, and its future possibilities as a
alcoholic liver disease [70] and chronic HCV infection [71]. biomarker and therapeutic target.
Despite low levels of adiponectin being related to several hepatic
diseases, mainly NAFLD [72,73], cirrhosis patients of any aeti- 3.1. NAFLD
ology paradoxically have high levels of this adipokine [74,75],
suggesting an independent mechanism by which the liver exerts a This common cause of chronic liver disease in many coun-
regulatory effect on the release and/or degradation of circulating tries comprises a wide spectrum of liver damage, including
adiponectin. simple steatosis and NASH, with the possibility of progression
While the liver is most likely not a relevant source of cir- to cirrhosis and HCC [93,94]. NAFLD is present in 17–40% of
culating adiponectin, it is nonetheless a major target organ for various populations and NASH may be found in one-third of
many adiponectin effects, including regulation of steatosis, IR, all NAFLD cases. The rate of cirrhosis development in cases of
inflammation and fibrosis [76]. The role of adiponectin in liver NASH are reported to range from 5% to 20% over a period of
disease was first studied in animal models, which showed that 10 years and, once cirrhosis is established, the mortality rate
adiponectin improved hepatomegaly, steatosis and aminotrans- is between 12% and 25% over a period of 7–10 years [95].
ferases in mice with NAFLD [77] and liver fibrosis induced by Currently, NASH is the third most common indication for liver
carbon tetrachloride [78]. Adiponectin liver-protective proper- transplantation in the USA, with rates that have risen from 1.2%
ties, as described in several clinical and animal studies, include of the total number of transplants in 2001 to 9.7% in 2009
antisteatotic [77], anti-inflammatory [79] and antifibrotic [78] [96].
effects (Table 1). Table 2 summarizes the main clinical studies investigating
The antisteatotic effect results partly from the ability of the relationship between adiponectin and NAFLD. In a meta-
adiponectin to increase carnitine palmitoyltransferase-1 (CPT1) analysis of 27 studies and a total of 2243 subjects, Polyzos et al.
activity and enhance hepatic fatty acid oxidation, while reduc- [107] revealed that serum adiponectin was higher in controls
ing the activities of two key enzymes involved in fatty acid than in NAFLD or NASH patients and higher in NAFLD com-
synthesis—namely, acetyl-CoA carboxylase and fatty acid syn- pared with NASH patients. However, adiponectin levels were
thase [77]. It also suppresses the expression of sterol regulatory similar between controls and simple steatosis patients when only
element-binding protein (SREBP)-1c, the master regulator that controls subjected to liver biopsy were analyzed. These findings
controls and upregulates enzymes involved in fatty acid syn- suggest an important pathophysiological role of hypoadiponecti-
thesis [80]. The anti-inflammatory effect of adiponectin is naemia in the progression from NAFLD to NASH, although the
associated with inhibition of the synthesis and/or release of role of this adipocytokine in the development of NAFLD (simple
TNF-␣ (so preventing lipopolysaccharide-induced liver injury) steatosis) remains unclear [107].
[81] and induction of IL-10 [84]. Adiponectin also exhibits Levels of adiponectin and AdipoR2 mRNA expression
antifibrotic properties by suppressing the proliferation and were significantly reduced in liver biopsies from patients
migration of stellate cells through attenuation of the expression with NASH compared with patients with simple steatosis
of transforming growth factor beta 1 (TGF-␤1), a regulator of [101]. Furthermore, hypoadiponectinaemia was associated with
extracellular matrix synthesis [78,87,88]. NASH independently of BMI, IR and other adipokines such
In healthy people, adiponectin levels were negatively as TNF-␣ [68,73,100]. Some studies have found an association
correlated with alanine aminotransferase (ALT) and gamma- between adiponectin levels and histological severity, with an
glutamyltransferase (GGT) levels before and after adjusting for inverse relationship between adiponectinaemia and intensity of
gender, age, BMI and IR, which suggests a contribution of steatosis and necroinflammatory activity in patients with NASH
adiponectin to the maintenance of liver integrity through regu- [72,73,100]. The relationship between low levels of adiponectin
lation of both insulin sensitivity and/or inflammatory responses and fibrosis in patients with NASH, however, remains contro-
[89]. Indeed, studies in healthy subjects show a positive cor- versial [72,73,100,108]. These findings are supportive of a role
relation between visceral fat and liver enzymes in both men for low circulating adiponectin in the pathogenesis of NAFLD,
and women [90], and a significant negative correlation between and confirm the strong association among reduced adiponectin
adiponectin and liver enzymes in men, suggesting that visceral production by adipose tissue, NAFLD and IR, together with
obesity and hypoadiponectinaemia are significant determinants the hypothesis that an imbalance between proinflammatory and
 T.E. Silva et al. / Diabetes & Metabolism 40 (2014) 95–107 99

Table 1
Proposed liver-protective effects of adiponectin (Ad).
Reference Year Subjects Effects

Antisteatotic
Xu et al. [77] 2003 Animals Increases CPT1 activity, enhances hepatic fatty acid oxidation, decreases activity of two enzymes involved
in fatty acid synthesis: acetyl-CoA carboxylase and fatty acid synthetase
Awazawa et al. [80] 2009 Animals Suppresses expression of SREBP-1c, which controls and upregulates enzymes involved in fatty acid
synthesis
Anti-inflammatory
Xu et al. [77] 2003 Animals Suppresses hepatic production and plasma concentrations of TNF-␣
Masaki et al. [81] 2004 Animals Prevents lipopolysaccharide (LPS)-induced hepatic injury by inhibiting synthesis and/or release of TNF-␣
in KK-Ay obese mice
Matsumoto et al. [82] 2006 Animals Suppresses TNF-␣ production and induces IL-10 production by Kupffer cells in response to LPS stimula-
tion; lack of adiponectin enhances LPS-induced liver injury
Wolf et al. [83] 2006 Animals Upregulated Ad expression in concanavalin A-mediated acute liver failure, so may play a role in con-
trol/limitation of liver inflammation, suggesting a role in Ad-mediated IL-10 induction
Mandal et al. [84] 2010 Animals gAd prevents LPS-stimulated TNF-␣ expression in Kupffer cells via activation of IL-10/STAT3/HO-1
pathway
Nepal et al. [85] 2012 Animals gAd prevents ethanol-induced apoptosis in human hepatoma (HepG2) cell lines via HO-1 induction,
revealing a novel biological gAd liver-protective response against alcohol abuse
Ouchi et al. [36] 2000 Humans Modulates inflammatory response of endothelial cells via crosstalk between cAMP–PKA and NF-␬B
pathways
Ouchi et al. [79] 2001 Humans Suppresses macrophage-to-foam cell transformation, so may act as a modulator
Antifibrotic
Kamada et al. [78] 2003 Animals Attenuates liver fibrosis induced by carbon tetrachloride through reduction of TGF-␤1 effects in hepatic
stellate cells (HSC)
Ding et al. [86] 2005 Animals May reverse HSC activation, maintain HSC quiescence and, significantly, have important therapeutic
implications for liver fibrosis
Adachi et al. [87] 2008 Humans Ad and AMPK inhibit HSC proliferation and hepatic fibrosis via multiple molecular mechanisms
Shafiei et al. [88] 2011 Animals PPAR-␥ effect on HSC activation and fibrogenetic cascade may be Ad-dependent, but Ad inhibition of
HSC activation is not dependent on PPAR-␥, suggesting PPAR-␥-dependent and -independent pathways
in HSC

CPT1: carnitine palmitoyltransferase-1; SREBP-1c: sterol regulatory element-binding protein 1c; gAd: globular adiponectin; STAT3/HO-1: signal transducer and acti-
vator of transcription 3/heme oxygenase 1; cAMP–PKA: cyclic adenosine monophosphate–protein kinase A; NF-␬B: nuclear factor-kappaB; TGF-␤1: transforming
growth factor beta 1; AMPK: adenosine monophosphate-activated kinase protein; PPAR-␥: peroxisome proliferator-activated receptor-gamma.

anti-inflammatory cytokines may have a pathogenetic role in were associated with a 12-fold greater risk of NASH [104]. How-
the development of liver damage in NAFLD [99]. ever, adiponectin exhibited an AUROC of only 0.654 with high
Given the importance of adiponectin in the pathophysio- specificity (95.8%), but low sensitivity (36.4%), for predicting
logy of NAFLD, some studies have assessed the relevance of NASH. A formula combining adiponectin, leptin and ghrelin
these adipokine levels for the identification of NASH in NAFLD showed good accuracy for NASH with an AUROC of 0.789,
patients. The association between adipokines and the presence a specificity of 76.1% and a sensitivity of 81.8% [104]. Shi-
of NASH was assessed using non-invasive diagnosis by the mada et al. [110] observed that the combination of adiponectin,
so-called NASH test. The most important predictors of bor- HOMA–IR and serum type IV collagen presented with high sen-
derline NASH were adiponectin and high-density lipoprotein sitivity and specificity for a steatohepatitis diagnosis (94% and
(HDL) as protective factors and, as risk factors, leptin, abdom- 74%, respectively).
inal obesity, triglycerides and glycosylated haemoglobin. The Recent studies have demonstrated an association between
area under the receiver operating characteristic (AUROC) curve NASH and increased bile acids [111,112]. Bechmann et al. [106]
for predicting NASH was 0.75 for leptin [confidence inter- noted that, in obese patients with NAFLD, bile acid synthesis
val (CI): 0.7–0.8] and 0.74 for adiponectin (CI: 0.68–0.80). and serum bile acid levels directly correlated with disease sever-
Taken together, adiponectin and leptin exhibited an AUROC ity, while an inverse correlation was found with adiponectin. In
of 0.81 (CI: 0.76–0.86), demonstrating that the combination their study, adiponectin levels < 29.16 ng/mL were associated
of these two adipokines had predictive value for early-stage with histological severity, higher bile acid levels, lower expres-
NASH [109]. Another study evaluating liver histology in mor- sion of bile acid metabolism-related genes and increases in the
bidly obese individuals found that adiponectin levels < 23 ng/mL cytochrome P450 7A1 (CYP7A1) enzyme responsible for bile
100 T.E. Silva et al. / Diabetes & Metabolism 40 (2014) 95–107

Table 2
Clinical studies of adiponectin (Ad) in non-alcoholic fatty liver disease (NAFLD).
Reference Year Disease Subjects (n) Primary findings

Hui et al. [73] 2004 NAFLD 191: 80 with NASH, 29 with simple Hypoadiponectinaemia is a feature of NASH indepen-
steatosis, 82 controls dent of IR; reduced Ad levels are associated with
more extensive necroinflammation and may contribute
to necroinflammatory forms of NAFLD
Targher et al. [97] 2004 NAFLD 68 obese: 43 with steatosis, 25 without Decreased plasma Ad levels are closely correlated with
steatosis, by ultrasonography NASH in healthy obese individuals
Bugianesi et al. [98] 2005 NAFLD 216: 174 with NAFLD, 42 controls Hypoadiponectinaemia in NAFLD is part of a metabolic
disturbance characterized by ectopic fat accumulation in
the central compartment
Pagano et al. [99] 2005 NAFLD 37: 9 with steatosis, 8 with NASH, 20 Low circulating Ad in pathogenesis of NAFLD; confir-
controls mation of close association between reduced Ad
production by adipose tissue, NAFLD and IR
Musso et al. [100] 2005 NASH 65: 20 with NASH, 30 insulin- Hypoadiponectinaemia is a feature of NASH and may
sensitive controls, 15 insulin-resistant have pathogenetic role in beta-cell dysfunction, hepatic
controls necroinflammation and fibrosis independent of IR, vis-
ceral fat accumulation, TNF-␣ axis activity and dietary
habits
Kaser et al. [101] 2005 NASH after 22: 13 with NASH, 9 with steatosis Reduced hepatic expression of Ad and adipoR2 may have
bariatric surgery pathophysiological relevance in NAFLD
Kim et al. [102] 2005 NAFLD 213: 75 with NAFLD by ultrasonogra- Serum Ad level and baPWV are significantly associated
phy, 138 controls with NAFLD and various liver enzymes, especially in
women
Targher et al. [72] 2006 NAFLD 120: 50 with NASH, 10 with steatosis, Low Ad levels are strongly associated with severity of
60 controls liver histology, further supporting the hypothesis that Ad
may be involved in the development of NAFLD
Yalniz et al. [68] 2006 NASH 62: 37 with NASH, 25 controls Ad and ghrelin levels are lower in NASH than in controls;
significant relationship between NASH, adipokines and
ghrelin independent of BMI and glucose metabolic status
Hamano et al. [103] 2012 NAFLD 5588 healthy Japanese men Hypoadiponectinaemia is a significant determinant of
steatotic dysfunction at all levels of alcohol consumption
Machado et al. [104] 2012 NAFLD 82 morbidly obese, biopsy-proven Imbalance between Ad, leptin and ghrelin may be asso-
NAFLD: 11 with NASH, 71 without ciated with more severe NAFLD
NASH
van der Poorten et al. [105] 2013 NASH 119: 65 with biopsy-proven advanced Relationship between Ad, bile acids and adipocyte
NASH (fibrosis stage 3/4), 54 with FXR activation seen in vivo and in vitro, suggest-
mild NASH (fibrosis stage 0/1) ing hepatocyte–adipocyte crosstalk; serum Ad levels
in advanced NASH are independently associated with
hepatic fat loss; Ad may be partly responsible for ‘burnt-
out’ NASH
Bechmann et al. [106] 2013 NAFLD 98 morbidly obese: 59 with NASH, 39 Bile acid synthesis and serum bile acid levels correlate
with steatosis, 10 controls with disease severity in NAFLD; Ad levels are inversely
correlated with NAFLD disease severity; bile acid accu-
mulation in NASH induces hepatocyte cell death; late
FXR activation fails to prevent hepatocyte injury due to
decreased Ad; early treatment with FXR ligands and/or
Ad-receptor agonists might prevent NASH

NASH: non-alcoholic steatohepatitis; IR: insulin resistance; TNF-␣: tumour necrosis factor-alpha; baPWV: brachial–ankle pulse wave velocity; BMI: body mass
index; FXR: farsenoid X receptor.

acid synthesis. It was also demonstrated that, in NASH, bile adiponectin and bile acids reveals a potential direct effect of
acid accumulation induced hepatocyte cell death, while late far- adiponectin on bile acid homoeostasis [106]. Nevertheless, the
nesoid X receptor (FXR) activation failed to prevent hepatocyte exact mechanism linking bile acid metabolism, hepatocellular
injury due to decreased adiponectin levels, suggesting that early death and adipocytokines is still not completely understood.
treatment with FXR ligands and/or adiponectin receptor agonists Based on the fact that adiponectin levels are elevated in
might prevent NASH [106]. This inverse relationship between patients with cirrhosis of variable aetiology, van der Poorten
 T.E. Silva et al. / Diabetes & Metabolism 40 (2014) 95–107 101

et al. [105] investigated the role of this adipokine in advanced in such infections [121,126]. Steatosis has been reported in
NASH. The researchers concluded that the relatively high levels around 50% of liver biopsies of patients with chronic HCV
of adiponectin in compensated late-stage NASH were signifi- infection [134] and is especially associated with HCV geno-
cantly related to hepatic fat loss independent of metabolic factors type 3 [120,135]. Unlike other genotypes in which BMI was an
and liver dysfunction, and were likely responsible, at least in important pathogenic factor of steatosis [136], steatosis is more
part, for the paradox of ‘burnt-out’ NASH [105]. The most prob- pronounced in genotype 3 and significantly correlated with intra-
able cause of the increased adiponectin levels in advanced NASH hepatic HCV RNA levels. Furthermore, the steatosis in patients
is bile acid-mediated hepatocyte–adipocyte crosstalk [105,113]. with HCV genotype 3 disappears after treatment achieving a
This hypothesis was supported by an experiment wherein differ- sustained virological response, suggesting that, in these cases,
entiated 3T3-L1 adipocytes were treated with bile acid receptor steatosis is the morphological expression of viral cytopathology
agonists (FXR agonist fexaramine and TGR5 agonist taurolitho- [135].
cholic acid), and demonstrated > 10-fold increased adiponectin In chronic HCV infection, levels of adiponectin are reduced
secretion, thereby suggesting that bile acids act directly to regu- [119,127,132] and significantly lower in patients with vs with-
late adiponectin synthesis in adipocytes [105]. These data, albeit out steatosis [119], and inversely correlated to grade of steatosis,
contradictory to some extent, provide clues to the relationship histological activity index and stage of fibrosis [132]. These find-
between the liver and adipose tissue, and serve as a basis for ings suggest that hypoadiponectinaemia may be contributing to
new therapeutic targets in NAFLD. It is possible that the type of hepatic steatosis and liver injury progression in these patients, an
bile acid may have influenced these results, as demonstrated by outcome most likely related to the effect of adiponectin on lipid
van der Poorten et al. [105], whose study showed that levels of metabolism [119]. A recent study found hypoadiponectinaemia
deoxycholic acid (DCA) and glycine-conjugated DCA, but not in non-obese mice with HCV-induced hepatic steatosis as well as
cholic acid, chenodeoxycholic acid and ursodeoxycholic acid, improvement in steatosis after treatment with adiponectin [137].
paralleled the increases in adiponectin. Also, studies by Liu et al. [121] and Jonsson et al. [120] found
Given that hypoadiponectinaemia is an important risk fac- reductions in the expression of hepatic receptors of adiponectin
tor for the progression of NAFLD, therapeutic strategies to in patients with chronic HCV infection. In addition, Corbetta
increase these adipokine levels have been assessed. Clinical et al. [133] suggested that adiponectin resistance may be induced
treatment with PPAR-␥ agonists (thiazolidinedione) has shown by IR and may be contributing to the progression of liver fibrosis
promising results, while a study that included 47 patients with in those infected by HCV.
NASH showed that pioglitazone increased adiponectin levels Despite studies demonstrating that adiponectin is not related
by 2.3 times, improved IR and was associated with histologi- to histological parameters in hepatitis C, low levels of the
cal improvement of steatosis, inflammation and fibrosis [114]. adipokine have been associated with high viral loads and HCV
Studies with rosiglitazone showed that it increased circulating genotypes 2 [121] and 3 [127]. In addition, weight loss in
adiponectin and improved steatohepatitis [115,116] by acting overweight HCV-infected patients has been associated with an
directly on the modulation of AdipoR1 and AdipoR2 recep- increase in serum levels of adiponectin, improvement in fibro-
tors, and indirectly by decreasing serum TNF-␣ [115]. A mouse sis, and reductions in steatosis and abnormal liver enzymes,
study showed that PPAR-␥ has potent inhibitory effects on the despite persistence of the virus [51,138]. This highlights the
growth of stellate cells and TGF-␤1-induced connective tis- importance of obesity and adiponectin in the modulation of
sue growth factor (CTGF) expression, suggesting a potential immune responses in chronic HCV infection [126]. Low lev-
antifibrotic effect of thiazolidinediones [117]. In a randomized els of adiponectin have also been identified as independent
controlled study comparing the efficacy of vitamin E and piogli- predictors of liver steatosis and failing to achieve a sustained
tazone vs placebo, the group receiving pioglitazone showed virological response at the end of antiviral therapy in chronic
reduced steatosis and lobular inflammation compared with the hepatitis C [127].
placebo group. However, the drug was not superior to vitamin Few studies have evaluated the role of adiponectin in chronic
E and failed to reach the predetermined primary study end- HBV infection. In these patients, levels of adiponectin are lower
point [118]. This suggests that adiponectin may be an important [123] or similar [139] to those of patients with HCV. The higher
therapeutic target in NAFLD. However, further studies of such levels of adiponectin in HCV carriers may be partly responsible
therapeutic strategies at different stages of disease are neces- for the slower progression of chronic hepatitis C [123]. How-
sary. ever, in HBV patients, a fourfold increase in serum adiponectin
was detected in those with more advanced stages of fibrosis
3.2. Other liver diseases [125]. Furthermore, adiponectin appears to have a direct effect
on fibrosis progression, with a marked decline in its levels after
Table 3 summarizes the main clinical studies investigating the antiviral therapy being associated with reduced fibrosis [125].
relationship between adiponectin and different liver diseases. However, another study including HBV patients showed an asso-
ciation between hepatic necroinflammation and TNF-␣ and IL-6
3.2.1. Viral hepatitis only, and not adiponectin, which was decreased in patients with
HCV infection is another disease in which adipokines may IR and hepatic steatosis [130]. The investigators concluded that
represent the link between IR and viral infection, emphasizing adiponectin protects against IR and hepatic steatosis, but has
the important role of adiposity in regulating immune responses no effect on liver lesions related to HBV. This suggests that
102 T.E. Silva et al. / Diabetes & Metabolism 40 (2014) 95–107

Table 3
Clinical studies of adiponectin (Ad) in different liver diseases.
Reference Year Disease Subjects (n) Primary findings

Tietge et al. [74] 2004 Cirrhosis 20 cirrhotic: 6 alcoholic, 6 with HBV Liver is a major source of Ad; Ad plasma levels are significantly elevated
& HCV, 6 with biliary disease, 2 cryp- and not correlated with parameters of body composition or metabolism,
togenic, 20 controls but correlate exclusively with reduced liver function and altered hepatic
haemodynamics
Petit et al. [119] 2005 HCV 71: 42 with steatosis, 29 without Hypoadiponectinaemia is significantly associated with liver steatosis;
steatosis plasma levels of Ad are inversely correlated with steatosis, suggesting that
hypoadiponectinaemia may contribute to hepatic steatosis progression and
liver injury in HCV
Jonsson et al. [120] 2005 HCV 194 with HCV Adiponectinaemia is associated with steatosis only in men and paradoxically
increases with inflammation
Liu et al. [121] 2005 HCV 95 with HCV Low levels of Ad are significantly associated with male gender, IR, large
HCV load and genotype 2, suggesting a correlation between Ad and HCV
factors in serum and liver tissue
Tacke et al. [122] 2005 Chronic 111: 18 without cirrhosis, 35 Child A, Ad is elevated and correlates with inflammation and liver damage; high Ad
liver 44 Child B, 14 Child C, 226 healthy levels after bile duct ligation in mice and in human bile in cholestasis suggest
diseases controls that biliary secretion is involved in Ad clearance; Ad could serve as a novel
marker for cholestasis in liver cirrhosis
Siagris et al. [123] 2007 HCV, HBV 145: 72 with HCV, 73 with HBV Higher levels of serum Ad in HCV vs HBV may be related to slower disease
progression of chronic HCV; no clear positive association between Ad and
hepatic necroinflammation found
Cua et al. [124] 2007 HCV 315: 240 with HCV (not treated), 154 Adipocytokines leptin and Ad were not associated with histological features
with fibrosis stage 0–2, 75 healthy of chronic HCV; HCV-associated IR is most likely an adipocytokine-
controls independent effect of HCV on modulation of insulin sensitivity
Hui et al. [125] 2007 HBV 100: 66 without liver cirrhosis, 34 with Serum Ad may affect fibrosis progression; marked decline in serum Ad after
cirrhosis antiviral therapy is associated with fibrosis reduction
Palmer et al. [126] 2008 HCV, cir- 35: 15 treatment responders, 20 non- Reciprocal association between BMI, Ad and anti-HCV immune responses
rhosis responders in chronic HCV emphasizes the importance of adiposity in regulating
immune responses in HCV infection
Zógrafos et al. 2008 HCV, HBV 142: 83 HCV, 59 HBV, 43 controls HCV genotype 3 may directly affect Ad; further supported by significant
[127] increase of Ad after treatment only in HCV genotype 3 patients; serum Ad
at baseline may be an independent predictor of liver steatosis and end-of-
treatment virological responses
Floreani et al. 2008 PBC 304: 137 PBC, 30 with NAFLD, 137 Ad levels are higher in PBC than in either NASH or controls and associated
[128] controls with histological progression of PBC; high Ad levels may be a possible
protective factor against atherosclerosis
Durazzo et al. 2009 AIH 115: 42 with AIH, 31 with NASH, 42 Significantly higher Ad levels in AIH vs controls despite higher HOMA–IR
[129] controls values; significant correlation between Ad and serological features of
cholestasis suggest a role in biliary function; Ad may be a marker of AIH
disease progression
Wong et al. [130] 2010 HBV 266: 68 with cirrhosis Ad protects against IR and hepatic steatosis, but has no effect on liver injury
Balmer et al. [75] 2010 Chronic 232: 45 with cirrhosis, 64 with Circulating Ad levels are significantly lower in NAFLD vs other chronic
liver NAFLD, 71 with viral hepatitis, 18 liver diseases; Ad is significantly higher in patients with vs without cirrho-
diseases with autoimmune disease, 3 with sis; Ad levels correlate positively with surrogate markers of hepatic fibrosis
alcohol-induced liver disease, 31 with (transient elastography, fasting serum bile acids and hyaluronate)
elevated liver enzymes of unknown
origin, 20 controls
Salman et al. [131] 2010 Cirrhosis, 90: 40 with cirrhosis, 30 with cirrhosis Ad is elevated in cirrhosis and correlates with degree of hepatocellular injury
cholestasis & cholestasis, 20 controls and cholestasis, but not with parameters of body composition or metabolic
activity; exclusively correlates with reduced liver function
Latif et al. [132] 2011 HCV, cir- 60: 30 with steatosis, 30 without Serum Ad levels are inversely correlated with grade of steatosis, histological
rhosis steatosis activity index and stage of fibrosis
Corbetta et al. 2011 HCV 108: 54 with HCV, 54 controls Fibrosis is associated with hyperadiponectinaemia; hepatocytes in chronic
[133] HCV show reduced AdipoR1 expression, suggesting Ad resistance

HBV: hepatitis B virus; HCV: hepatitis C virus; BMI: body mass index; PBC: primary biliary cirrhosis; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic
steatohepatitis; AIH: autoimmune hepatitis; HOMA–IR: homoeostasis model assessment–insulin resistance.
 T.E. Silva et al. / Diabetes & Metabolism 40 (2014) 95–107 103

adipokines and viral factors may be independent contributors to adiponectin levels in cirrhosis were associated with variables
liver injury in chronic hepatitis B [130]. related to liver dysfunction, but not with IR [122,131]. However,
these studies were limited by their relatively small numbers of
3.2.2. Cholestatic hepatic diseases and autoimmune patients, and lack of stratification by gender and adjustments for
hepatitis other important variables. Thus, the factors related to elevated
Patients with biliary liver diseases and cholestasis have the levels of adiponectin in cirrhosis have yet to be ascertained.
highest adiponectin levels, indicating that the liver is possibly
involved in its excretion through bile [122]. Although some stud- 4. Perspectives
ies suggest renal excretion of adiponectin [140,141], Tacke et al.
[122] demonstrated higher levels of adiponectin in human bile Over the past 10 years, there has been a considerable increase
from patients with cholestatic hepatic disease and in mice after in our awareness of the relationship between adipose tissue
bile duct ligation, indicating that biliary secretion is involved and liver disease pathophysiology. The central role of the
in adiponectin clearance. However, recent evidence suggest- liver in metabolic syndromes explains the large number of
ing the participation of bile acids in the process of adiponectin studies of adipokines in NAFLD and other components of
liberation by adipocytes has revealed a new potential mecha- such syndromes. Several studies have looked at the connec-
nism for elevated levels of this adipokine in cholestatic diseases tion between adipokines and mechanisms of hepatic lesions
[105]. Salman et al. [131] observed that levels of adiponectin and, not surprisingly, reported controversial results [144]. As
were higher in patients with cirrhosis and cholestasis than in in chronic kidney disease [145], the effect of increased plasma
those without cholestasis, and also that adiponectin correlated adiponectin levels in liver diseases is complex, and it may be
with liver cell injury, a marker of inflammation, liver synthetic hypothesized that, in cirrhosis, high adiponectin levels reflect
function and markers of cholestasis. In patients with primary protein energy malnutrition, impaired hepatic function and
biliary cirrhosis (PBC), the increase in adiponectin levels was reduced adiponectin excretion by the liver. However, the impact
also higher than in patients with NASH [128]. It was there- of increased adiponectin levels on insulin metabolism, body
fore suggested that this increase in adiponectin levels might composition and cardiovascular function in cirrhotic patients
be a protective factor against atherogenesis, a theory based remains unclear.
on the fact that cardiovascular risk in PBC patients is not Independent studies suggesting the therapeutic use of recom-
increased compared with the general population despite the binant adiponectin have been promising, especially because of
higher rates of hypercholesterolaemia observed in such indi- its insulin-sensitizing properties, and cardioprotective, hepato-
viduals [128]. protective and antiangiogenic functions [146,147]. Strategies
Only one study has investigated adiponectin in patients with directed towards increasing adiponectin production and its
autoimmune hepatitis (AIH) [129], and found that levels were circulating concentrations include lifestyle interventions (diet
significantly higher than in either healthy controls or patients and weight loss), pharmacological therapy (thiazolidinediones,
with NASH. The significant correlation between adiponectin angiotensin converting-enzyme inhibitors, endocannabinoid
levels and serological features of cholestasis suggest an associ- antagonists) and possibly nutritional supplements (soya protein,
ation with biliary function, and indicate that adiponectin may linoleic acid), and have proven to be effective approaches for the
serve as a possible marker of disease progression in AIH [129]. prevention and treatment of IR, the metabolic syndrome, DM2
and cardiovascular disease [5,56]. AdipoR activation to mimic
3.2.3. Liver cirrhosis adiponectin actions may also prove beneficial in the reduction of
Several studies have reported significantly elevated serum metabolic risk factors in conditions such as obesity, in which low
levels of adiponectin in patients with advanced cirrhosis, regard- adiponectinaemia prevails [146]. It is possible that these might
less of aetiology [74,75,98,125,127,131,133]. Moreover, there also be viable options for the treatment of liver diseases either
was a positive correlation between adiponectin levels and mark- as a primary approach (as in cases of NAFLD) or as adjunctive
ers of hepatic fibrosis (transient elastography, fasting serum bile treatment, with a goal to slow the evolution of fibrosis in various
acids and hyaluronate) [75]. Various mechanisms have been pro- liver diseases.
posed to explain the raised levels of adiponectin with fibrosis However, many questions still need answering before
progression, such as an imbalance between the production of adiponectin can be used as a therapeutic target. Indeed, the pres-
adiponectin by adipocytes and its excretion by the liver [142], ence of various adiponectin oligomeric isoforms and production
an increase in adiponectin production by hepatic stellate cells sites, the gender dimorphism of adiponectin concentrations and
(HSC) [86] and anti-inflammatory mechanisms [143]. oligomeric isoform distributions, and the identification of multi-
Tietge et al. [74] investigated adiponectin levels in 20 ple receptors with different affinities for adiponectin oligomers
patients with cirrhosis and found an association between all add to the complexity of adiponectin activities across a wide
adiponectinaemia and parameters of hepatic synthesis (albumin array of physiological processes and diseases [148]. More stud-
and prothrombin time) and haemodynamics (portal pressure, ies are now needed to better evaluate the relationship between
hepatic vascular resistance and effective hepatic blood flow). adipokines and various liver diseases, and especially to investi-
In that study, variables related to body composition and gate its role in the maintenance of liver integrity through the
metabolism had no influence on adiponectin levels. Simi- regulation of insulin sensitivity and inflammatory responses
lar findings were described in two other studies in which [89].
104 T.E. Silva et al. / Diabetes & Metabolism 40 (2014) 95–107

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