Adipokines in nonalcoholic fatty liver disease

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Available online at www.sciencedirect.com

Metabolism www.metabolismjournal.com

Review article

Adipokines in nonalcoholic fatty liver disease Stergios A. Polyzos a,⁎, Jannis Kountouras a , Christos S. Mantzoros b, c a

Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA c Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA b

A R T I C LE I N FO

AB S T R A C T

Article history:

Since the discovery of adipose tissue as a higly active endocrine tissue, adipokines, peptides

Received 4 October 2015

produced by adipose tissue and exerting autocrine, paracrine and endocrine function, have

Accepted 20 November 2015

gained increasing interest in various obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD). Data regarding the association between NAFLD and circulating leptin and adiponectin levels are generally well documented: leptin levels increase, whereas

Keywords:

adiponectin levels decrease, by increasing the severity of NAFLD. Data regarding other

Adipokines

adipokines in histologically confirmed NAFLD populations are inconclusive (e.g., resistin,

Adiponectin

visfatin, retinol-binding protein-4, chemerin) or limited (e.g., adipsin, obestatin, omentin,

Leptin

vaspin etc.). This review summarizes evidence on the association between adipokines and

Nonalcoholic fatty liver disease

NAFLD. The first part of the review provides general consideration on the interplay between

Nonalcoholic steatohepatitis

adipokines and NAFLD, and the second part provides evidence on specific adipokines

Resistin

possibly involved in NAFLD pathogenesis. A thorough insight into the pathophysiologic mechanisms linking adipokines with NAFLD may result in the design of studies investigating the combined adipokine use as noninvasive diagnostic markers of NAFLD and new clinical trials targeting the treatment of NAFLD. © 2015 Elsevier Inc. All rights reserved.

Abbreviations: AMPK, 5′-adenosine monophosphate–activated protein kinase; APJ, apelin receptor; ASP, acylation-stimulating protein; BMI, body mass index; C5L2, chemoattractant receptor-like protein; CAP, adenylyl cyclase-associated protein; CCRL, chemokine (CC motif) receptor-like; ChemR, chemerin receptor; CMKLR, chemokine receptor-like; DCN, decorin; ERK, extracellular signal-regulated kinase; FFA, free fatty acid; Fox, forkhead box protein; GLP-1R, glucagon-like peptide receptor 1; GLUT, glucose transporter; GPR, G protein coupled receptor; HCC, hepatocellular carcinoma; HMW, high-molecular-weight; HSCs, hepatic stellate cells; IL, interleukin; IR, insulin resistance; IRS, insulin receptor substrate; JAK, Janus kinase; LepR, leptin receptor; LMW, low molecular weight; MAPK, mitogen-activated protein kinase; MMW, middle-molecular-weight; MMP, matrix metalloproteinases; MRI, magnetic resonance imaging; mTOR, mammalian target of rapamycin; NAD, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NAFLD, nonalcoholic fatty liver disease; NAMPT, nicotinamide phosphoribosyl-transferase; NASH, nonalcoholic steatohepatitis; PBEF, pre-B cell colony-enhancing factor; PI3K, phosphatidylinositol-3 kinase; PPAR, peroxisome proliferator-activated receptor; RBP, retinolbinding protein; RELMs, resistin-like molecules; ROR, receptor tyrosine kinase-like orphan receptor; SH2-B, src homology 2 domaincontaining adapter protein B; SOCS, suppressor of cytokine signaling; SS, simple steatosis; STAT, signal transducer and activator of transcription; STRA, stimulated by retinoic acid; T2DM, type 2 diabetes mellitus; TIMP, tissue inhibitor of metalloproteinase; TGF, transforming growth factor; TLR, toll-like receptor; TNF, tumor necrosis factor; VLDL, very low-density lipoprotein. ⁎ Corresponding author at: 13 Simou Lianidi, 551 34, Thessaloniki, Macedonia, Greece. Tel./fax: + 30 2310424710. E-mail address: [email protected] (S.A. Polyzos). http://dx.doi.org/10.1016/j.metabol.2015.11.006 0026-0495/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Polyzos SA, et al, Adipokines in nonalcoholic fatty liver disease, Metabolism (2015), http://dx.doi.org/ 10.1016/j.metabol.2015.11.006

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1.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem [1], with a prevalence of 6–45% (median 20%) in the general population, depending on the studied population and the method of diagnosis [2]. It is considered to be the hepatic component of metabolic or insulin resistance (IR) syndrome, increasing in parallel with the epidemics of obesity and type 2 diabetes mellitus (T2DM) [3,4]. Contemporary research renders NAFLD more than a simple “component” or “manifestation” of IR, because there is evidence that NAFLD increases the risk for cardiovascular disease, including subclinical atherosclerosis, independently from IR syndrome and other conventional risk factors [5], thereby implying an additional synergistic effect of NAFLD and IR on cardiovascular morbidity. NAFLD ranges from nonalcoholic simple steatosis (SS) to nonalcoholic steatohepatitis (NASH), characterized by inflammation and/or fibrosis [3]. NAFLD has hepatic and systemic consequences: NASH may lead to subacute liver failure, liver cirrhosis and/or hepatocellular carcinoma (HCC); it is also related with systemic metabolic complications, chronic kidney and cardiovascular disease, mainly contributing to liverrelated, cardiovascular and cancer-related mortality observed in NAFLD patients [6]. Although NAFLD is a field of intensive research, its underlying pathophysiologic mechanisms are not fully elucidated and its treatment remains an unmet medical need [7]. Since its pathogenesis is multifactorial [8], multiple and diverse factors (“hits”) have been proposed to contribute, some of which are regarded as classic, including dietary factors (e.g., fructose, especially when combined with excess energy intake [9]), IR and adipokines [3], whereas other needs further verification, including genes, innate and adaptive immunity, dysbiosis of the gut microbiota [10], Helicobacter pylori infection [11] and endocrine disruptors [12]. Adipokines are polypeptides produced by adipose tissue and exert autocrine, paracrine and endocrine function. There is increasing evidence that adipokine alterations, which occur during the expansion of adipose tissue, contribute to the development of SS, but also to the progression to NASH and possibly to NASH-related cirrhosis [3]. This review summarizes evidence on the association between adipokines and NAFLD. The first part of the review provides general consideration on the interplay between adipokines and NAFLD, and the second part provides evidence on specific adipokines involvement in NAFLD pathogenesis. A thorough insight into the pathophysiologic mechanisms linking adipokines and NAFLD may result in the design of studies investigating the combined adipokine use as noninvasive diagnostic markers of NAFLD and new clinical trials targeting the treatment of NAFLD.

2. General Insight Into the Relationship Between Adipokines and NAFLD Traditionally, adipose tissue was regarded as an inert energystorage organ and even classic textbooks of physiology did not devote over a couple of paragraphs to describe its role.

Since the discovery of leptin, the prototypical adipocytesecreted hormone or adipokine, in 1994 [13], this conventional consideration has been radically changed. Currently, adipose tissue is considered to be the major and possibly the largest endocrine organ, with a network of signaling pathways enabling the organism to adapt to a wide range of different metabolic challenges; its functional pleiotropism relies on its ability to synthesize and release a variety of hormones, cytokines, complement and growth factors, extracellular matrix proteins and vasoactive agents, collectively called adipokines, with multi-potent effects on health and disease [14]. More than 700 different proteins have been described as being potentially secreted by the adipose tissue; however, these proteins need further study and validation regarding their expression, secretion and function, before full characterization as putative novel adipokines [15]. Furthermore, publications are accumulating on the endocrine function of adipose tissue, and the new editions of physiology textbooks devote many pages to describe the endocrine function of adipose tissue [14]. Generally, adipokines include peptides that are mainly, although not exclusively, produced by adipocytes (e.g., adiponectin, leptin). Adipose tissue also produces other peptides (including classical cytokines), which are mainly, but not exclusively, produced by immune cells infiltrating adipose tissue (e.g. tumor necrosis factor [TNF]-α, interleukin [IL]-6) or endothelial cells of adipose tissue [3,16]. Numerous immune cells, including macrophages, B-cells, T-cells and neutrophils have been identified in adipose tissue; obesity influences both the quantity and the nature of immune cell subtypes; when adipose tissue expands, it is infiltrated by more and different immune cells, which increase the burden of low-grade, but chronic inflammation of adipose tissue [17]. A complicated communication network between adipocytes and immune cells with potential consequences on NAFLD seems to exist: for example macrophages serve as the source of the majority of adiposederived inflammatory factors, but they are affected by ever changing inputs from surrounding adipocytes to exert their inflammatory potential. Conversely, cytokines produced by immune cells may affect the adipocytes to change their secretory profile, thereby establishing a vicious cycle [3,18]. In this regard, both the innate and the adaptive immune systems play a significant role in the pathogenesis of NAFLD; the organ-specific immunity is involved in the onset and progression of this disease, which draw complex pathways and offer various possible targets for future treatment. Adipokines may be also divided, according to their potential impact on NAFLD, into those having a positive or negative impact. Adiponectin is an adipokine with potential beneficial effect on NAFLD [19], whereas others, including resistin, TNF-α, IL-6 have possibly an adverse effect on NAFLD. It seems that a continuous dynamic cross-talk between adipokines with a positive or negative impact on NAFLD exists, resulting in a beneficial or detrimental final effect, respectively. However, this final effect is not permanent, but temporary, since an everchanging metabolic milieu affected by both innate (e.g., genetic susceptibility) and exogenous factors (e.g., lifestyle) leads to an ever-changing adipokine profile and subsequent an ever-changing effect on NAFLD. The deeper knowledge of these sophisticated interactions and the their ever-changing, possibly non-linear,

Please cite this article as: Polyzos SA, et al, Adipokines in nonalcoholic fatty liver disease, Metabolism (2015), http://dx.doi.org/ 10.1016/j.metabol.2015.11.006

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dynamic nature, resembling the ever-changing milieu of a stock market, may result in more focused and possibly personalized treatment strategies for NAFLD in the future [14]. A simplistic example of the antagonistic relationships among beneficial and detrimental adipokine interplay in IR and NAFLD refers to the opposed effects of adiponectin and TNF-α [8,20]. Adiponectin reduces IR and has an anti-steatotic and antiinflammatory effect, while TNF-α increases IR and has a proinflammatory effect. Specifically, high TNF-α and low adiponectin is a condition capable of leading to IR and NAFLD [20]. It seems that these two key players in the pathogenesis of NAFLD inhibit the synthesis and activity of each other, thereby targeting to metabolic balance. Adiponectin inhibits the expression, secretion and action of TNF-α, thereby improving insulin sensitivity. TNF-α suppresses adiponectin transcription, secretion and action, thus increasing IR [8,20]. Normally, there is a balance between adiponectin and TNF-α, but, by adipose tissue expanding, this critical balance is impaired. This leads to lowgrade, but chronic, inflammation, IR and NAFLD [20]. Another example is the interplay among visfatin, TNF-α and IL-6. As an immunomodulatory and proinflammatory adipokine, visfatin induces the synthesis of TNF-α and IL-6 [21]. Subsequently, TNFα, which is also a major trigger for the production of IL-6 by a variety of cells, upregulates visfatin in adipose tissue [22], thus providing positive feedback to the circuit. On the contrary, IL-6 downregulates visfatin in adipocytes [23], thus possibly proving negative feedback to the circuit. The above-mentioned classification of adipokines into beneficial and detrimental, as well as the examples on the interplay among various adipokines, provide a general clue, but they are also simplistic. The role of adipokines may be dual-faceted in the pathogenesis of NAFLD [24]. Most alterations of adipokines during the expansion of adipose tissue are compensatory and they generally target to provide a positive effect or to neutralize a

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negative effect triggered by another factor. Under normal conditions, the alterations may be successful to an extent, thereby metabolic homeostasis is achieved. However, during these alterations side effects may be simultaneously triggered [24]. For example, leptin increases with increasing adipose mass, as a compensatory mechanism to preserve insulin sensitivity, thereby exerting an anti-steatotic effect on the liver. This may be initially achieved, but, if adipose tissue continues to expand, leptin fails to compensate for a continuous increasing of IR and hepatic steatosis [25,26]. This may ultimately lead to harmful side effects, because leptin, apart from its anti-steatotic effect, acts simultaneously as an inflammatory and fibrogenic adipokine [25,26]. Another example refers to adiponectin, which reduces when the SS progresses to NASH [19]. However, adiponectin has a non-linear distribution within the NAFLD spectrum and it increases when NASH progresses to cirrhosis [27]. Although its decreased clearance and/or a compensatory increase are probable explanations, a potential harmful effect of adiponectin, when NASH progresses to cirrhosis, could not be excluded. Resistin, as third example, also increases with adipose tissue expansion, possibly targeting to decrease adipogenesis, but it simultaneously results in IR increase, stimulation of other inflammatory cytokines (e.g., TNF-α) and liver fibrinogenesis [24]. TNF-α also increases with adipose tissue expansion, mainly because, the expansion of adipose tissue results in its infiltration by more macrophages; subsequently, macrophage-produced TNF-α increases IR, fibrogenesis and apoptosis of the hepatocytes. Nevertheless, increased TNF-α simultaneously induces cellprotective mechanisms in hepatocytes, by enhancing antiapoptotic and regenerative mechanisms [28]. It seems that various adipokines are in balance, when adipose tissue is in normal range, but if adipose tissue expands, this balance tends to be lost. Compensatory adipokine alterations may be initially efficient to preserve insulin sensitivity and deter hepatic steatosis

Table 1 – The main proposed receptors for selected adipokines. Adipokine

Receptor(s)

Leptin Adiponectin

Leptin receptor (LepR); isoforms LepRa to LepRf (mainly LepRb) Adiponectin receptor (AdipoR) 1, AdipoR2 T-cadherin Toll-like receptor (TLR) 4 Decorin (DCN) isoform Δ (ΔDCN) Receptor tyrosine kinase-like orphan receptor (ROR) 1 Adenylyl cyclase-associated protein (CAP) 1 Intracellular action (enzymatic): nicotinamide phosphoribosyl-transferase (NAMPT) Extracellular action (cytokine-like): unknown Stimulated by retinoic acid (STRA) 6 Chemokine-like receptor (CMKLR) 1 Chemerin receptor (ChemR) 23 Chemokine (CC motif) receptor-like (CCRL) 2 Chemoattractant receptor-like protein (C5L2) Unknown Angiotensin-like receptor 1 or apelin receptor (APJ receptor) G protein coupled receptor (GPR) 39 Glucagon-like peptide receptor 1 (GLP-1R) Unknown Unknown

Resistin a

Visfatin RBP-4 a Chemerin

ASP a Adipsin Apelin Obestatin a Omentin Vaspin

Abbreviations: ASP, acylation-stimulating protein; RBP, retinol-binding protein. a Insufficient data.

Please cite this article as: Polyzos SA, et al, Adipokines in nonalcoholic fatty liver disease, Metabolism (2015), http://dx.doi.org/ 10.1016/j.metabol.2015.11.006

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Table 2 – Potential effects of selected adipokines in insulin resistance and hepatic steatosis, inflammation and fibrosis (data derived from experimental studies). Adipokine Leptin Adiponectin Resistin Visfatin RBP-4 Chemerin

Insulin resistance Improvement Improvement Deterioration Controversial Deterioration Deterioration

a

Hepatic steatosis

Hepatic inflammation

Hepatic fibrosis

Improvement Improvement Deterioration Controversial Deterioration Controversial

Deterioration Improvement Deterioration Deterioration Deterioration Deterioration

Deterioration Improvement b Deterioration Controversial Controversial Controversial

Abbreviations: RBP, retinol-binding protein. a Improvement under normal conditions; deterioration in leptin resistance. b Unknown in burnt-out NASH or NASH-related cirrhosis.

or the progression to NASH; however, if adipose tissue continues to expand, adipokine alterations may be more detrimental than beneficial for NAFLD. Although the aforementioned considerations are appealing, and, if further validated, may have therapeutic consequences in the future, they all need to be more thoroughly evaluated.

3.

Specific Adipokines in NAFLD

In this part of the review, data on specific adipokines in NAFLD are presented. For each adipokine, firstly, a relevant background

is presented, and then data from clinical studies in NAFLD (preferentially histologically confirmed) are provided. Since leptin and adiponectin have more extensively investigated in NAFLD, they are more extensively presented. Newer adipokines are only briefly presented, due to their limited evidence in NAFLD involvement. Classical cytokines (e.g. TNF-α, IL-6 etc.), predominantly produced by immune cells infiltrating adipose tissue, have been reviewed elsewhere [3,29] and are not summarized in this review. The proposed receptors, through which selected adipokines act, are summarized in Table 1. The potential effects of selected adipokines in insulin resistance and hepatic steatosis, inflammation and fibrosis, as derived from experimental studies,

Fig. 1 – Potential effects of selected adipokines in insulin resistance and the specific histological lesions of nonalcoholic fatty liver disease, i.e., hepatic steatosis, inflammation and fibrosis, as derived mainly from experimental studies. Adiponectin, leptin*, obestatin, omentin and vaspin decrease, whereas resistin, RBP-4 and chemerin increase insulin resistance. Adiponectin and leptin decrease, whereas resistin and RBP-4 increase hepatic steatosis. Adiponectin decreases, whereas leptin, resistin, visfatin, RBP-4, chemerin, ASP and apelin increase hepatic inflammation. Adiponectin* decreases, whereas leptin, resistin and apelin increase hepatic fibrosis. *Leptin improves insulin resistance under normal conditions, but it may increase insulin resistance in leptin resistance states. *The role of adiponectin, when the disease progresses to burnt-out NASH or NASH-related cirrhosis, is not fully elucidated. Abbreviations: ASP, acylation-stimulating protein; NASH, nonalcoholic steatohepatitis; RBP, retinol-binding protein. Please cite this article as: Polyzos SA, et al, Adipokines in nonalcoholic fatty liver disease, Metabolism (2015), http://dx.doi.org/ 10.1016/j.metabol.2015.11.006

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Table 3 – Main trends of circulating levels of selected adipokines in histologically confirmed NAFLD patients vs. controls, as well as within NAFLD (SS vs. NASH) patients (data derived from human studies). Adipokine

NAFLD patients

SS patients

NASH patients

Level of evidence a

Leptin

Higher vs. controls [54]

Higher vs. controls [54]

Meta-analysis

Adiponectin

Lower vs. controls [68]

Lower vs. controls [68]

Resistin

Higher [108,109] or similar [112–115] vs. controls

Higher [110,111] or similar [114–116] vs. controls

Visfatin

Similar vs. controls [129]

Similar vs. controls [130]

RBP-4

Higher vs. controls [110,147]

Higher [110,147] or similar [55] vs. controls

Chemerin

Higher vs. controls [164–166]

Unknown vs. controls

ASP

Higher vs. controls [170]

Unknown vs. controls

Adipsin

Similar vs. controls [165]

Unknown vs. controls

Apelin

Higher vs. controls [178,179]

Unknown vs. controls

Obestatin

Similar vs. controls [179]

Unknown vs. controls

Omentin

Higher vs. controls [165]

Unknown vs. controls

Vaspin

Higher [166,179] or similar [164] vs. controls

Unknown vs. controls

Higher vs. controls [54] Higher vs. SS [54] Lower vs. controls [68] Lower vs. SS [68] Higher [111] or similar [114–117] vs. controls Higher [108,118] or similar [111,113–116] vs. SS Similar vs. controls [130,131] Similar vs. SS [114,130,132] Higher [147] or similar [55] vs. controls Lower [150,151] or similar [55,147–149] vs. SS Unknown vs. controls Higher [164] or similar [55,161] vs. SS Unknown vs. controls Unknown vs. SS Unknown vs. controls Similar vs. SS [119] Unknown vs. controls Similar vs. SS [178,179] Unknown vs. controls Similar vs. SS [179] Unknown vs. controls Similar vs. SS [165] Higher vs. controls [187] Similar vs. SS [164,179]

Meta-analysis Observational studies

Observational studies Observational studies

Observational studies

Observational studies Observational studies Observational studies Observational studies Observational studies Observational studies

Abbreviations: ASP, acylation-stimulating protein; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; RBP, retinolbinding protein; SS, simple steatosis. a For adipokines, which data from meta-analyses were available for, references from individual original studies were not added to the table.

are summarized in Table 2 and Fig. 1. The main trends of circulating levels of selected adipokines in histologically confirmed NAFLD patients as compared with controls, as well as within NAFLD patients (SS vs. NASH) are summarized in Table 3.

3.1.

Leptin

3.1.1.

Background

Leptin (named after the Greek word “leptos” meaning thin) is the aforementioned first described adipokine [13]. Leptin is mainly produced in adipose tissue, but is also synthesized in other, non-adipose tissue sites. It plays an important role in the regulation of energy homeostasis, and in metabolic, reproductive and neuroendocrine functions [30]. There are also emerging roles of leptin, including cognition, immune function and related autoimmune disorders, as well as bone metabolism [31]. Leptin is secreted proportionally to the amount of white adipose mass; circulating leptin levels reflect primarily the body energy stores and secondarily acute changes in caloric intake [32]. The importance of leptin could be derived from animal and human pathophysiology. Mice homozygous for mutations in the obese (ob) gene (ob/ ob), which prevent leptin production or lead to secretion of an inactive leptin molecule, exhibit hepatic steatosis and NASH together with hyperphagia, IR, early-onset obesity, diabetes and several neuroendocrine abnormalities, which

are, at least partly, improved by exogenous leptin administration [30,31]. In the liver cells, leptin acts mainly through the isoform b of leptin receptor (LepRb), which results in the activation of the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway [33]. Subsequently, the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and STAT5 pathways are activated. Concurrently, STAT3 activation leads to increased transcription and expression of suppressor of cytokine signaling (SOCS)-3, which acts as a feedback inhibitor molecule, attenuating LepRb signaling [33]. Apart from this main hepatic leptin pathway, leptin may also act via the phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), the 5′-adenosine monophosphate– activated protein kinase (AMPK), the forkhead box protein (Fox) O1 and the Hedgehog pathway [31]. There is evidence for an overlap of leptin and insulin signaling in the liver [25,26]. SOCS-3 is induced by both leptin [33] and insulin [34], and, when overexpressed, impairs both leptin [35] and insulin [36] signaling. Notably, the inhibition [36] or the elective deletion [37] of SOCS-3 improves IR, leptin resistance and hepatic steatosis. Furthermore, a loss-offunction mutation of the src homology 2 domain-containing adapter protein B (SH2)-B (which normally interacts with both JAK2 and insulin receptor substrate [IRS]-1 and IRS-2 [38]) has

Please cite this article as: Polyzos SA, et al, Adipokines in nonalcoholic fatty liver disease, Metabolism (2015), http://dx.doi.org/ 10.1016/j.metabol.2015.11.006

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metabolic consequences, including hyperleptinemia, hyperinsulinemia and hepatic steatosis [39,40]. It seems that leptin and insulin cross-talk in the liver with potential implications, but also therapeutic perspectives, on NAFLD, but further evidence is required to fully elucidate the extent of interplay and its pathophysiological rational. In animal models, leptin seems to exert a dual action on NAFLD, as it has been elsewhere summarized in detail [26]: it may protect from hepatic steatosis, at least at the initial stages of the disease, but it may act as an inflammatory and fibrogenic factor, when the disease persists or progresses. Leptin provides an insulin sensitizing and anti-steatotic effect by suppressing hepatic glucose production, inhibiting hepatic de novo lipogenesis, and by stimulating fatty acid oxidation [26]. Both ob/ob mice and fa/fa Zucker rats, which lack leptin or have a defective LepR, respectively, develop hepatic steatosis, together with IR, obesity and diabetes [41,42]. Both models are sensitive to further pathogenetic “hits” (e.g., endotoxinemia), thus quickly progressing from SS to NASH [43]. Importantly, leptin administration or liver-specific overexpression of LepRb, respectively, improves or prevents hepatic steatosis [41,44]. On the other hand, leptin treatment seems to favor hepatic inflammation and fibrosis in animal models. Activated hepatic stellate cells (HSCs) express LepRb, whose activation increases certain proinflammatory and proangiogenic cytokines, and growth factors contributing to hepatic inflammation and fibrosis [45]. Furthermore, leptin upregulates collagen type 1 [46], stimulates the production of tissue inhibitor of metalloproteinase (TIMP)-1 [47] and represses the gene expression of matrix metalloproteinase (MMP)-1 [48], changes mediating hepatic inflammation and fibrosis. Kupffer and sinusoidal endothelial cells also express LepRb, through which leptin upregulates the expression of transforming growth factor (TGF)-β, regarded as a key factor in hepatic fibrogenesis [49]. Notably, the upregulation of CD14 (an endotoxin receptor recognizing bacterial lipopolysaccharide) in Kupffer cells resulted in NASH progression in high-fed diet-induced steatosis mice, but not in chow-fed-control mice [50]. However, when leptin was co-administered in chow-fed mice, an upregulation of CD14 in Kupffer cell was observed, resulting in hepatic inflammation and fibrosis without steatosis. On the contrary, recombinant leptin administration to ob/ob mice did not upregulate CD14 or induce inflammation and fibrosis, despite severe steatosis [50]; these results provided evidence that leptin deficiency may lead to hepatic steatosis but not inflammation or fibrosis, whereas leptin in excess may favor hepatic inflammation and fibrosis. The pathway through which leptin induces inflammation and/or fibrosis has not been fully elucidated; however, there is evidence that leptin-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase upregulates the levels of miR21, which is a key regulator of TGF-β signaling. The resultant upregulation of miR21 causes fibrogenesis by pairing TGF-β and SMAD2/3-SMAD4 in the nucleus, whereas repressing SMAD7 [51]. Upregulation of miR21 also decreases the functionality of nitric oxide synthase-3, which subsequently results in increased sinusoidal cell injury, regarded as an early event in NASH [52]. In addition, leptin may promote hepatic fibrosis by reducing peroxisome proliferator-activated receptor (PPAR)-γ expression in HSCs, since PPARγ seems to

inhibit the activation of HSCs. Specifically, leptin upregulates GATA binding protein-2 through β-catenin and sonic hedgehog pathways in HSCs, which decreases PPARγ expression and increases the activated number of HSCs [53].

3.1.2.

Leptin in Human NAFLD

Most data for leptin in human NAFLD come from case–control studies. We have recently performed a meta-analysis of 33 studies, which include 2612 individuals (775 controls and 1837 NAFLD patients) [54]. Higher circulating leptin levels were observed in SS patients than controls, NASH patients than controls, and NASH than SS patients. These results remained essentially unchanged after excluding studies on pediatric/ adolescent populations and/or studies on morbidly obese adults subjected to bariatric surgery. Since, there was moderate-to-severe heterogeneity among studies in all comparisons, meta-regression analysis demonstrated that body mass index (BMI), which was inversely associated with leptin, accounted approximately for 25–30% of the between-study variance. However, when studies on morbidly obese adults subjected to bariatric surgery were excluded, BMI did not significantly explain the between-study variance [54]. This meta-analysis may render circulating leptin a factor needing re-evaluation for the use in prognostic non-invasive algorithms for NASH. Data regarding leptin within specific histological endpoints are generally controversial, as reviewed in detail elsewhere [26]. We recently showed higher circulating leptin levels in NAFLD patients with higher than lower stage of fibrosis or lobular or portal inflammation, but not steatosis [55]; however, further studies are needed. Data from prospective cohort studies are also limited. In a 3-year prospective study with paired-biopsies (n = 52), serum leptin decreased more in patients with stable or improved disease compared with those with worsened disease; however leptin change could not predict the disease progression or fibrosis independently from BMI change, which followed a similar pattern [56]. In another 7-year prospective study, individuals without NAFLD at baseline (n = 147) who developed NAFLD at 7 years (n = 28) had higher baseline leptin levels, as well as BMI and waist circumference, compared with those who remained without NAFLD. However, among individuals with NAFLD at baseline (n = 66), leptin levels were similar in those with or without disease remission [57]. Limitation of this study was that NAFLD diagnosis was not histologically proven. Further prospective studies with paired-biopsies and long-term follow-up would be of importance. Small interventional studies provided a notion that circulating leptin diminishes together with BMI after successful weight loss following lifestyle modifications or bariatric surgery [26]. Studies on the effect of other medications (antidiabetic, anti-lipidemic, anti-obesity) on leptin levels in NAFLD populations are limited and inconclusive [26]. Data from small and uncontrolled studies in patients with lipodystrophy and NAFLD showed that recombinant leptin treatment decreased hepatic volume and steatosis, but had no effect on inflammation and fibrosis [58,59]. Based on these data, and although the aforementioned dual leptin action has not been validated in humans, leptin administration in NAFLD patients with normoleptinemia or hyperleptinemia is

Please cite this article as: Polyzos SA, et al, Adipokines in nonalcoholic fatty liver disease, Metabolism (2015), http://dx.doi.org/ 10.1016/j.metabol.2015.11.006

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discouraged [14]. However, large, well-controlled studies in cautiously selected NAFLD patients with hypoleptinemia (i.e., lipodystrophy) are needed to clarify whether leptin treatment has any therapeutic role in this exceptionally small NAFLD sub-population. Furthermore, novel leptin analogs preserving the anti-steatotic, but lacking the potential inflammatory and fibrogenic leptin action would be of paramount importance. In this regard, a new leptin analog (7i) was shown to exert beneficial effect on body weight and hepatic steatosis in a mouse model of diet-induced obesity [60].

3.2.

Adiponectin

3.2.1.

Background

Adiponectin (named after adipose tissue) was identified in 1995, soon after the identification of leptin [61]. It is one of the most abundant and adipose tissue-specific adipokines, although, apart from mature adipocytes, other cells including hepatocytes, may also produce adiponectin when challenged (e.g., hepatocytes as a response to hepatic injury) [62]. Contrary to other adipokines, adiponectin is paradoxically decreased when adipose mass increases [63]. Once synthesized, adiponectin undergoes post-translational modifications (mainly hydroxylation and glycosylation), and, before its secretion, it forms trimers [low-molecular weight (LMW)], hexamers [middle molecular weight (MMW)] and 18-mers [high-molecular-weight (HMW)] isoforms; most metabolic actions of adiponectin have been related to its HMW isoform [64]. Adiponectin acts mainly through two transmembrane receptors (AdipoR1, AdipoR2) [65]. Both receptors are mostly presented in the skeletal muscle and moderately expressed in the liver. Although AdipoR2 is more abundant in the liver, AdipoR1 can also be found in human hepatocytes, pointing out the essential part played by both receptors in the pathogenesis of liver diseases. An additional cell membrane receptor for adiponectin is T-cadherin, but it seems to lack an intracellular domain and its effect on cellular signaling is unknown. Adiponectin in the liver acts mainly through the AMPK and PPAR-α pathway [64]. Adiponectin has anti-steatotic effect on the hepatocytes, because it increases free fatty acid (FFA) oxidation, and decreases gluconeogenesis, FFA influx and de novo lipogenesis [64]. Importantly, adiponectin protects hepatocytes from apoptosis [66], a hallmark of NAFLD. Furthermore, adiponectin, by acting on HSC, Kupffer and possibly sinusoidal cells, exerts anti-inflammatory and anti-fibrotic action. Its anti-inflammatory action is mainly achieved by suppressing pro-inflammatory cytokines (e.g., TNF-α and IL-6), and inducing anti-inflammatory cytokines (e.g., IL-10) [8]. Its anti-fibrotic action is mainly achieved via reducing HSC activation and proliferation, whereas inducing their apoptosis. In this regard, adiponectin downregulates TGF-β, connective tissue growth factor and collagen, and favors matrix degradation by changing the molecular ratio of MMP-1 to TIMP-1 [19,67].

3.2.2.

Adiponectin in Human NAFLD

Most data for adiponectin in human NAFLD come from case– control studies. We performed a meta-analysis of 27 studies, which include 2243 individuals (698 controls and 1545 NAFLD

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patients) [68]. Lower circulating adiponectin levels were observed in SS patients than controls, NASH patients than controls, and NASH than SS patients. Since, there was moderate-to-severe heterogeneity among studies in all comparisons, meta-regression analysis demonstrated that only the performance of liver biopsy on controls had a significant effect on the outcome, accounting approximately for 23–85% of the between-study variance. In studies with histologically confirmed controls, adiponectin levels were similar between SS patients and controls, whereas remained lower in NASH patients than controls [68]. However, this finding should be also cautiously considered, because a selection bias may have also committed in most studies with histologically confirmed controls, because they were morbidly obese patients subjected to bariatric surgery or patients subjected to surgery for other disease. Importantly, serum adiponectin has been incorporated in at least two prognostic non-invasive algorithms for NASH [69,70]. When NASH progresses to cirrhosis, circulating adiponectin seems to increase [27]. There are two possible mechanisms proposed for the paradoxical increase in adiponectin in cirrhosis: the decreased hepatic clearance of adiponectin and/or a compensatory increase toward the overwhelming production of proinflammatory cytokines in cirrhosis, as briefly discussed above. Interestingly, in compensated late stage (or burnt-out) NASH, circulating adiponectin was independently associated with hepatic fat loss, usually observed at the late stage NASH and cirrhosis [71]. This study strengthens the hypothesis that adiponectin may mediate the liver fat loss, which often accompanies advanced fibrosis and cirrhosis (the paradox of burnt-out NASH), a finding delaying the linkage of NASH to cryptogenic cirrhosis [71]. Data regarding adiponectin within specific histological end-points generally show a trend towards lower levels in more severe lesions, but this is not a constant finding, as reviewed in detail elsewhere [19]. We recently showed higher circulating adiponectin levels in NAFLD patients with lower than higher stage of fibrosis or lobular or portal inflammation, but not steatosis [55]; however, further studies are needed to clarify this finding. Data from prospective cohort studies are limited. In the above-mentioned 3-year prospective study with paired-biopsies (n = 52), neither baseline serum adiponectin nor its change (baseline to month 36) was associated with the disease or fibrosis progression [56]. In the 7-year prospective study, individuals without NAFLD at baseline (n = 147) who developed NAFLD at 7 years (n = 28) had lower baseline adiponectin levels compared with those who remained without NAFLD, but could not independently predict NAFLD development. However, among individuals with NAFLD at baseline (n = 66), adiponectin levels were similar in those with or without disease remission [57]. In another 7-year study, adiponectin at the end of follow-up was lower in individuals who developed NAFLD than those who did not, despite similar baseline levels [72]. Finally, in a 4-year prospective study, three single nucleotide polymorphisms of adiponectin gene (rs2241767, rs1501299, rs3774261) were proposed to increase NAFLD progression [73]; however, NAFLD was also not histologically confirmed in this study. Further prospective studies with paired-biopsies and longterm follow-up are needed.

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Although controversy still exists, data from NAFLD population generally suggest that circulating adiponectin increases after successful weight loss following lifestyle modifications [74], pharmacologic interventions [75], or bariatric surgery [76,77]. However, it seems that marked weight loss (> 10%) is needed to significantly increase adiponectin [19]. The main pharmacologic intervention considered to constantly increase adiponectin levels is thiazolidinediones, which are PPAR-γ agonists (e.g., pioglizone) [7], and this upregulation of adiponectin may account, at least partly, for the beneficial effect of thiazolidinediones in NAFLD, despite the observed weight increase [78]. Currently, selective PPAR-γ are under investigation, targeting to sustain the pharmacological advantages of the category, but minimize their side effects. Adiponectin properties render it appealing as therapeutic target for NAFLD; recombinant adiponectin exerted hepatoprotective effect in mice with NASH [79,80]. However, it is practically difficult to produce functionally active recombinant adiponectin, because its molecule is subjected to extensive post-translational modifications and is secreted in complex multimers [81,82]. For this reason, the discovery of adiponectin analogs, such as osmotin (a ligand for the yeast homologue of the adiponectin receptor) [83], might provide a therapeutic alternative for NASH. Another way is the indirect upregulation of innate adiponectin expression and secretion through marked and sustained weight loss or pharmacologic agents (e.g., pioglitazone) [81,82], as above mentioned.

3.3.

Resistin

3.3.1.

Background

Resistin (named after “resistance to insulin”) was described in 2001 as a peptide produced during adipocyte differentiation [84]. It belongs to the family of resistin-like molecules (RELMs), also known as “found in inflammatory zone” (FIZZ). Resistin circulates in two forms, the LMW trimer, which regarded as more bioactive, and the HMW hexamers, which are predominant [85]. Although its receptors have not been fully elucidated, resistin has been proposed to act via the tolllike receptor (TLR) 4 [86], the decorin (DCN) isoform Δ (ΔDCN) [87], the receptor tyrosine kinase-like orphan receptor (ROR) 1 [88] and the adenylyl cyclase-associated protein 1 (CAP) 1 [89]. Although in mice, resistin is predominantly produced by adipocytes [84], its distribution in humans is not well documented; the molecule is different in mice and humans, resistin-α encoding gene is absent in humans, resistin is produced in lower quantities in human adipose tissue and circulates in lower concentration in human serum (about 1/ 250) compared with mice [90]. It seems that resistin is produced by macrophages infiltrating human adipose tissue rather than adipocytes [91]. Peripheral blood mononuclear cells also significantly contribute to human resistin levels [92]. Resistin is also expressed in the liver, where its production seems to increase with increasing liver damage [93,94]. Treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action, thereby inducing IR; on the contrary, administration of anti-resistin antibody improves insulin sensitivity in mice with dietinduced obesity [84]. This action may be partly mediated by the activation of AMPK, thus decreasing the expression of

hepatic gluconeogenic enzymes; in this regard, mice lacking resistin exhibited low glucose levels after fasting, due to reduced hepatic glucose production [95]. There is also evidence that resistin treatment induces the expression of SOCS3 [96], an inhibitor of insulin signalling, as above mentioned. In diet-induced obese mice lacking resistin (knockout), the secretion of very low-density lipoprotein (VLDL) and hepatic steatosis were decreased, although knockout mice had similar body weight and fat as wild-type mice (either when fed on chow or a high-fat diet) [97]. Similarly hepatic steatosis was drastically decreased in ob/ob mice lacking resistin. The anti-steatotic effect of resistin deficiency was related to reduced expression of genes involved in hepatic lipogenesis and VLDL export [97]. Furthermore, resistin acts as a proinflammatory cytokine by stimulating other proinflammatory factors, including TNF-α, IL-1β, IL-6 and IL-12 in macrophages and mononuclear cells, but also be induced by TNF-α, IL-1 and IL-6 [98–100]. Apart from contributing to this proinflammatory cascade, resistin increases hepatic inflammation in animal models via MAPK pathway and activation of the coagulation cascade [101]. Finally, resistin may modulate hepatic fibrosis, via activating the HSCs and enhancing the production of TGF-β and collagen type I by Kupffer cells [67]. Exposure of human HSCs to recombinant resistin resulted in increased expression of the proinflammatory neutrophil chemokine IL-8 and monocyte chemoattractant protein-1, through activation of nuclear factor (NF)-κB [93]. Weight loss resulted in downregulation of resistin in visceral adipose tissue of rats [102], but controversy exists in humans. Similarly, the effect of exercise on resistin is inconclusive, and may be related to intensity of exercise (e.g., its levels were decreased after mild exercise [103], but increased after strenuous exercise [104]). Thiazolidinediones seem to downregulate resistin in both mice [84] and humans [105]. Metformin was also shown to decrease circulating resistin in individuals with glucose intolerance [106].

3.3.2.

Resistin in Human NAFLD

Although the association between resistin, and IR, hepatic steatosis, inflammation and fibrosis is sufficiently documented in rodents, the topic remains inconclusive in human NAFLD. Circulating resistin was reported to be positively associated with liver fat, assessed by MRI, in patients with T2DM [105]; notably, the decrease in resistin, observed after pioglitazone treatment, was positively associated with the decrease in hepatic fat content and improvement in hepatic insulin sensitivity in the same study [105]. However, other authors reported an inverse association between resistin and hepatic fat content in nondiabetic individuals [107]. In histologically confirmed NAFLD, some authors have reported higher circulating resistin levels in NAFLD [108,109], or SS [110,111], or NASH [111] patients than controls. However, other authors reported similar resistin levels between NAFLD [112–115], or SS [114–116], or NASH [114–117] patients and controls. In the comparison between NASH and SS patients, some authors reported higher resistin levels in NASH [108,118], whereas others reported similar levels [111,113– 116]. To the best of our knowledge, in only one study with pediatric NAFLD, lower resistin levels were observed in

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patients with more severe hepatic lesion (NASH than SS) [119]. Resistin has been included in a combined noninvasive algorithm for NASH [69]; however, the same group did not include resistin in the algorithm predicting NASH or NASHrelated fibrosis in a more recent study [120]. Interestingly, the aforementioned 7-year prospective study showed that resistin levels, either at baseline or the end of follow-up, were not associated with the development of NAFLD [72]. Regarding specific hepatic lesions, circulating resistin was positively associated with hepatic steatosis [109,121] and inflammation [109,110] in some studies, but other authors observed no significant association between circulating resistin and specific histological lesions [115,119,120]. Despite inconclusive data on circulating levels, existing data on hepatic resistin expression are more unanimous. Higher hepatic resistin mRNA expression in NASH patients than either SS patients or controls, as well as in SS patients than controls was reported in a study [111]. Interestingly, in the same study, the distribution of resistin was predominant in perisinusoidal cells (i.e., Kupffer cells and HSCs) [111]. Other authors reported higher resistin expression in hepatic progenitor cells in children with NASH than controls [94]. A positive association between hepatic resistin mRNA expression and hepatic steatosis, inflammation and fibrosis was also reported [111]. Furthermore, resistin expression in hepatic progenitor cells was associated with hepatic fibrosis in another study with pediatric population [94]. Likewise, other authors reported higher resistin mRNA expression in subcutaneous adipose tissue of NAFLD patients than controls (lean or obese) [108], as well as a positive association between peripheral leucocyte resistin expression and hepatic steatosis, inflammation and fibrosis [122]. In summary, despite the differences between mice and humans regarding resistin and inconclusive evidence for circulating resistin in human NAFLD, existing data support that resistin may play a local hepatic role in inflammation and fibrosis. However, more studies are needed toward this direction.

3.4.

Visfatin

3.4.1.

Background

Visfatin (named after visceral fat) corresponds to the product of the gene pre-B cell colony-enhancing factor (PBEF) described in 1994 as a proinflammatory cytokine [123]. Apart from its extracellular action, visfatin has been shown to have intracellular enzymatic activity, as a nicotinamide phosphoribosyltransferase (NAMPT), catalyzing the rate-limiting step in nicotinamide adenine dinucleotide (NAD), thereby regulating growth, apoptosis, DNA replication, repair, angiogenesis and cellular energy metabolism [124]. Visfatin is produced by various tissues and has been proposed as a multifaceted peptide, as mirrored by its potential involvement in a wide range of disorders, including metabolic, inflammatory and neurodegenerative ones, atherosclerosis, myocardial failure, malignancies, septicemia and human immunodeficiency virus infection [125]. In adipose tissue, visfatin is predominantly produced by macrophages infiltrating it rather than adipocytes [91]; importantly, visfatin may also inhibit macrophage apoptosis, thereby prolonged their action and its own secretion [126].

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Although an insulin-mimetic effect had been attributed to visfatin, by binding the insulin receptor [127], other groups did not replicate these findings, and the initial publication was retracted. Nevertheless, other authors showed that the intracellular visfatin action is crucial for pancreatic β-cell function, since inhibition of NAMPT leads to defective glucose-stimulated insulin secretion, thereby possibly being an important regulator of glucose homeostasis and IR [128]. On the contrary, the extracellular visfatin action seems to be mainly proinflammatory. Visfatin induces the production of other inflammatory cytokines, including TNF-α, IL-6 and IL1β. However, higher concentrations of visfatin may induce the expression of anti-inflammatory cytokines, e.g., IL-10 [21], possibly as a counterbalancing mechanism to confine the overwhelming production of inflammatory cytokines [21]. Taken together, visfatin might potentially adversely affect hepatic inflammation in NAFLD. However, a positive effect on hepatic steatosis, through the regulation of glucose homeostasis in β-cells and IR, remains to be elucidated by mechanistic studies. Similarly, its effect on hepatic fibrosis remains inconclusive [67].

3.4.2.

Visfatin in Human NAFLD

Data from human histologically confirmed NAFLD are limited and inconclusive. Most authors reported similar circulating visfatin levels between NAFLD [129], or SS [130], or NASH [130,131] patients and controls. However, some authors reported higher visfatin levels in NAFLD than controls [112], or lower visfatin levels in either SS or NASH patients than controls [132]. In a study, similar visfatin levels in NAFLD patients and BMI-matched controls were reported, whereas higher levels in NAFLD patients than controls of lower BMI [114]. To the best of our knowledge, all authors reported similar visfatin levels between NASH and SS patients [114,130,132]. Furthermore, similar hepatic visfatin expression between NASH and SS patients has been reported [133]. Regarding specific hepatic lesions, most authors did not observe any association between circulating visfatin and hepatic steatosis, inflammation or fibrosis [129,130,134]. Aller et al. reported that the rates of portal inflammation, but not steatosis, fibrosis or portal inflammation, were higher in the group of higher visfatin levels [135]. Kukla et al. reported similar hepatic visfatin expression regardless the grade of steatosis, lobular and portal inflammation, but higher in patients with than without fibrosis; however, hepatic visfatin expression was similar between patients with mild and advanced fibrosis [133]. There may be some speculations for the inconsistent data on visfatin in NAFLD and metabolic diseases. First, since visfatin is produced by many tissues, the comorbidity and concomitant medications may be important confounders. Second, visfatin is affected by adipose mass, which may also account for the heterogeneity among studies. Third, circulating visfatin may not reflect its local levels in adipose tissue and the liver. Finally, visfatin intracellular (enzymatic) and extracellular (cytokine-like) actions may be opposite in NAFLD. Current data do not favor a specific role for visfatin in the pathogenesis of NAFLD, or in noninvasive assessment or treatment of NAFLD patients. Further mechanistic studies are needed to elucidate whether the pharmacological

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inhibition of visfatin could be beneficial for NASH, as proposed for the treatment of malignant and inflammatory diseases, including rheumatoid arthritis [136].

3.5.

Retinol-Binding Protein (RBP) 4

3.5.1.

Background

RBP-4, was described as an adipokine in 2005 [137] and is predominantly expressed in visceral rather than subcutaneous adipose tissue [138], and the liver [139]. RBP-4 had been long ago described as a transport protein for retinol (vitamin A) from the liver to its peripheral targets [139]. Although its receptor remains largely unknown, the membrane stimulated by retinoic acid (STRA) 6 receptor has been propose to mediate RBP-4 actions on adipogenesis [140]. RBP-4 is elevated in IR states, including obesity and T2DM, in both animals [137] and human [138,141], and its levels have been inversely related to the adipocyte glucose transporter (GLUT) 4, which plays a key role in the muscle and liver IR [137,141]. In the liver, RBP-4 also induces the hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase, thereby increasing basal glucose production [137]. Circulating RBP-4 was shown to decrease after weight loss [142]. Notably, exercise reduced RBP-4 levels only in individuals with concomitant reduce in IR [141]. Thiazolidinediones, agents with a beneficial effect on IR and NAFLD [78], reduced RBP-4 levels in mice [137] and humans [143], thereby exerting an action opposite than that observed on adiponectin levels [7]. Furthermore, fenretinide, a synthetic retinoid increasing the urinary excretion of RBP-4, normalizes circulating RBP-4 levels and improves insulin resistance in mice [137].

3.5.2.

RBP-4 in Human NAFLD

Similarly to IR and to the other components of IR syndrome (including obesity, dyslipidemia and blood pressure) [141], RBP-4 seems to be positively correlated with liver fat, as assessed by magnetic resonance imaging (MRI), in healthy individuals [144]. Furthermore, in studies without histological confirmation, RBP-4 was generally higher in NAFLD patients than controls, in either adult [145] or children [146] populations, although controversy still exists. However, data are inconclusive in studies with histologically confirmed NAFLD. Some authors reported higher circulating RBP-4 levels in SS [110,147], or NASH [147] patients than controls. In our series, similar RBP-4 levels between NAFLD patients and obese controls were observed, but also a trend toward higher levels in either NAFLD patients or obese controls compared with lean controls; notably, this difference became robustly significant after adjustment for BMI [55]. In the comparison between NASH and SS patients, some authors reported similar levels [55,147–149], whereas others reported lower levels in NASH than SS [150,151]. Interestingly, similar RBP-4 mRNA expression was observed among morbidly obese patients with and without NAFLD in the adipose tissue (visceral or subcutaneous) or the liver [147]. Regarding specific hepatic lesions, some authors reported a positive association between circulating RBP-4 levels and ballooning [55], whereas others an inverse association with fibrosis [150,151]. On the contrary, hepatic RBP-4 expression was positively associated with fibrosis in another study [152]. Finally,

other authors reported no association between circulating RBP-4 and steatosis, inflammation or fibrosis [110,149]. Although definite conclusion could not be drawn, because of the nature (cross-sectional) of the aforementioned studies and their controversial, to a degree, results, we could speculate that circulating RBP-4 levels may be primarily associated to obesity and IR rather than NAFLD itself. However, mechanistic studies are needed to elucidate whether NAFLD may impair or enhance hepatic RBP-4 production and whether hepatic RBP-4 levels may have a distinct role rather than its circulating levels on hepatic histology.

3.6.

Chemerin

3.6.1.

Background

Chemerin is an adipokine secreted in an inactive form (prochemerin) and activated through C-terminal cleavage by inflammatory and coagulation serine proteases [153]. It acts through the chemokine-like receptor (CMKLR) 1, a G-protein coupled receptor (GPR), the chemerin receptor (ChemR) 23 and the chemokine (CC motif) receptor-like (CCRL) 2 [154]. Although chemerin and its receptors exist throughout the human body, the adipose tissue (mainly visceral) and the liver (mainly the hepatocytes) are major sources of chemerin production [155,156]. Chemerin levels are generally higher in obesity and IR states and decreases after weight loss [157]. Obese animal models of obesity and IR, such as ob/ob and db/db mice, have increased chemerin expression [158]. However, other authors showed that chemerin-deficient mice are also glucose intolerant [159] and that chemerin has insulinsensitizing effects on β-cells [159] and adipocytes [160]. Chemerin was also shown to contribute to inflammation; it is positively associated with visceral adipose tissue macrophages [157], hepatic expression of CD68 cells (e.g. Kupffer cells) [161] and proinflammatory cytokines, including hepatic expression of TNF-α [156]. Regarding hepatic fibrosis, chemerin related experimental data are very limited and inconclusive [67]. Experimental data from mice studies on NAFLD are also limited and conflicting. Hepatic chemerin mRNA was significantly increased in the liver of mice fed on a high fat diet and positively correlated with body weight [156] in one study, and reduced hepatic steatosis was reported in mice lacking CMKLR1 in another [162]. On the contrary, other authors reported that lipid accumulation, immune cell infiltration, hepatic inflammatory and fibrotic gene expression were not affected in mice lacking CMKLR1 [163].

3.6.2.

Chemerin in Human NAFLD

In studies with histologically confirmed NAFLD, most [164– 166], but not all [55], authors have reported higher circulating chemerin levels in NAFLD patients than controls. In another study, hepatic chemerin expression was also higher in NAFLD patients than controls [156]. In the comparison between NASH and SS patients, some authors reported higher circulating chemerin levels in NASH [164], whereas others reported similar levels [55,161]. Despite similar circulating levels, higher hepatic chemerin and CMKLR1 mRNA expression in NASH than SS were observed in one study [161]; notably, hepatic chemerin expression was correlated with CMKLR1 expression, but not with circulating chemerin levels [161].

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Regarding specific hepatic lesions, data are also inconclusive. Different studies showed higher chemerin levels in: a) fibrosis and portal inflammation, but not steatosis or lobular inflammation [157]; b) fibrosis only [165], c) ballooning, but not steatosis, inflammation or fibrosis [164], whereas other studies showed no significant association between circulating chemerin and any histological lesion [55]. Importantly, the hepatic chemerin, but not CMKLR1, expression was positively and independently associated with hepatic steatosis, lobular inflammation, ballooning and fibrosis in one study [161]. In another study, visceral chemerin expression, but not subcutaneous or hepatic expression, or circulating chemerin, was negatively and independently associated with hepatic steatosis, lobular and portal inflammation (but not fibrosis) [167]. Circulating chemerin levels were not correlated with visceral, subcutaneous or hepatic chemerin expression in the same study [167]. In summary, data on chemerin in human NAFLD are controversial; it seems that circulating chemerin levels do not accurately reflect the hepatic or adipose tissue expression, implying that a potential role of chemerin in the pathogenesis of NAFLD could not be estimated by its circulating levels. Furthermore, circulating chemerin is likely linked to increased β-cell function observed in NAFLD patients, rather than NAFLD itself. Moreover, since chemerin is a multifactorial peptide, a tissue specific action could not be excluded. However, more mechanistic studies are needed toward this direction.

3.7.

Adipokines with Limited Evidence in NAFLD

In this section, adipokines with limited data in human NAFLD are summarized. After a brief introduction on each adipokine, studies in histologically confirmed NAFLD populations are presented. Acylation-stimulating protein (ASP), also known as C3adesArg, is a strong stimulator of triglyceride synthesis in adipocytes and is also implicated in the inflammatory response. ASP is produced from complement factor C3 through an interaction requiring factor B and adipsin (factor D) [168] and has been proposed to act through the chemoattractant receptor-like protein (C5L2) [169]. Circulating ASP levels seems to increase in obesity, T2DM, dyslipidemia and cardiovascular disease [168]. In the unique histologically confirmed study, ASP levels were higher in NAFLD patients than controls (of similar BMI) [170]. In this study, ASP levels were positively associated with BMI and HOMA-IR [170]. Adipsin is one of the most abundant adipokines, is almost exclusively produced by adipocytes [171] and, similarly to adiponectin, paradoxically declines in many animal models of obesity and diabetes [172]. Adipsin catalyzes the ratelimiting step of the alternative pathway of complement activation, being the factor D. Although its metabolic effects remain largely unknown, it has been recently proposed as a link between adipocytes and β-cell function [173]. Similar adipsin levels were observed in histologically confirmed NAFLD patients and controls, as well as between SS and NASH patients [165]. Likewise, similar adipsin levels were observed between SS and NASH in a pediatric population [119]. Neither study showed an association between adipsin and hepatic steatosis, inflammation or fibrosis [119,165].

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Apelin was identified in 1998 as the ligand of the angiotensin-like receptor 1 or apelin receptor (APJ receptor), a GPR [174]. Apelin and AJP receptor are widely expressed in many tissues, including the adipose tissue and the liver [175]. Apelin was shown to affect both glucose and lipid metabolism, and to contribute to inflammation and angiogenesis [176]. In cirrhotic rats, apelin was highly expressed in activated HSCs, whereas APJ receptor overexpressed in the hepatic parenchyma. Importantly, treatment with an apelin receptor antagonist diminished hepatic fibrosis and neoangiogenesis, and improved cardiovascular and renal function in rats [177]. Higher apelin levels in obesity and IR states have been observed in most, but not all studies [176]. Higher apelin levels were also shown in patients with cirrhosis compared with healthy individuals [177]. There are two studies reporting on circulating apelin levels in human histologically confirmed NAFLD. Both studies showed higher apelin levels in NAFLD patients than controls (of lower BMI), but similar between SS and NASH patients [178,179]. Furthermore, apelin levels were positively correlated with HOMA-IR in both studies [178,179], and with BMI in one of them [178]. Further studies are needed to elucidate whether apelin contributes to the pathogenesis of NAFLD, or it is simply a by-stander of obesity, usually coexisting in NAFLD patients. Obestatin is a pleiotropic adipokine, which may play a role in regulating β-cell survival and insulin secretion, thereby participating in glucose and lipid metabolism. It also exhibits an autoimmune regulatory effect on energy metabolism and the gastrointestinal system. It has been proposed to act via two membrane receptors, GPR39 and glucagon-like peptide receptor 1 (GLP-1R) [180]. Although controversy exists, obestatin levels are decreased in human obesity and seem to be negatively associated with IR [181]. In a study with histologically confirmed NAFLD, similar obestatin levels were observed in NAFLD patients and controls (of lower BMI), and in SS and NASH patients [179]. Interestingly, no association between obestatin levels and BMI or HOMA-IR was observed in the same study [179]. In another study, similar obestatin levels were also observed in SS and NASH in morbidly obese patients [182], though obestatin was higher in the group with higher fibrosis grade. Notably, obestatin decreased after bariatric surgery and its baseline levels were associated with the rate of weight loss [182]. Omentin is an adipokine predominantly expressed in visceral adipose tissue and it is considered to have an insulin-sensitizing role [183]. Circulating omentin has been inversely related to obesity and IR [3]. In the unique to-date study in patients with histologically confirmed NAFLD, circulating omentin levels were higher in NAFLD patients than controls (of lower BMI) [165]. However, similar omentin levels between SS and NASH patients were observed. Furthermore, omentin was positively associated with ballooning, but not hepatic steatosis or fibrosis [165]. Vaspin, initially identified as the serpin member A12 of the serine protease inhibitor family, was introduced as an adipokine in 2005 [184]. Vaspin is expressed in human adipose tissue (predominantly visceral) and the liver and has been proposed to exert an insulin sensitizing and anti-orexigenic effect [185]. Recent data provide evidence for higher vaspin levels in obesity

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and T2DM; furthermore, changes in the vaspin gene have been linked to its compensatory effects on obesity and glucose homeostasis [186]. In studies with histologically confirmed NAFLD, higher circulating vaspin levels were observed in NAFLD [166,179] or NASH [187] patients than controls. Other authors reported similar vaspin levels between NAFLD patients and controls [164]. It is highlighted that controls were of lower BMI than patients in all the above studies. In the comparison between SS and NASH patients, similar vaspin levels were observes in two studies [164,179]. Regarding specific hepatic lesions, no association between circulating vaspin and hepatic steatosis, inflammation or ballooning was observed in two studies [164,187], whereas a positive association with hepatic fibrosis was shown in another study [179]. Although future studies may elucidate the role of these adipokines in NAFLD, if any, existing data may show tendencies, but do not allow drawing definite conclusions. Other adipokines (e.g., nesfatin-1, neopterin, neuregulin-4 etc.) might be candidates for study in NAFLD, but there are todate no data in patients with histologically confirmed NAFLD.

4.

Closing Remarks

Obesity is a global epidemic [188] associated with increased morbidity and mortality [189,190]. In the USA, 70% of adults and 32% of children and adolescents are overweight or obese according to the most recent National Health and Nutrition Examination Survey [191]. Due to its high healthcare and economic burden, obesity is currently a field of extensive research. The identification of adipokines, hormones secreted by the adipose tissue, pathogenetically linked, at least partly, obesity with its related morbidity and gave birth to new perspectives for the treatment of obesity-related disorders, including NAFLD [18]. What was considered to be an inert depot storage organ 20 years ago, is now regarded as an active endocrine organ releasing several adipokines acting locally, in an autocrine and paracrine fashion, or peripherally, in an endocrine fashion [14]. The identification of leptin was initially regarded as panacea for common obesity and related morbidity, including NAFLD [26]. Circulating leptin increases by increasing the severity of NAFLD [54], possibly as a compensatory anti-steatotic mechanism. Therefore, despite the initial expectations, its action is expected to fail due to the already high levels observed in the advanced NAFLD. Leptin resistance, evident in common obesity that usually co-exists with NAFLD, is also another deterring reason to use recombinant leptin in NAFLD with hyperleptinemia [26]. A third reason is experimental evidence showing that leptin treatment may improve steatosis, but exacerbates inflammation and fibrosis [50]. On the other hand, recombinant leptin (metreleptin) replacement therapy in patients with NAFLD and lipodystrophy (for which leptin replacement therapy has been approved [14]) decreased hepatic volume and steatosis, though had no effect on hepatic inflammation and fibrosis [58,59,192]. Based on these data, it seems that the effect of leptin treatment is different when circulating leptin levels are low (leptin replacement) compared to normal or high.

Adiponectin, which decreases by increasing the severity of NAFLD [68], would also be another ideal target to treat NAFLD, at least before the late stage of burn-out NASH, in which adiponectin paradoxically increases [71]. However, its complicated structure and extensive post-translational modifications render the production of functionally active recombinant adiponectin practically impossible [81,82]. Therefore, research has been oriented to the identification of adiponectin analogs or medications upregulating innate adiponectin [81,82]. Apart from leptin and adiponectin, the association between other adipokines and NAFLD is more obscure. Resistin seems to have a distinct role in animal models and humans [90]; existing data do not favor a certain role for circulating resistin, but its liver expression may play a role in hepatic inflammation and fibrosis [94]. Visfatin has distinct intracellular (enzymatic) and extracellular (cytokine-like) actions, which makes the interpretation of its role in NAFLD, if any, complicated [125]. RBP-4 has not provided consistent evidence in NAFLD, although it is associated with obesity and IR [141]. Evidence on circulating chemerin in NAFLD is also inconclusive, but hepatic chemerin may exert a role in NAFLD. Other adipokines, including ASP, adipsin, apelin, obestatin, omentin and vaspin, have limited evidence in NAFLD, whereas the newer identified ones have no evidence in histologically confirmed NAFLD. A given limitation of the existing literature is the observational nature of the majority of relevant studies. Most clinical studies are case–control or cross-sectional, which makes the causality impossible to deduce, and even a definite conclusion on the association difficult, because of the heterogeneity between studies (e.g., age, sex, race, BMI, co-morbidity, staging, grading and duration of the disease). In our opinion, the most important confounding is adiposity; controls are of lower BMI and waist circumference in most studies, and only in a minority of them, an adjustment for BMI or waist circumference was performed. It is acknowledged that it is rather difficult to find obese controls (without NAFLD) to match with NAFLD population, but it is considered to be of high importance in the future studies. Prospective cohort studies with paired biopsies will definitely offer a higher level of evidence on adipokine changes when NAFLD progresses or regresses overtime, thereby elucidating their pathophysiologic interplay and asking the question whether some adipokines may help in the noninvasive diagnosis of NAFLD; however, these studies are limited by the need for repeat liver biopsies, which usually result in high drop-out rates. Another important issue, which future research should be target to, is the hepatic expression of certain adipokines, which might affect NAFLD in an autocrine and/or paracrine fashion, without similarly affecting their circulating levels. Based on the existing data, we hardly could propose the use of a single adipokine or a combination of them for the noninvasive diagnosis of NAFLD. Although a certain profile of adipokines (e.g., a combination of high leptin, resistin, RBP-4, and low adiponectin) would favor NASH over SS, this is currently only a hypothesis remaining to be elucidated. In conclusion, there is still much uncertainty around the pathophysiologic association between adipokines and NAFLD, partly owing to the fact that: a) multiple cells may produce multiple adipokines in an ever-changing metabolic milieu; b) the hepatic effects of many adipokines may not be reflected to their

Please cite this article as: Polyzos SA, et al, Adipokines in nonalcoholic fatty liver disease, Metabolism (2015), http://dx.doi.org/ 10.1016/j.metabol.2015.11.006

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circulating levels; c) each adipokine has unique characteristics; d) the heterogeneity between studies renders the conclusions insecure to a large extend. However, since much have changed since the introduction of adipose tissue as a highly active endocrine organ 20 years ago, new evidence is expected to provide further pathogenetic insights for NAFLD, which is a disease strongly associated with excessive fat storage and, therefore, with adipokine imbalance. Novel pathogenetic evidence may provide the soil for the noninvasive diagnosis of NAFLD and clinical trials investigating the effect of adipokine-targeted interventions on NAFLD treatment, which is currently an unmet medical need. The list of adipokines, together with our interest on them, is continuously being enriched, but we should keep in mind that the best way to fight both adipokine imbalance and NAFLD is to prevent excessive fat, before the global epidemics of obesity makes us rename NAFLD to Nonalcoholic Fatty Future Disease.

Funding No sources of financial support for this study.

Disclosure Statement SAP and JK: No conflict of interest; CSM has served as consultant for Astra Zeneca and had received research support through his institution from Amgen.

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