Potential conflict of interest: Nothing to report.
Adipokines are polypeptides secreted in the adipose tissue in a regulated manner. While some of these molecules are expressed only by adipocytes, resident and infiltrating macrophages and components of the vascular stroma markedly contribute to expression of other adipokines. As a result, adipose tissue inflammation is associated with a modification in the pattern of adipokine secretion. Leptin, adiponectin, and resistin are the best-studied molecules in this class, but cytokines such as tumor necrosis factor or interleukin-6 are also secreted at high levels by the adipose tissue. Several other molecules have been recently identified and are actively investigated. Adipokines interfere with hepatic injury associated with fatty infiltration, differentially modulating steatosis, inflammation, and fibrosis. Several studies have investigated plasma levels of adiponectin in patients with nonalcoholic fatty liver disease, to establish correlations with the underlying state of insulin resistance and with the type and severity of hepatic damage. Hepatitis C is another disease where adipokines may represent a link between viral infection, steatosis, and metabolic disturbances. Identification of the mediators secreted by expanded adipose tissue and their pathogenic role is pivotal in consideration of the alarming increase in the prevalence of obesity and of the detrimental role that this condition exerts on the course of liver diseases. (HEPATOLOGY 2009.)
“Thou seest I have more flesh than another man, and therefore more frailty”
William Shakespeare, Henry IV, Part I: Act 3
White adipose tissue, the most abundant in adults, has three main functions: (1) storage of energy; (2) hydrolysis of triglycerides to provide free fatty acids, supporting the energy needs of tissues; and (3) release of adipokines (or adipocytokines). The relevance of adipose tissue to hepatic diseases is indicated by the higher prevalence of cirrhosis in obese patients than in the general population.1 Although the burden of nonalcoholic fatty liver disease (NAFLD) is clearly important, obesity also worsens the course of chronic hepatitis C (CHC) and alcoholic liver disease2 and is associated with increased mortality for several cancers of the gastrointestinal tract, including hepatocellular carcinoma (HCC).3
The term “adipokines” (adipose tissue cytokines) comprises polypeptide factors which are expressed significantly, although not exclusively, by adipose tissue in a regulated manner. Besides adipocytes, accounting for one-third of the cells, adipose tissue is composed of stromal cells, including macrophages, fibroblasts, and infiltrating monocytes, all of which contribute to adipokine production (Fig. 1). A particular role is played by ectopic fat, i.e., expansion of adipose tissue at sites such as the omentum (visceral fat) or the heart (epicardial or mediastinal fat). Ectopic fat represents a dysfunctional tissue more likely to undergo inflammation and to contribute to the pathogenesis of obesity-related disorders.4 In the context of hepatic diseases, visceral adipose tissue is unique, because the factors produced at this level directly target the liver through the portal vein. In terms of adipokine secretion, some factors are preferentially expressed at the level of visceral rather than subcutaneous fat (Table 1).
Table 1. Predominant Expression of Different Adipokines in Subcutaneous or Visceral Tissue
Indicates molecules for which no clear prevalence has been demonstrated or with conflicting data.
We will first outline the principal characteristics of the major adipokines, their metabolic actions (Table 2), and their action in cellular and animal models of liver injury. The effects of adipokines on the basic components of steatohepatitis are illustrated in Fig. 2.
Table 2. Adipokine Actions Relevant to Metabolism
The effects are listed irrespective of the prevalent site where adipokines act. (R) indicates data predominantly obtained in rodent models.
Inhibition of food intake
Stimulation of energy expenditure
Suppression of hepatic glucose production
Suppression of fatty acid biosynthesis (inhibition of stearoyl coenzyme A desaturase-1 [SCD-1])
Stimulation of fatty acid oxidation in the liver and skeletal muscle
Stimulation of glucose uptake in skeletal muscle
Stimulation of insulin secretion
Stimulation of adiponectin expression
Stimulation of proinflammatory cytokines (e.g., IL-6 and TNFα)
Suppression of resistin expression
Suppression of RBP4 expression
Suppression of hepatic glucose production
Suppression of hepatic lipogenesis
Stimulation of glucose uptake by skeletal muscle
Stimulation of fatty acid oxidation in the liver and skeletal muscle
Stimulation of insulin secretion
Modulation of food intake and energy expenditure
Inhibition of proinflammatory cytokines (e.g., IL-6 and TNFα)
Induced by PPAR-γ agonists (thiazolidinediones)
Reduction of peripheral insulin sensitivity (R)
Increased in endogenous glucose production by the liver (R)
Induction of insulin resistance (R)
Stimulation of proinflammatory cytokines (e.g., IL-6 and TNFα)
Retinol binding protein 4
Stimulation of hepatic gluconeogenesis (R)
Impairment of insulin signaling in skeletal muscle (R)
Induction of insulin resistance (R)
Stimulation of insulin secretion (R)
Stimulation of proinflammatory cytokines (IL-6 and TNFα)
Induction of nicotine adenine dinucleotide synthesis
Enhancement of insulin-stimulated glucose transport in adipocytes
Improvement in insulin sensitivity (R)
Suppression of leptin, resistin, and TNFα expression
Enhancement of insulin-stimulated glucose uptake
Stimulation of adiponectin expression
Inhibition of proinflammatory cytokines (e.g., IL-6 and TNFα)
Regulation of blood pressure and fluid homeostasis
Stimulated by insulin or TNF
Regulation of food intake
Inhibition of glucose-mediated insulin secretion
Tumor necrosis factor-α (TNFα)
Induction of insulin resistance via impairment of insulin post-receptor signaling
Induction of insulin resistance
Induction of leptin resistance
Monocyte chemoattractant protein-1 (MCP-1)
Induction of insulin resistance
Expression of leptin, the product of the obese (ob) gene, is predominant in the adipose tissue, but is also found at many other sites.5 Six isoforms of leptin receptors have been identified (ObRa through ObRf) and are expressed in the central nervous system and in a wide range of peripheral tissues, including the liver. ObRb mediates most of the biological effects of leptin via activation of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (Stat3) pathway. ObRe is a soluble receptor that forms complexes with circulating leptin. The free-to-bound leptin ratio regulates its biological activity, and high levels of circulating ObRe have been related to reduced leptin action.5 Secretion of leptin is proportional to the fat mass and provides antiobesity signals, regulating food intake, sympathetic tone, and energy expenditure in conditions of energy excess, through hypothalamic pathways. This action is reflected by the phenotype of ob/ob mice, which lack functional leptin and are obese and hyperphagic. However, obese patients have elevated levels of leptin, suggesting that they are resistant to the action of this adipokine.5 The mechanisms of leptin resistance are essentially central, in relation to defective leptin transport and alterations in ObRb signaling, including overexpression of suppressor of cytokine signaling-3 (SOCS3),5 a molecule that inhibits leptin signaling (Fig. 3).
The marked steatosis observed in leptin-deficient, ob/ob mice indicates that leptin prevents fatty liver, both indirectly, through central neural pathways, and directly, via hepatic activation of adenosine monophosphate–activated protein kinase (AMPK).6, 7 Similarly, in generalized lipodystrophy, which is another condition of leptin deficiency, leptin replacement improves fatty liver.8 In contrast, the observation that patients with obesity have a fatty liver despite elevated leptin levels has suggested the presence of hepatic leptin resistance. A role for nutrients has been recently suggested in this disturbance, because fructose induces hyperleptinemia and hepatic leptin resistance, interfering with Stat3 signaling.9 Other mechanisms of leptin resistance in this model include increased levels of SOCS3, which impairs postreceptor signaling, and leads to reduced AMPK activation.10 Activation of the cannabinoid receptor CB1 is an additional pathway implicated in the pathogenesis of leptin resistance.11 The liver is also involved in the regulation of the different isoforms of leptin receptor. The soluble leptin receptor is expressed by the liver under the control of insulin, as shown by the increase in soluble leptin receptor observed in mice with liver-specific deficiency for the insulin receptor, although in this model, the sensitivity to leptin is maintained.12 In contrast, leptin resistance is observed in diet-induced obesity, in association with reduced expression of hepatic leptin receptors.13
Leptin is also involved in innate and adaptive immunity. Ob/ob mice are protected from injury in models of autoimmune disease and in T cell–mediated hepatitis induced by injection of concanavalin A.14 Conversely, leptin-deficient animals are more susceptible to bacterial or viral infections, and show increased hepatotoxicity and mortality following endotoxin administration.15 Thus, leptin generally acts as a proinflammatory agent and participates in the protection from microbial infections. Additionally, leptin has a protecting role in models of alcoholic liver damage.16, 17
Leptin has also been extensively characterized for its profibrogenic role.18 Decreased fibrogenesis in ob/ob mice is reverted by leptin but not by food restriction, making a strong case for this factor as a profibrogenic agent.19 Several cell types contribute to the fibrogenic action of leptin. Leptin activates Kupffer cells and macrophages, and stimulates endothelial cells to secrete transforming growth factor-β.18 More important, leptin directly targets hepatic stellate cells (HSCs) via activation of ObRb. Virtually all features of the activated phenotype of HSCs are modulated by leptin in a profibrogenic manner, as reviewed in detail elsewhere20 and summarized in Table 3. Of note, the actions of leptin on HSCs also include activation of NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase and production of reactive oxygen species, which regulate chemokine expression and phagocytosis of apoptotic bodies.21, 22 Once activated, HSCs contribute to leptin expression, whereas low levels of leptin in quiescent HSCs are associated with higher expression of adiponectin.23 A critical aspect that remains to be investigated is whether resistance to the metabolic actions of leptin is accompanied by resistance of hepatic nonparenchymal cells to the proinflammatory and profibrogenic actions of this adipokine.
Table 3. Modulation of the Biology of Activated Hepatic Stellate Cells by Leptin or Adiponectin
• Stimulation of proliferation
• Suppression of PDGF-induced proliferation Inhibition of migration
• Suppression of apoptosis
• Inhibition of TGF-β–induced expression of profibrogenic genes (e.g., CTGF)
• Stimulation of mRNA and protein expression of type I procollagen
• Inhibition of cytokine-mediated chemokine secretion
• Up-regulation of TIMP-1 expression Induction of VEGF
• Stimulation of secretion of proinflammatory chemokines
• Suppression of α-SMA expression
• NF-κB activation
• Induction of caspase-mediated apoptosis
• Up-regulation of TGF-β1
• Stimulation of the ability to phagocyte apoptotic bodies
• Inhibition of NF-κB
• Activation of NADPH oxidase and ROS generation
Leptin-deficient mice show altered liver regeneration both after partial hepatectomy and toxic injury.24, 25 However, restoration of circulating levels of leptin failed to rescue regeneration after partial hepatectomy, suggesting that prolonged deficiency of leptin causes complex perturbations of the regenerative ability of hepatocytes.26 Leptin has been recently associated with cancer development, both directly and through increased angiogenesis. Leptin acts on endothelial cells27 and up-regulates expression of vascular endothelial growth factor by HSCs,28 and lack of leptin action reduces angiogenesis and formation of preneoplastic foci in experimental steatohepatitis.29 Moreover, ObR is expressed at higher levels in human HCC, and poorly differentiated HCCs have higher vascularization and ObR expression, showing that leptin/ObR correlate with angiogenesis in HCC in vivo.30, 31 Leptin also promotes proliferation, migration, and invasiveness of HCC cells,31 and increases proliferation and metastatic potential of cholangiocarcinoma cells.32 Leptin's mitogenic action in HepG2 cells has been recently shown to require expression of methionine adenosyltransferase 2A and 2β.33 Thus, in the context of chronic liver diseases, leptin may favor HCC development by accelerating fibrogenesis, inducing angiogenesis, and acting directly on neoplastic cells. On the other hand, the interference of leptin with the immune system could have a beneficial effect, as recently reported in a model of xenotransplantation, where leptin administration increased the number of natural killer cells and reduced tumor size.34
Adiponectin comprises a collagen-like domain linked to a globular domain that maintains biological activity after cleavage.35 Full-length adiponectin circulates in complexes of different size, but the metabolic activities are mostly related to the high-molecular weight form.7 Adiponectin binds at least two specific receptors, AdipoR1 and AdipoR2. AdipoR1 is expressed in skeletal muscle and other tissues, whereas AdipoR2 is mostly expressed in the liver.35 The main downstream effector of AdipoR1 is AMPK, whereas AdipoR2 signals via peroxisome proliferator-activated receptor-α (PPAR-α). The functional significance of T-cadherin, an additional receptor for adiponectin, is still uncertain.35
Adiponectin concentrations inversely correlate with fat mass and are down-regulated in obesity and type 2 diabetes. Adiponectin exerts insulin-sensitizing effects in the liver, skeletal muscle, and adipose tissue (Table 2). Like leptin, adiponectin regulates whole-body lipid partitioning and has hepatoprotective and antifibrogenic effects in conditions of liver injury. In experimental alcoholic and nonalcoholic steatohepatitis (NASH), administration of adiponectin ameliorated necroinflammation and steatosis, partly via inhibition of tumor necrosis factor-α (TNF-α).36 In addition, consumption of diets rich in saturated fat, which protect from alcoholic liver damage, increases adiponectin secretion.37 Conversely, chronic alcohol exposure decreased circulating adiponectin and increased homocysteine, while betaine reduced homocysteine and increased adiponectin levels.38 Accordingly, in obese mice, which are more susceptible to galactosamine/lipopolysaccharide, adiponectin administration improved liver injury, reducing TNF and increasing PPAR-α.39 Additional studies in ob/ob mice showed that a modest increase in adiponectin levels is accompanied by reduced inflammation and increased PPAR-γ in the adipose tissue. In this model, adiponectin provides signals that convey triglycerides to adipose tissue, sparing the liver and the muscle, and improves insulin sensitivity even in spite of adipose tissue expansion.40 These actions are similar to the ones induced in humans by thiazolidinediones, which increase adiponectin levels.41
Glucose metabolism is also profoundly affected by adiponectin, which suppresses hepatic glucose production via AMPK activation.6 Additionally, adiponectin improves insulin signaling via inhibition of protein tyrosine phosphatase PTP1B.42 However, adiponectin resistance has been suggested to occur in a model of hepatic insulin resistance (IR), where adiponectin administration was unable to lower glucose levels or to induce AMPK activation despite normal levels of AdipoR1 and AdipoR2.43 The close relationship between insulin and adiponectin in the liver is further demonstrated by the observation that insulin reduces the expression of AdipoR1/AdipoR2 via activation of the phosphoinositide 3-kinase/Forkhead Box O1 pathway.44 On the other hand, signals from the liver may influence adiponectin secretion in the adipose tissue. Hepatic secretion of fetuin-A, which is increased in steatosis and the metabolic syndrome, lowers expression of adiponectin, inducing low-grade inflammation.45
Although both adiponectin and leptin counteract ectopic fat deposition, they have divergent effects on inflammation. In general, adiponectin reduces inflammation, stimulating secretion of anti-inflammatory cytokines (e.g., interleukin-10 [IL-10]), blocking nuclear factor κB (NF-κB) activation, and inhibiting release of TNF-α, IL-6, and chemokines.46 In addition, adiponectin is a potent inhibitor of the atherogenic process.47 Conversely, inflammation blocks adiponectin secretion, and specifically, adipose tissue inflammation contributes to reduce plasma adiponectin levels in obesity. In terms of liver, leptin-deficient, ob/ob mice are protected from T cell–mediated hepatitis, whereas lipodystrophic mice, which lack both adiponectin and leptin, are not, suggesting a key role of adiponectin in conferring protection from injury. Accordingly, adiponectin administration protects both lipodystrophic and ob/ob mice, whereas leptin administration worsens their conditions.48 Adiponectin has been recently shown to protect also against Fas-mediated hepatocyte death, with possible implications for patients with CHC.49 Therefore, adiponectin may be envisioned as a negative modulator of the systemic and hepatic inflammation that characterizes the metabolic syndrome.50 However, this paradigm should not be considered too strictly, because in some circumstances, such as in steatotic livers undergoing ischemia/reperfusion, adiponectin may have injurious effects.51
Adiponectin knockout mice develop more extensive fibrosis than wild-type animals after chronic CCl4 intoxication, demonstrating that adiponectin has antifibrogenic effects independently of metabolic actions.52 Reduced fibrogenesis is mediated at least in part by modulation of the activated phenotype of HSCs (Table 3). HSCs express both adiponectin receptors,23 and activation of AMPK has been identified as a pivotal mechanism mediating the antifibrogenic effects of adiponectin.53, 54 AMPK activation occurs downstream of AdipoR1, but interference with AdipoR2 signaling has been recently shown to be sufficient to block the progression of experimental steatohepatitis.55 Little information is available on the role of adiponectin in liver cancer, although recently, administration of a choline-deficient, amino acid–defined diet to adiponectin-deficient mice resulted in increased incidence of liver tumors.56 Whether this was dependent on reduced damage or on a direct action on cancer cells needs to be established. Lack of adiponectin was recently found to delay liver regeneration.57
In rodents, resistin is expressed by adipose tissue and plasma concentrations are increased in diet-induced or genetic obesity.58 Elegant data in rodent models have shown that resistin may be a link between obesity and IR.7 The effects on the liver are also mediated centrally, because administration of resistin into the third cerebral ventricle stimulates hepatic glucose production independently of circulating levels of glucose-controlling hormones.59 Reduced hepatic glucose production in the absence of resistin is also associated with higher hepatic AMPK activation.60 In addition, fatty infiltration and very low density lipoprotein secretion are decreased in resistin-deficient mice placed on a high-fat diet, suggesting a role for resistin in the induction of hepatic steatosis.61 In humans, the biology of resistin is not clearly defined, and most studies demonstrate that resistin is expressed predominantly by bone marrow–derived cells and inflammatory cells.5
A possible connection with inflammation is also indicated by increased resistin expression in monocytes treated with proinflammatory cytokines, and by the fact that resistin stimulates the secretion of proinflammatory cytokines.5 Additional lines of evidence link the biology of resistin with hepatic inflammation. In rats, resistin administration significantly worsens inflammation after lipopolysaccharide injection, through the involvement of the coagulation cascade.62 In addition, in a model of cirrhosis, higher gene and protein expression of resistin and TNF-α was observed in epididymal fat, and TNF injection up-regulated resistin.63 Expression of resistin has been documented in quiescent HSCs, whereas activated human HSCs respond to resistin with increased expression of proinflammatory chemokines and NF-κB activation.64, 65
Fat on Fire: Proinflammatory Cytokines
The association between obesity and elevated TNF-α levels has led to the identification of adipose tissue as a major site of production of this cytokine. Together with IL-6 and chemokines, TNF mediates macrophage infiltration which causes adipose tissue “inflammation” in obesity, resulting in IR and dysregulated secretion of adipokines.66 Like other adipokines, TNF acts both locally, and at distant sites, in an endocrine fashion. TNF is a critical mediator of IR, activating proinflammatory pathways such as NF-κB and c-jun N-terminal kinase66 (Fig. 3).
IL-6 is also overexpressed in the adipose tissue of obese patients. IL-6 has pleiotropic actions, and it has even been associated in animal models with protection from steatosis. IL-6 signals via gp130 and activation of the Jak/Stat pathway, similarly to leptin. IL-6 signaling is also associated with induction of SOCS3 expression, contributing to IR and leptin resistance. Adipose tissue chemokines, particularly monocyte chemoattractant protein-1, are involved in macrophage recruitment and the resulting inflammation.66 These cytokines are regulated by NF-κB in response to TNF and/or other proinflammatory mediators.
Expression of proinflammatory cytokines and chemokines is neither restricted nor prevalent in the adipose tissue. Focusing on the liver, it is difficult to establish to what extent circulating cytokines reaching the hepatic tissue are relevant in comparison to those produced locally as the result of injury, and to what extent different tissues contribute to increased plasma levels. Due to space constraints, a detailed review of adipose tissue inflammation50, 67 and of the role of proinflammatory cytokines in liver pathophysiology68 is outside the scope of this review.
New Kids on the Block
Retinol-Binding Protein 4.
A specific transport protein for vitamin A, retinol-binding protein 4 (RBP4) is secreted by hepatocytes and, to a lesser extent, by adipocytes. Recent studies have suggested a link between IR and high levels of serum and adipose tissue RBP4.7 Experimentally-induced increase in RBP4 levels into normal mice causes IR, but not all studies in humans supported such correlation.
Apelin is the endogenous ligand of the angiotensin-like receptor 1, involved in modulation of cardiovascular tone and food intake.69 Adipocyte and plasma levels of apelin are higher in obese, insulin-resistant animals and humans. In the liver, apelin positively correlates with leptin, oxidative stress, and inflammation in rats fed a high-fat diet.70 During chronic toxic damage, hepatic expression of apelin and its receptor are increased, and treatment with a receptor antagonist reduces fibrosis and improves renal function and ascites.71 The apelin system also contributes to splanchnic angiogenesis in portal hypertensive rats.72
Initial studies suggesting that visfatin is preferentially expressed in visceral adipose tissue have not been confirmed. In humans, visfatin is increased in association with type 2 diabetes and the metabolic syndrome.7 Recently, visfatin has been identified as a circulating nicotinamide phosphoribosyltransferase, which catalyzes formation of nicotinamide mononucleotide.73 A role of visfatin in inflammation has also been suggested.
Information on other adipokines (Table 2) may be found in recent reviews,7, 74 and data on their role in hepatic diseases is likely to be available soon.
AMPK, adenosine monophosphate–activated protein kinase; BMI, body mass index; CHC, chronic hepatitis C; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HSC, hepatic stellate cell; IL, interleukin; IR, insulin resistance; mRNA, messenger RNA; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor κB; PPAR, peroxisome proliferator-activated receptor; RBP4, retinol-binding protein 4; SOCS3, suppressor of cytokine signaling-3; TNF-α, tumor necrosis factor-alpha.
Adipokines in Human Liver Disease
Analysis of the circulating levels of leptin in patients with NAFLD has provided results more conflicting than those obtained in the laboratory. Leptin levels almost invariably correlate with body fat, the major site of production in humans and rodents. Circulating leptin was found to be increased in NASH independently of body mass index (BMI), with higher levels in patients with more advanced disease.75 Similar data have been obtained in children with NASH, where TNF-α and leptin predict a NAS score ≥5.76 However, in another study in adult patients, leptin levels directly correlated with the severity of steatosis but not with inflammation or fibrosis,77 and other investigators failed to find significant differences in serum leptin between patients with NASH and controls.78, 79 Thus, the strong evidence for leptin as a fibrogenic agent in animal models is not clearly paralleled by evidence on circulating levels in patients.
Reduced adiponectin levels were found in patients with NASH in comparison to matched controls and patients with simple steatosis, independently of IR or the waist-hip ratio.80 IR and low adiponectin were associated with increased steatosis and necroinflammation, but not with severe fibrosis, which was predicted only by IR. In another group of nonobese, nondiabetic patients with NASH, reduced adiponectin levels were suggested to play a pathogenic role in pancreatic β-cell dysfunction.81 In this study, adiponectin was also associated with fibrosis, although only a limited number of patients were included. Adiponectin was also negatively associated with more severe histological damage in another study,82 and in a large cohort of Japanese workers, it was found to be inversely correlated to alanine aminotransferase levels.83 Patients with IR undergoing bariatric surgery have lower adiponectin messenger RNA (mRNA) in adipose tissue than those without IR, and lower serum levels, that predict the presence of NASH.84 Bugianesi et al. found that adiponectin levels correlate with suppression of endogenous glucose production, and predict the presence of the metabolic syndrome. However, adiponectin was inversely associated only with intrahepatic fat but not with inflammation and fibrosis.85 The correlation of adiponectin with hepatic fat content, IR, and altered lipid metabolism has been described in other studies investigating nondiabetic subjects.86, 87 Also in patients with diabetes, levels of adiponectin are inversely correlated to hepatic fat content and to endogenous glucose production, suggesting that adiponectin may represent a link between hepatic fat and IR.88
Low levels of adiponectin expression may be detected in the liver, and both adiponectin and AdipoR2 mRNA were found to be reduced in the liver of patients with NASH compared with those with simple steatosis. Moreover, AdipoR2 expression was inversely related to alanine aminotransferase and fibrosis stage.89 However, Vuppalanchi et al.90 failed to detect adiponectin mRNA in the liver, and the expression of AdipoR2 was actually higher in NASH than in patients with simple steatosis. Taking all data together, adiponectin levels generally predict steatosis and severity of liver disease, although to what extent this is a direct effect, or related to the presence of more severe IR, remains to be addressed. Nevertheless, reduced levels of adiponectin in obesity and IR establish a proinflammatory milieu, and individual susceptibility to lipotoxicity could determine which subjects ultimately progress from simple steatosis to NASH and develop advanced fibrosis.
Adiponectin is also implicated in the increased cardiovascular risk observed in patients with fatty liver,91 and part of the risk is associated with the proatherogenic lipid profile observed after a fat load.81, 86 The magnitude of postprandial lipemia was related to baseline circulating levels of adiponectin, possibly linked to chronic hyperinsulinemia, which reduces adiponectin secretion,92 and to the type of fat consumed, because patients ate a diet richer in saturated fat and lower in protective polyunsaturated fatty acids than did controls.93 In addition, in patients with NASH, adiponectin levels failed to rise significantly after an oral fat load,81 although this observation is not in complete agreement with other studies, possibly on the basis of differences in the composition of the meal.90 Genetic factors may also mediate alterations in the adiponectin system. Polymorphisms of the adiponectin gene have been associated with higher risk of type 2 diabetes and cardiovascular disease.94 Moreover, in subjects with an unfavorable haplotype, which is more prevalent in patients with NAFLD than in the general population, adiponectin does not increase after a fat meal.95 Polymorphisms in the gene encoding AdipoR1 have been associated with IR and liver fat content.96 Interestingly, patients with primary biliary cirrhosis have higher concentrations of adiponectin than patients with NASH, and high adiponectin may explain the low cardiovascular risk in primary biliary cirrhosis, despite hypercholesterolemia.97 Regardless of the role of genetic and acquired factors, adiponectin appears to be strongly linked with both the hepatic phenotype and cardiovascular risk, which are the major causes of mortality in NASH, and represents an appealing target for treatment.
Measurement of circulating resistin levels in patients with NAFLD has yielded conflicting results. Pagano et al. found increased plasma concentrations and adipose tissue mRNA levels of resistin when patients with NAFLD were compared with healthy subjects, and resistin levels were directly correlated with the NASH score.98 However, others reported that patients with NAFLD have lower resistin concentrations, which are inversely correlated with intrahepatic fat content, but not with IR.99 In patients undergoing bariatric surgery, expression of resistin in visceral adipose tissue was unchanged, whereas serum levels of resistin were higher in patients with NASH and IR.84 Finally, hepatic expression of resistin was increased in alcoholic steatohepatitis and NASH, and correlated with inflammatory cell infiltration.64
A few studies have investigated the possible role of other adipokines in this setting. Visfatin levels were found to be lower in patients with NASH than in those with simple steatosis or obese controls, and in general, they were higher in all groups of obese patients.100 In another study, high levels of visfatin predicted the presence of portal inflammation.101 In apparently healthy subjects, circulating RBP4 correlates negatively with insulin sensitivity and positively with IR and liver fat.102 Accordingly, in nondiabetic individuals, levels of RBP4 were independently associated with peripheral insulin sensitivity, indicating that RBP4 is a robust marker of IR.103 Increased RBP4 levels have been shown also in diabetic patients with NAFLD, and again correlated with liver fat and IR.104 It should be taken into account that RBP4 is produced both by the liver and the adipose tissue, and that therefore additional studies are required to elucidate to what extent RBP4 is a cause, or a marker, of fatty liver.
Obesity, steatosis, and IR have a negative impact on disease progression and the response to antiviral therapy in patients with CHC.105 In turn, CHC is often associated with alterations in glucose metabolism leading to hepatic steatosis, IR, and type 2 diabetes mellitus.106 Fatty liver is generally more evident in patients infected with hepatitis C virus (HCV) genotype 3, where virus-specific mechanisms play a pivotal role (so-called “viral steatosis”). On the contrary, “metabolic steatosis” is associated with HCV genotypes other than genotype 3, with host factors playing a major pathogenic role.
The role of leptin in IR, steatosis, and liver injury in CHC is not clearly defined. Increased levels of leptin have been found in patients infected with HCV compared to healthy controls,107 whereas in other studies comparable, or even lower concentrations of leptin were reported.75, 108, 109 Similarly, a positive correlation between leptin and the severity of fibrosis has been found in some,110, 111 but not other studies.108, 112 The relation between leptin and HCV-induced steatosis is also unclear. In one series, leptin levels were associated with steatosis only by univariate analysis,112 whereas another study, comprising a larger number of subjects, showed a correlation with steatosis in patients infected with genotype 1 but not with genotype 3 HCV.113 Other authors failed to demonstrate changes in leptin levels with respect to the grade of steatosis.108, 110
Differently from NAFLD, the relationship between adiponectin levels and hepatitis C is conflicting. Several studies have indicated that serum adiponectin is not modulated in HCV-infected patients when compared to healthy subjects matched for age, gender, and BMI, and does not correlate with histological changes,114–116 Lower adiponectin levels have been associated with high viral load and genotype 2 infection.114 Another recent report did not find any associations between histological features and serum adiponectin, leptin, or IL-6, whereas TNF correlated with portal inflammation.117 The lack of differences in the adipokine profile suggested that virus-related, adipokine-independent effects could explain the more severe IR observed in patients with CHC. Petit et al. identified an association between adiponectin levels and hepatic steatosis,118 whereas in other series these changes were limited to males.119 An association between hypoadiponectinemia and the severity of hepatic steatosis in CHC has been shown in other studies, and a pathogenetic role of an altered balance between adiponectin and TNF-α was suggested.120 In patients infected with HCV genotype 3, adiponectin levels are lower, irrespectively of steatosis,120, 121 and levels increase after successful antiviral treatment, suggesting that the virus directly affects adiponectin.122 Low adiponectin levels also predict the lack of response to antiviral therapy.122 Recently, higher levels of total and high molecular weight adiponectin were associated with the presence of a cellular immune response against HCV, indicating a role of adiponectin in the regulation of immunity during CHC.123 In chronic hepatitis B, adiponectin levels were found to be lower124 or similar125 to those in patients infected with HCV. In addition, adiponectin was increased in advanced liver fibrosis and correlated with fibrosis stage.126
Other adipokines that have been studied in CHC include resistin, the levels of which were higher in patients with chronic hepatitis than in those with NASH. Lower resistin levels were associated with moderate/severe fibrosis.125 In another recent study, elevated RBP4 levels were found in patients with CHC (genotype 1) independently of obesity and IR, suggesting that RBP4 may be a virus-related factor inducing hepatic fat accumulation.127
In end-stage liver disease, changes in the adipokine profile may occur independently of the underlying etiology, as a result of altered catabolism and/or extraction, or the presence of a proinflammatory state. Before leptin was shown to be a profibrogenic factor, McCullough et al. demonstrated that serum levels of leptin are increased in patients with alcoholic cirrhosis, independently of BMI.128 In another series of patients with alcoholic liver disease, the correlation of leptin with the presence of cirrhosis was lost after correction for BMI.129 In addition, leptin was lower in patients with low/moderate steatosis. When patients with viral or alcoholic cirrhosis were compared, leptin was reduced in virus-induced cirrhosis.130 In another group of patients with virus-related cirrhosis, free leptin did not differ from controls, and was related to fat mass, whereas the increase in the bound fraction correlated with energy expenditure and the possible presence of a catabolic state.131 The same investigators recently reported that while free leptin is positively correlated with metabolic parameters, bound leptin and soluble leptin receptor are linked to proinflammatory cytokines and sympathetic activity, suggesting distinct roles.132 Decreased renal extraction and increased release from subcutaneous fat depots are the most likely mechanisms of increased leptin in cirrhosis, whereas hepatosplanchnic extraction is similar to controls.133
In apparent contrast to its hepatoprotective action, circulating adiponectin has been shown to be increased in cirrhosis, both in mice and in humans.89, 134 Adiponectin levels increase along with the severity of disease (whereas hepatic extraction decreases134) and parallel portal pressure, but do not correlate with IR.134, 135 In one study, patients with biliary cirrhosis showed the highest adiponectin levels, suggesting that biliary secretion may be involved in the clearance of this adipokine.135
Increased levels of resistin have also been reported in patients with cirrhosis, along with the severity of disease. Serum resistin was inversely correlated with insulin sensitivity and positively correlated with markers of inflammation and with portal hypertension.136, 137 Moreover, resistin was higher in hepatic veins than in arterial blood, and remained elevated after liver transplantation, despite the improvement of IR.138 In contrast, circulating levels of visfatin and hepatic visfatin mRNA were reduced in patients with cirrhosis.139 Visfatin levels decreased with reduced liver function and were directly correlated with arterial ketone body ratio, and index of hepatic nicotinamide adenine dinucleotide generation, indicating a link between visfatin and metabolism.139
A role of apelin in the hemodynamic complications of cirrhosis has been recently proposed, based on the increased levels in patients with cirrhosis.71 Finally, serum RBP4 levels were lower in patients with cirrhosis than in controls, and unlike in patients with NAFLD, they did not correlate with insulin resistance, but were linked to the hepatic biosynthetic capacity.140
Summary and Perspectives
The last 10 years have witnessed a tremendous increase in our knowledge on the relations between factors produced by the adipose tissue and pathophysiology of hepatic diseases. The central role of the liver in the metabolic syndrome explains the high number of studies on adipokines in fatty liver disease, and on the metabolic alterations associated with CHC. Elegant work in cultured cells and in animal models have shown direct and strong connections between adipokines and mechanisms of hepatic damage and repair (Fig. 2). Not surprisingly, the results have been more controversial in the setting of studies in patients due to their inherent complexity. Nonetheless, this group of molecules represents a convincing target for development of novel therapies in liver diseases, and the adiponectin system appears as the forerunner candidate. Actually, the effects of drugs currently employed in clinical practice, such as thiazolidinediones and metformin, depend in part on adiponectin or interfere with its downstream pathways. The appearance of novel approaches is eagerly awaited.
We are grateful to Nadia Navari for precious help in assembling the manuscript.