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World J Gastroenterol. Dec 28, 2014; 20(48): 18070-18091
Published online Dec 28, 2014. doi: 10.3748/wjg.v20.i48.18070
Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease
Sanja Stojsavljević, Marija Gomerčić Palčić, Lucija Virović Jukić, Lea Smirčić Duvnjak, Marko Duvnjak
Sanja Stojsavljević, Marija Gomerčić Palčić, Lucija Virović Jukić, Marko Duvnjak, Department of Gastroenterology and Hepatology, Clinic of Internal medicine, Clinical hospital center “Sestre milosrdnice’’, 10000 Zagreb, Croatia
Lea Smirčić Duvnjak, University Hospital for Diabetes, Endocrinology, and Metabolic Diseases Vuk Vrhovac, 10000 Zagreb, Croatia
Author contributions: Stojsavljević S, Gomerčić Palčić M, Virović Jukić L and Duvnjak M contributed equally to this work; Duvnjak M provided the conception of the review; Stojsavljević S, Gomerčić Palčić M and Virović Jukić L participated in acquisition of data, analysis and interpretation of revised literature; Duvnjak M and Smirčić Duvnjak L critically revised the final manuscript and approved it for final submission.
Correspondence to: Marko Duvnjak, MD, PhD, Professor, Chief, Department of Gastroenterology and Hepatology, Clinic of Internal medicine, Clinical hospital center “Sestre milosrdnice’’, Vinogradska cesta 29, 10000 Zagreb, Croatia. marko.duvnjak1@gmail.com
Telephone: +385-98-9838930 Fax: +385-1-3787448
Received: June 24, 2014
Revised: October 21, 2014
Accepted: November 18, 2014
Published online: December 28, 2014

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The “two-hit“ hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.

Key Words: Nonalcoholic fatty liver disease, Cytokines, Adipokines, Adiponectin, Leptin, Tumor necrosis factor-α, Interleukin-6, Interleukin-1, Interleukin-18, Ghrelin

Core tip: The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is still not fully elucidated. We explored the role of the following adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD: adiponectin, leptin, ghrelin, resistin and visfatin among adipokines, and tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1 among proinflammatory cytokines. Although a definite conclusion is complex, from analyzed data we could conclude that adiponectin, des-acyl ghrelin and leptin are adipokines that decrease, while TNF-α and IL-6 are cytokines that enhance insulin resistance and subsequently NAFLD. Acting on these premises, new therapeutic possibilities emerge; however, much work remains to be done.


Citation: Stojsavljević S, Gomerčić Palčić M, Virović Jukić L, Smirčić Duvnjak L, Duvnjak M. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20(48): 18070-18091
INTRODUCTION

In nonalcoholic fatty liver disease (NAFLD) excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis[1]. NAFLD represents a complex spectrum of diseases, and is usually classified into nonalcoholic fatty liver (simple steatosis) and nonalcoholic steatohepatitis (NASH). Simple steatosis is characterized by the presence of steatosis without evidence of significant inflammation or fibrosis, while in NASH, steatosis is associated with hepatic inflammation that may be histologically indistinguishable from alcoholic steatohepatitis, and is often accompanied by progressive fibrosis. Long-standing NASH may progress to liver cirrhosis and is probably an important cause of cryptogenic cirrhosis; end-stage liver disease and hepatocellular carcinoma may be possible outcomes[2].

NAFLD is regarded as a hepatic manifestation of metabolic syndrome (MS), and patients with NAFLD, particularly those with NASH, often have one or more components of the MS: obesity, hypertension, dyslipidemia and raised fasting plasma glucose levels or overt type 2 diabetes (T2DM).

The epidemiological data for NAFLD vary depending on the population and region studied, but estimated prevalence of NAFLD worldwide is around 20%, with 2%-3% of adults having NASH. It is the most common liver disorder in the Western industrialized countries, where the major risk factors for NAFLD are common. Clinical studies have revealed an increasing prevalence of NAFLD worldwide, and especially worrying data come from studies of children and adolescents where NAFLD is on the rise, together with obesity and MS, and such an early onset of the disease may provide more time for its deleterious evolution through the lifetime. The pathogenesis of NAFLD and NASH is still extensively researched. Although it is sometimes explained by a “two-hit“ hypothesis, it should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis[3].

Strong epidemiological, biochemical, and therapeutic evidence implicate insulin resistance (IR) as the primary pathophysiological derangement and the key mechanism leading to hepatic steatosis[4]. Insulin actions are altered in IR and MS, resulting in increased lipolysis and synthesis of free fatty acids (FFA) and decreased apolipoprotein B-100 in the liver.

Accumulation of triglycerides in the liver thus represents the primary insult or the “first hit” in the pathogenesis of NAFLD, but the progression of NASH requires the presence of additional pathophysiological abnormalities. The next step or the “second hit“ is the result of reactive oxygen species (ROS) that increase oxidative stress within the hepatocytes, and by that mediate progression from steatosis to steatohepatitis and fibrosis. Also a “third hit” has been proposed, based on the fact that oxidative stress causes progressive cell death with diminished replication of mature hepatocytes and subsequent increased progenitor cell expansion, leading to progression of liver cirrhosis and hepatocellular carcinoma.

A number of recent reviews have pointed out the importance of gut microbiota, which is now considered also as a metabolic organ, in the pathogenesis of metabolic and inflammatory diseases such as obesity and T2DM[5-7]. Aron-Wisnewsky et al[8] summarized the influence of gut microbiota in promoting NASH in five steps. Disregulated microbiota promotes energy yield from food, as was observed in animal (obese animals had a greater capacity to extract and store energy in comparison with lean ones) and human studies (obese patients had increased Firmicutes and decreased Bacteroidetes compared with lean ones)[9]. Secondly, microbiota regulates gut permeability, participating in that way in the innate and adaptive immune responses as well as in contributing to low grade inflammation[10]. Gut permeability and bacterial overgrowth of the small intestine have been associated with the stage of steatosis and higher endotoxin levels as found in adults and children with NASH[11]. Another mechanism is the alteration of the choline metabolism. Namely, dysregulated microbiota produces enzymes that catalyze the breakdown of choline into toxic methylamines which can, through enterohepatic circulation, induce liver inflammation[12]. Furthermore, dietary saturated fats influence the composition of bile acid metabolism, which is not only important in the digestion and absorption of metabolites but also for antimicrobial activity, thus promoting dysbiosis[13]. Finally, patients with NASH had an increase of alcohol producing bacteria, such as Escherichia, which is important, since metabolites of endogenously produced alcohol can influence the production of ROS and subsequently cause liver inflammation[14].

Factors that determine the presence and extent of necroinflammation are not yet well understood. Several possible mechanisms have been theorized, including host factors, such as defects in mitochondrial structure and function, altered expression of proinflammatory cytokines, impaired free oxygen radical scavenging, increased hepatic iron, and hepatotoxic byproducts of intestinal bacteria. The factors involved in hepatic fibrogenesis are slowly becoming understood. Activation of both lobular stellate cells and hepatic progenitor cells has been observed in NAFLD.

Most of the data on the pathophysiology and natural course of the disease therefore come from animal studies. In the last few years, animal studies have yielded an impressive list of molecules associated with NAFLD and NASH pathogenesis. Animal models of NAFLD/NASH are classified into genetic models, nutritional models, and combined models of genetic and nutritional factors[15-17]. Numerous rodent models of NAFLD/NASH have been reported to date; however, no animal model completely reflects liver histopathology and pathophysiology of human NAFLD/NASH.

Adipose tissue, as an endocrine organ, participates in energy balance. Adipose tissue, in response to peripheral tissue and central brain signals, secretes various chemokines. These adipokines are characterized by a spectrum of local, peripheral, and central effects[18]. These chemokines activate macrophages, which release pro- and anti-inflammatory cytokines, and by this enhance inflammatory and suppress anti-inflammatory adipokines[19,20]. Obesity, which is often associated with IR, is therefore often seen as a chronic systemic low-grade inflammation, in which adipose tissue and its hormones have a central role[21-23].

Here, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 (RBP4) among adipokines, and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.

ADIPOKINES AND NAFLD

Adipose tissue is, as mentioned earlier, not only a source of lipids, but also an endocrine organ, since it produces adipokines that have local, peripheral and central effects[24]. Although adipose tissue secretes the majority of adipokines, they are also produced by other organs, such as the gastrointestinal tract, and these other sources of adipokine production should not be disregarded. Thus, adipokines represent a heterogeneous group of mediators such as adiponectin, leptin, resistin, visfatin, ghrelin, and RBP4, but more than 50 others have been described so far.

ADIPONECTIN AND NAFLD

In 1999 Arita et al[25] isolated a product of the apM1 gene, previously cloned by Maeda et al[26], a kind of soluble matrix protein, which they named adiponectin. Adiponectin circulates as several oligomeric isoforms in serum and isoform-specific effects have been described in the literature[27-29]. The three most common isoforms are: trimers (low molecular weight-LMW), hexamer (middle molecular weight-MMW) and oligomeric complexes (high molecular weight-HMW)[30]. In serum it can also exist as a proteolytic cleavage fragment of the full-length protein known as globular adiponectin[25,31].

Two transmembrane proteins, AdipoR1 and AdipoR2, are identified as adiponectin receptors. Both receptors are mostly present in skeletal muscle and moderately expressed in the liver[32]. Although AdipoR2 is more abundant in the liver, AdipoR1 can be found in human hepatocytes, pointing out the important part played by both receptors in the pathogenesis of liver diseases[33].

A great number of studies, reported in Table 1, have investigated in human, animal and in vitro models the pathogenesis and molecular mechanisms through which adiponectin influences obesity, IR, NAFLD and other components of MS. Plasma concentrations of adiponectin were found to be significantly lower in obese subjects (visceral fat predomination), although adiponectin is secreted only from adipose tissue[25,34-38]. Serum levels of adiponectin were reduced in T2DM and IR[39-44], which was confirmed in animal studies as well as through various molecular mechanisms[45-47]. Certain genotypes of the adiponectin gene were associated with a higher risk for developing IR and T2DM[48,49]. In vivo studies showed that low serum levels of adiponectin were associated with MS, NAFLD and tumor formation[50-63]. In vitro and in vivo studies suggest that oligomeric complexes of adiponectin can modulate the biological actions of several growth factors by controlling their bioavailability at a pre-receptor level and that this effect might partly account for the anti-atherogenic, anti-angiogenic, and anti-proliferative functions[64-69]. However, not all mentioned studies concur regarding the level of adiponectin receptor and adiponectin itself, a phenomenon which could be explained by an adiponectin resistant state; more studies are needed to draw firm conclusions. There have been reports of adiponectin as a good predictor of the necroinflammatory grade and fibrosis in NAFLD through mechanisms which were clarified in vitro[70-73]. Regarding the treatment protocols with adiponectin, in humans a diet high in polyunsaturated fatty acids is recommended (it enhances adiponectin expression), but larger studies are needed to confirm the benefit of such therapy[74]. Different distribution of specific adiponectin isoforms and lower levels of HMW adiponectin were found in obese patients compared to normal weight individuals. This explains the metabolic complications related to obesity and T2DM, and in future, evaluation of adiponectin actions, specific isoforms should be taken in account[75-78].

Table 1 Studies and their findings on adiponectin.
StudyFindingRef.
HumanAdiponectin levels reduced in obese individuals[25,34,35]
Adiponectin levels higher in women[36]
Adiponectin levels reduced in T2DMHypoadiponectinemia associated with visceral fat accumulation[37]
High concentrations of adiponectin correlated with a decreased risk of developing T2DM[41-43]
Adiponectin mRNA decreased in obese T2DM[40]
SNP +45T>G genotypes and lower adiponectin level associated with higher FBG, insulin levels and HOMA-IR in obese women[48]
SNPs: 3971 A/G (rs822396), +276 G/T (rs1501299), -4522 C/T (rs822393) and Y111H T/C (rs17366743) significantly associated with hypoadiponectinemia[49]
High adiponectin/leptin ratio associated with lower plasma triglyceride, HOMA-IR and higher HDL[44]
Lower adiponectin levels an independent risk factor for NAFLD[51]
In human liver biopsies, hepatic adiponectin receptor mRNAs increased in biopsy-proven NASH[52]
Similar levels of adiponectin receptor mRNA in normal, steatotic liver and NASH[53,54]
Reduced AdipoR2 protein in NASH compared to steatotic liver[55]
Adiponectin levels lower in NASH and correlated with the progression of the disease[56,70-72]
HMW adiponectin isoforms increased after biliopancreatic diversion in obese subjects[77]
AnimalAdiponectin lowers gluconeogenesis in the liver, increases fatty acid oxidation in muscle and reduces IR[45]
Disruption of both adiponectin receptors (adipo R1 and R2) increased tissue triglyceride content, inflammation, oxidative stress and IR[46]
Adiponectin enhanced the progression of hepatic steatosis, fibrosis, and hepatic tumor formation in NASH[57]
Adiponectin prevents lipid accumulation by increasing β-oxydation and by decreasing synthesis of FFA in hepatocytes in NASH[47,58-60]
Association of NAFLD and reduced expression of hepatic adiponectin receptors not consistently reported[61,62]
Peripheral injection of adiponectin resulted in reduction in body weight and improvement of peripheral IR[47]
Adiponectin reduced TNF-α and induced IL-10 release from Kupffer cells[63]
Pretreatment with adiponectin ameliorated D-galactosamine/LPS induced elevation of serum AST and ALT levels, and the apoptotic and necrotic changes in hepatocytes[64]
In vitroAdiponectin inhibited TNF-α induced expression of endothelial adhesion molecules and decreased LPS induced TNF-α production[66]
Adiponectin mediated anti-inflammatory activity by lowering NFκB action[67]
Adiponectin increased IL-8 and monocyte chemotactic protein-1 production, and activated the proinflammatory transcription factor NFκB[68]
Adiponectin acted antifibrotic through antagonizing leptin-induced STAT3 phosphorylation in activated hepatic stellate cell who promote fibrosis[73]
Lower HMW adiponectin closely associated with obesity-related metabolic complications and T2DM[75]
LEPTIN AND NAFLD

Leptin is a peptide hormone secreted mainly by adipocytes of white adipose tissue (WAT). It is a product of the ob gene. Leptin modulates food intake, body fat composition, insulin activity, thermogenesis, angiogenesis, and the immune system[79]. It is considered an anorexigen hormone; in the brain it decreases food intake and increases energy expenditure. Leptin circulates in the plasma as a free adipokine, or bound to proteins. Leptin requires an interaction with a specific transmembrane receptor for its metabolic effect. Ob-R, which represents the leptin receptor, is a member of the class-1 cytokine receptor family. In lean individuals it is mostly bound to proteins, and in the obese it circulates in the free form[80,81]. The levels of leptin in adipose tissue and plasma are dependent on the amount of adipose tissue as well as the status of energy balance. Therefore, leptin levels are higher in obese individuals (central obesity) and increase with overfeeding[82-86]. Leptin downregulates transcription of the preproinsulin gene and insulin excretion, which could be connected with high leptin levels in IR[84,87]. Studies on a non-lipoatrophic diabetes population (human and animal models) lead to the conclusion that total absence of leptin leads to obesity. However, in non-lipoatrophic obese individuals, although total leptin levels are elevated, its action is not amplified due to the condition called leptin resistance (reduced sensitivity to the anorectic response to exogenous administrated leptin), which has also been confirmed in animal studies[88-104].

Women have higher circulating levels of leptin than men, which could be associated with a stimulating role of estrogen, or a suppressing role of androgens on leptin production, since studies[105-107] have demonstrated that higher leptin levels in women were independent of fat mass.

Certain inflammatory and infectious stimuli, such as IL-1, lipopolysaccharides (LPS) and TNF-α, can also increase leptin levels, which correlate with the level of inflammation. Levels of leptin are enhanced by pro-inflammatory cytokines and help to perpetuate the loop of chronic inflammation in obesity[108,109].

IR and T2DM are correlated with higher leptin levels in plasma independently of adipose tissue[110,111] although not all studies concur[112]. Genetic polymorphism of the leptin receptor and leptin itself were investigated, and certain genotypes were associated with MS, IR and obesity in human and animal studies[113-115].

Leptin seems to participate in both hits of NASH development (contributing to IR and steatosis as mentioned earlier), and through the proinflammatory role in regulation of hepatic stellate cells (HSCs) in promoting liver fibrosis[24]. Leptin levels are increased in NASH patients and are related to the grade of hepatic steatosis[116-119]. In contrast, there have been studies that did not show a considerable discrepancy in leptin concentrations comparing patients with steatohepatitis and healthy subjects, or in connection to the severity of liver fibrosis[120-122].

Regarding the reviewed studies, leptin levels correlate with obesity and steatosis, while it is still unclear how leptin is upregulated in NASH and how it contributes to fibrosis; locally produced leptin and/or leptin resistance may have a crucial role[123]. To facilitate the understanding of certain studies in different animal, human and in vitro models, findings of those studies together with references regarding the role of leptin are stated in Table 2. Larger studies with carefully matched controls are needed to draw further conclusions regarding the influence of leptin in NAFLD.

Table 2 Studies and their findings on leptin.
StudyFindingRef.
HumanLeptin levels higher in obese individuals and increased with overfeeding[82,83]
Higher leptin levels in women independent of fat mass[104-107]
Body mass index and IR strongly correlated with leptin levels[84]
Central obesity correlated with higher leptin levels in comparison with non-central obesity[86]
Administration of leptin to individuals with lipoatrophic diabetes resulted in reduction of triacylglycerol concentrations, liver volume, glycated hemoglobin and discontinuation, or a large reduction in antidiabetes therapy[89]
Leptin inhibited insulin secretion and transcription of the preproinsulin gene[87]
IR associated with elevated plasma leptin levels independently of body fat[110]
Leptin/adiponectin ratio predicted T2DM in both sex[111]
Leptin C2549A AA genotype found at a higher rate in T2DM[114]
Leptin levels significantly higher in NASH, and correlated with the severity of hepatic steatosis, but not with the grade of necroinflammation or fibrosis[116-118]
Leptin not found as a predictor of histological severity of NASH[119]
No significant difference in leptin concentrations between NASH patients and controls, or in connection to the severity of liver fibrosis[120,121]
IR and low leptin levels predictors of steatosis in the liver[122]
AnimalMice lacking the ob gene became severely obese[91]
Leptin infusion attenuated hepatic steatosis and hyperinsulinemia[92]
Mice without leptin signaling had an increased lipid accumulation in liver[93]
Leptin prevented lipid accumulation in nonadipose tissue through SREBP-1 modulation[94]
After long-term exposure to high-fat diet (> 20 wk), mice resistant to leptin even when directly infused into the brain[95-98]
Hyperleptinemia itself contributed to leptin resistance by down regulating cellular response to leptin[99]
Mice with poly (ADP-ribose) polymerase-1 deficiency susceptible to diet-induced obesity, hyperleptinemia, and IR[115]
Leptin-deficient, insulin-resistant mice developed leptin resistance on a high fat diet independently of hyperleptinemia, c-Jun N-terminal kinase inflammatory pathway relevant in the induction of diet-induced glucose intolerance[100]
Leptin increased expression of procollagen-I, transforming growth factor beta1, smooth muscle actin and TNF-α and thus increased liver fibrosis and inflammation[101]
Leptin-resistant mice exhibited significantly reduced fibrogenic response[102,103]
In vitroFibrogenic effect of leptin accomplished through hepatic stellate cells, leptin a potent mitogen and apoptosis inhibitor[23]
GHRELIN AND NAFLD

Ghrelin is a peptide hormone that was discovered in 1999, and it acts as a ligand of the growth hormone secretagogue receptor (GHS-R) with a unique posttranslational modification of the Ser3 residue. It is produced by the stomach, pancreas and the large intestine[124]. Ghrelin has a part in appetite stimulation and control of body mass[125]. Ghrelin O-acyl transferase (GOAT) is the enzyme which acylates the ghrelin peptide to form acyl-ghrelin (AG)[126]. Recent studies have shown that des-acyl ghrelin (DAG) is no longer regarded as an inert product of AG. Ghrelin stimulates liver gluconeogenesis, and prevents suppression of glucose production by insulin; however, DAG inhibits liver glucose production[127]. Studies involving ghrelin role in NAFLD and other components of MS are reported in Table 3.

Table 3 Studies and their findings on ghrelin.
StudyFindingRef.
HumanAG and the AG/DAG ratios positively associated with HOMA-IR in obese children[128]
IR obese subjects had elevated AG/DAG ratio compared with non IR obese subjects because of decreased DAG and total ghrelin levels[129]
Obese patients with MS had lower total ghrelin and DAG, comparable AG and higher AG/DAG, AG/DAG ratio correlated with IR[130]
Ghrelin significantly correlated with HOMA-IR, but was reduced in NAFLD[131]
Ghrelin levels were higher in higher stages of fibrosis in morbidly obese patients with NAFLD[132]
Higher total ghrelin concentrations in patients with NASH in comparison with steatosis and normal liver[54]
In vitroAdipocytes after incubation with AG and DAG significantly increased PPARγ and SREBP-1 mRNA levels and accumulated lipids[133]
Ghrelin inhibited AMP-activated protein kinase activity, through which also influenced PPAR-γ in liver and in adipose tissue[134]
Administration of ghrelin attenuated NAFLD-induced liver injury, oxidative stress, inflammation, and apoptosis partly through the action of serine/threonine kinase/AMPK and phosphoinositide 3-kinase/protein kinase B pathways in rats[135]

Studies have shown that obese individuals have lower concentrations of DAG than lean ones, while no difference was noticed in the concentrations of AG. It seems that obesity changes the concentration of DAG and AG with a relative AG excess or DAG deficiency which leads to obesity-associated IR in MS[128-130].

After assessing the influence of ghrelin on insulin sensitivity, other groups of investigators concentrated on the potential role of ghrelin in NAFLD. IR is a major factor controlling ghrelin levels in subjects with NAFLD, but the correlation with the progression of the disease shows conflicting results since all studies did not take into consideration DAG and AG concentrations[54,131,132].

Possible mechanisms through which ghrelin influences NAFLD progression were investigated in vitro, some taking into account AG and DAG respectively[133-135]. Summarizing these investigations, one can conclude that ghrelin has an important role in insulin sensitivity but its role in NAFLD has not yet been clarified. Further studies are needed, which should differentiate between the concentrations of DAG and AG.

RESISTIN AND NAFLD

Resistin is an adipocyte-derived signaling polypeptide that was initially found to be upregulated in obesity and IR[136,137]. It has a scarce tissue distribution, with the highest levels in adipose tissues[138]. Resistin circulates in two states, the high-molecular-mass hexamer that has a higher concentration and the low-molecular-mass complex which is more bioactive[139]. Peripheral blood mononuclear cells are main producers of resistin[140]. Studies have conflicting results regarding the influence of resistin in glucose metabolism, obesity and IR. There are numerous studies that have connected obesity with higher circulating resistin levels compared to lean controls in human and animal studies with conflicting results[141-143]. The correlation between resistin, obesity, T2DM and IR also remains controversial[144-148]. In NAFLD, concentrations of resistin were higher than in controls and positively correlated with liver inflammation and fibrosis severity, but this was not consistent in all undertaken studies[118,149-151]. Findings of the previously mentioned studies are displayed in Table 4.

Table 4 Studies and their findings on resistin, visfatin and retinol binding protein 4.
AdipocytokinesFindingRef.
ResistinResistin levels increased in morbidly obese humans[142]
Resistin levels in T2DM patients 20% higher when compared to non-diabetic patients[144]
No correlation between resistin and components of MS on T2DM patients[145]
Resistin did not correlate with BMI but significantly correlated with IR[146]
G/G -180C>G homozygotes for resistin had significantly higher resistin mRNA levels in abdominal subcutaneous fat[148]
Serum resistin levels not associated with the presence of NASH[149]
Serum resistin levels higher in NAFLD that in controls and positively correlated with liver inflammation and fibrosis severity[118,150]
Resistin serum levels in NAFLD patients were associated with histological severity of the disease but not with IR[151]
Expression of resistin in human peripheral-blood mononuclear cells upregulated by TNF-α and IL-6[152]
VisfatinSecretion of visfatin enhanced by glucose administration[153]
Plasma visfatin elevated in patients with T2DM[154]
Visfatin plasma concentrations markedly elevated in obese subjectsBariatric surgery reduced body mass index, visfatin, leptin and increased adiponectin after 6 mo[155]
Plasma visfatin levels elevated in subjects with MS[156]
Significantly higher visfatin mRNA in visceral fat of obese subjects compared with lean controls, and positively correlated with body mass index[158]
Visfatin level lower in NASH compared to NAFLD patients and healthy controls[159]
Visfatin level positively correlated with portal inflammation[160]
Retinol binding protein 4Serum RBP4 concentration elevated in IR, obese humans, T2DM and in subjects with a strong family history of T2DM[161,162]
Strong association of increased circulating RBP4 levels with IR and MS[163-166]
No connection of RBP4 with obesity, IR, or components of the MS[167-171]
RBP4 levels associated with inflammatory response in obese individuals[168,172]
Circulating RBP4 levels higher in subjects with NAFLDRBP4 liver expression higher in moderate/severe NASH compared to mild forms[173]
RBP4 level a risk factors for fibrosis ≥ 2 in NASHRBP4 and HOMA-IR independently associated with steatosis in patients with chronic hepatitis C[174]
In NAFLD patients, serum RBP4 significantly lower compared with controls, did not correlate with IRRBP4 liver tissue expression enhanced in NAFLD patients and correlated with NAFLD histology[175]
Serum RBP4 levels did not correlate with BMI, HOMA-IR, fasting blood glucose, or insulin levels in patients with simple steatosis and NASHPatients with cirrhosis and fibrosis had higher RBP4 compared to controls[176,177]

Data of in vitro studies concluded that resistin participates in the progression of inflammation[152]. Considering the connection between adipocytokines and inflammatory pathways, resistin may represent a link between MS and inflammation. Resistin and its role in the pathogenesis of NAFLD are still not sufficiently studied and new studies are needed.

VISFATIN AND NAFLD

Visfatin is also a hormone whose plasma levels are associated with obesity, visceral fat, T2DM, as well as MS. Secretion of visfatin was enhanced by glucose administration, and the glucose-derived rise of visfatin could be interrupted by co-administration of insulin or somatostatin[153]. Studies related to visfatin and its roles in metabolic processes are shown in Table 4. Plasma visfatin was higher in obese individuals, and those with T2DM and MS[154-156]. Some studies, however, did not confirm the previous association[157,158]. There are scarce data on the role of visfatin in NAFLD. Although the visfatin level was lower in NASH compared to NAFLD patients, a positive correlation with portal inflammation was found[159,160].

RETINOL-BINDING PROTEIN 4 AND NAFLD

RBP4 is predominately produced in visceral adipose tissue. Serum RBP4 concentration was elevated in insulin-resistant obese humans and in T2DM. It was found elevated in individuals who had a family history of T2DM and had normal glucose levels[161,162]. An association between increased RBP4 and MS was found, but other studies failed to detect the connection with single components of MS[163-171].

RBP4 levels were found to be associated with the inflammatory response in obese individuals[168,172]. The role of RBP4 in the pathogenesis of NAFLD is not sufficiently elucidated. Circulating RBP4 levels were higher in subjects with advanced stages of NAFLD[173-175]. However, some studies differed in their results[176,177]. All mentioned studies and their results are reported in Table 4.

PROINFLAMMATORY CYTOKINES AND NAFLD

Proinflammatory cytokine is a general term for those immunoregulatory cytokines that favor inflammation. They represent a heterogeneous group of molecules secreted by various cell types with numerous biological effects. They act as endogenous pyrogens, upregulate the synthesis of secondary mediators and other proinflammatory cytokines by both macrophages and mesenchymal cells, stimulate the production of acute phase proteins, or attract inflammatory cells. The major proinflammatory cytokines that have been studied in the pathogenesis of NAFLD include TNF-α, IL-6, IL-1α, IL-1β and IL-18.

TUMOR NECROSIS FACTOR ALPHA AND NAFLD

A balance between proinflammatory and anti-inflammatory cytokines seems to have a major role in systemic, local metabolic and inflammatory processes involved in the development of NAFLD and IR. TNF-α is the proinflammatory cytokine characterized by various biological effects including metabolic, inflammatory, proliferative but also necrotic, with enhanced expression in liver and adipose tissue thus making it an optimal causative agent for NAFLD. It is secreted by macrophages infiltrated in adipose tissue of obese models, by hepatocytes, Kupffer cells, and other cell types, as a response to chronic inflammatory activity. This was confirmed in numerous studies in which increased expression of TNF-α was found in adipose tissue of diverse animal models of obesity, IR and T2DM suggesting TNF-α is a key link in obesity-induced IR[178,179]. Among all proinflammatory cytokines involved in the pathogenesis of obesity, IR and NAFLD, TNF-α is the most commonly investigated and characterized by conflicting results, because of heterogeneity in study populations, small sample sizes and factors that possibly interfere with serum TNF-α level detection. Human[180] and experimental studies in dietary-induced NAFLD models with or without genetic modulation resulting in its impaired signaling or neutralization with antibodies, implied that TNF-α had a role in development of every setting of NAFLD (liver steatosis, necrosis, apoptosis and fibrosis) as well as IR; this is shown in Table 5.

Table 5 Studies and their findings on tumor necrosis factor alpha.
StudyFindingRef.
HumanHealthy subjects with highest serum TNF-α levels had significantly greater risk of developing NAFLD[180]
TNF-α infusion in healthy humans impaired insulin signaling via increased phosphorylation of p70 S6 kinase, extracellular signal-regulated kinase-1/2, c-Jun NH(2)-terminal kinase, and serine phosphorylation of IRS-1 as well as impaired phosphorylation of Akt substrate 160 thereby GLUT4 translocation and glucose uptake in skeletal muscle[181]
TNF-α gene polymorphism in the -238 A allele associated with susceptibility to NAFLD, correlated with IR and increased BMI in Chinese population[202,203]
TNF-α polymorphism at position 1031C and 863A in a Japanese population associated with NASH without significant difference between NAFLD patients and controls[188]
TNF-α and soluble TNFR2 plasma levels increased in NASH patients, independently of IR, compared to controls, but not among different stages of NAFLD[187],[192]
Serum TNF-α/TNFR1 increased in NASH patients as compared with other stages[189]
In obese NASH patients expression of liver and adipose TNF-α mRNA and its p55 receptor increased and correlated with advanced fibrosis[190]
In children serum TNF-α and leptin associated with a NAFLD activity score of 5 or more[191]
TNF-α mRNA cut-off of 100 ng/mL predicted NASH[192]
In morbidly obese NASH patients high TNF-α mRNA expression in liver correlated with plasma levels of LPS-binding protein[200]
Treatment with TNF-α inhibitor (pentoxifylline) for 6 mo reduced liver enzymes, serum TNF-α level and improved IR[204]
In NAFLD/NASH patients probiotic therapy decreased TNF-α levels[208]
Patients with MS with or without NAFLD treated with fish oil for 6 mo resulted in the reduction of oxidative stress and production of proinflammatory cytokines (TNF-α and IL-6)[214]
AnimalProlonged infusion of TNF-α in rats decreased ability of insulin to suppress hepatic gluconeogenesis and stimulate peripheral glucose utilization[178]
Obese mice with impaired TNF-α signaling protected from obesity-derived IR in peripheral tissues and had lower levels of circulating free fatty acids[179]
Mice deficient in both TNF-α receptors fed with MCD diet had attenuated liver steatosis, fibrosis and number of recruited Kupffer cellsTNF-α administration induced tissue inhibitors of metalloproteinases 1 mRNA expression in activated HSC and suppressed their apoptosis[193]
On MCD-diet induced NASH mice model NASH developed independently of TNF-α synthesis[186]
Fructose overfeeding in mice led to endotoxemia, increased TNF-α and liver steatosis that was reduced after treatment with antibiotics[197]
Mice lacking TNFR1 were resistant to fructose-induced steatosis (increased phospho AMPK and AKT levels, decreased SREBP-1 and FAS expression in the liver as well as RBP4 plasma levels)[198]
Dietary oleate reduced hepatic steatosis, inflammation, fibrosis and mRNA expression of TNF-α in MCD diet-induced NASH animal model[216]
TNF-α levels in liver were lower in dietary induced NASH animal model treated with glutamine[217]
α- and γ-tocopherol protected against LPS-triggered NASH in an obese mouse model, by decreasing liver necroinflammatory activity, levels of TNF-α, without affecting body mass or hepatic steatosis[219]
Obese mice on a HFD treated with thalidomide (100 mg/kg per day for 10 d) showed improvements in insulin sensitivity, through restoration of the hepatic insulin IRS-1 and AKT phosphorylation, an improvement in hepatic steatosis was also noticed, which correlated with reduced TNF-a levels[218]
Statins (rosuvastatin and pioglitazon) in diet-induced NASH rat models decreased serum TNF-α level[212,213]
Treatment with anti-TNF antibodies in ob/ob mice fed with HFD improved liver steatosis, insulin sensitivity, and serum ALT levels[209]
Treatment of HFD-rat with monoclonal TNF-α antibody, infliximab, reduced proinflammatory markers (TNF-α, IL-6, IL-1β), activity of JNK and IKK-B, SOCS-3 expression, and improved insulin signaling through JAK2/STAT-3 and IRS/AKT/FOXO1 pathway in the liverThis all led to reduced IR, fat liver accumulation and inflammation[210]
LPS derived TNF-α production enhanced expression of SREBP-1 mRNA leading to hepatic steatosis[201]
In vitroJNK2-/- hepatocytes resistant to TNF-α induced apoptosis[183]
Tiazolidinediones reversed TNF-α induced IR[211]
Quercetin decreased TNF-α expression in oleic acid induced steatotic HepG2 cells[215]

The complexity of TNF-α mechanisms of action has been extensively investigated. Once produced in adipose tissue, TNF-α causes impaired insulin-derived peripheral uptake of glucose by increasing serine phosphorylation of insulin receptor substrate 1 (IRS-1) and consequently inhibition of translocation of glucose transporter type 4 (GLUT4) to the plasma membrane resulting in peripheral IR[181]. It also stimulates hormone sensitive lipase resulting in increased serum FFA and their influx in the liver.

Lipid accumulation in the liver induces Bax (pro-apoptotic Bcl-2 family member) translocation to lysosomes causing their destabilization and release of lysosomal cysteine protease cathepsin B, through activation of inhibitor of nuclear factor kappa-B kinase (IKK-β) in hepatocytes this activates nuclear factor-kappaB (NFκB), and enhances gene expression of proinflammatory cytokines including TNF-α[182]. Additional generators of TNF-α in the liver are Kupffer cells in response to bacterial endotoxins, mediated by toll-like receptors (TLR). In hepatocytes, TNF-α induces suppressors of cytokine signaling (SOCS) that leads to decreased insulin signaling, as well as to induction of sterol regulatory element-binding protein-1c (SREBP-1c) and thus to liver steatosis. By activation of cytosolic sphingomyelinase, TNF-α produces ceramide that activates several kinases resulting in impaired insulin signaling, but also increases ROS synthesis. ROS further enhance TNF-α production, which increases mitochondrial permeability, releases mitochondrial cytochrome c, and aggravates ROS formation, resulting in hepatocyte death. Although two different TNF-α receptors exist, tumor necrosis factor receptor 1 (TNFR1) and 2 (TNFR2), only TNFR1 is a mediator of hepatocyte apoptosis. Some of the proposed mechanisms involved in hepatocyte apoptosis are TNF-related apoptosis inducing ligand (TRAIL), Fas-mediated apoptosis via proteolytic caspase-8, and JNK2 pathway[183,184].

All these biological effects of TNF-α result in evolution of NAFLD and are extensively investigated in vivo and in vitro, all in order to better understand the underlying insulin-mediated pathologic mechanisms, enabling new therapeutic strategies in NAFLD[185,186]. In humans it was shown that even healthy individuals with high basal TNF-α levels had significantly greater risk of developing NAFLD[180]. A great number of studies in adults and children revealed increased expression of TNF-α and its receptors in IR-derived NASH patients[180,187-192]. Although study results regarding the correlation of TNF-α with the progression of the disease are contradictory[187], quite a number of newer animal and human studies state that TNF-α is a predictor of NASH and correlates with advanced stages[189-193]. Indeed, in vitro and in an over-nutritioned animal model that lacks both TNF-α receptors, it was shown that TNF-α produced by Kupffer cells enhanced expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA in activated hepatic stellate cells and suppressed their apoptotic induction, thereby confirming its role in liver fibrosis[193].

In vitro and in vivo studies have shown that fructose-induced NAFLD correlates with endotoxemia which leads to activation of hepatic Kupffer cells in the liver and subsequently TNF-α production[194-201].

Genetic predisposition to NASH has lately been a matter of great interest; TNF-α polymorphism in certain populations was associated with susceptibility for NAFLD[188,202,203].

Since numerous studies confirmed TNF-α involvement in the complex net that leads to development of NAFLD, diverse therapeutic options were proposed. Pentoxifylline, a TNF-α inhibitor, was the most extensively studied. It was shown that patients with NASH, after treatment with pentoxifylline for 6 mo, had significantly reduced liver enzymes, serum TNF-α level and improved IR; after a year of treatment, additional improvements in steatosis, stage of fibrosis and lobular inflammation were noticed[204-207]. Furthermore, regarding the important role of microbiota in gut permeability and endotoxemia, therapeutical options with probiotics were also investigated and studies reported improved insulin sensitivity, liver histology, decreased TNF-α, total fatty acid content and serum ALT levels[208,209]. Treatment with the monoclonal TNF-α antibody, infliximab, reduced IR, hepatic fat accumulation and inflammation[210]. In experimental models of NASH, in vivo and in vitro, thiazolidinediones[211-213], fish oil[214], quercetin[215], dietary oleate[216], glutamine[217], thalidomide[218] and α- and γ-tocopherol[219] were therapeutic options that decreased proinflammatory activity, TNF-α among others, implying their possible benefit in NAFLD treatment.

Based on extensive literature from published studies, we can conclude that TNF-α is associated with IR, enhanced peripheral lipolysis, liver steatosis, inflammation, necrosis, apoptosis and fibrosis.

INTERLEUKIN-6 AND NAFLD

IL-6 is a proinflammatory pleiotropic cytokine produced by adipocytes, hepatocytes, immune and endothelial cells[18]. Even though smaller in size, visceral adipocytes are superior cytokine generators compared to subcutaneous adipocytes and it was shown that obese and lean NAFLD patients can display a similar cytokine profile regarding IL-6. Endotoxemia in obesity, resulting from small intestinal bacterial overgrowth, stimulates macrophages through TLR receptors to produce TNF-α that possibly up-regulates IL-6 production from adipocytes and macrophages infiltrated in adipose tissue[220]. Hence, adipose tissue in obese subjects has an important role in enhancing low-grade chronic inflammation leading to IR and lipid accumulation in liver. Accumulated FFAs in hepatocytes activate IKK-B and NF-κB, a transcription factor that plays a central role in coordinating the expression of various proinflammatory cytokines, including IL-6[221]. The role of IL-6 in glucose metabolism, IR, NASH pathogenesis and disease progression was investigated in experimental models of steatosis and liver injury, as well as in NAFLD patients and the findings of these studies are reported in Table 6.

Table 6 Studies and their findings on interleukin-6.
StudyFindingRef.
HumanIncreased plasma IL-6 in T2DM[222]
Elevated basal IL-6 levels in healthy humans present high relative risk of developing T2DM[224]
Obese patients after bariatric surgery who lost weight had decreased IR and IL-6[225][226]
IL-6 174C polymorphism associated with NASH and IR[239]
IL-6 levels higher in NAFLD patients, especially with advance stages, compared to ones with hepatitis B[240]
Increased serum IL-6 levels in biopsy proven NAFLD compared to controls[241]
No difference in IL-6 levels among T2DM patients with NASH/advanced fibrosis compared to those without NASH or light fibrosis[242]
No difference in serum IL-6 and its intrahepatic mRNA expression between NASH and steatosis[243,244]
In morbidly obese patients serum IL-6 levels correlated with progression of steatosis but in NASH declinedIL-6 > 4.81 pg/mL predicted liver steatosis[245]
Hepatocyte IL-6 expression positively correlated with degree of inflammation, stage of fibrosis and IR[246]
Increased circulating IL-6 and its soluble receptor in NASH patients compared with steatosis and healthy volunteers[189]
Normal IL-6 values exclude NASH[247]
IL-6, total cytokeratin-18 (M65) and adiponectin - a new panel for predicting NASH[248]
Decreased IL-6 levels after lifestyle changes and vitamin E administration[249]
AnimalChronic administration of IL-6 suppressed hepatic insulin signaling without effect on skeletal muscle[231]
Lep(ob) mice neutralized with IL-6 antibody showed increased insulin receptor signaling in the liver but not in peripheral tissues[232]
IL-6 decreases overall IR and hepatic inflammation[233]
Hepatoprotective and hepatoproliferative role of short-term exposure to IL-6 in ischaemic preconditioning models[234]
Treatment of IL-6-deficient mice acutely with IL-6 restored STAT3 binding and hepatocyte proliferation[235]
Chronic liver exposure to IL-6 led to cell death via Bax induction, activation of Fas agonist derived caspase-9 and cytochrome c release[236]
IL-6 showed inflammatory and antisteatotic effects in liver on mouse NASH model[237]
Hepatoprotective role of IL-6 by STAT3 activation in severe NASH model[238]
In vitroLPS through TLR receptors stimulated macrophages to produce TNF-α that up-regulated IL-6 production in adipocytes and macrophages[220]
IL-6 inhibited insulin-induced glycogenesis in hepatocytes[227]
IL-6 promoted IR in hepatocytes and HepG2 via decreased tyrosine phosphorylation of IRS-1, impaired association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1, inhibition of Akt and glycogen synthesis[228]
IL-6 impaired insulin signaling in 3T3-L1 adipocytes through inhibition of gene transcription of IRS-1, GLUT-4 and PPARγ[229]
IL-6-dependent IR mediated by induction of SOCS-3 protein in HepG2 cells[230]

Its role in the pathogenesis of T2DM was confirmed in several human studies suggesting that even healthy women with higher basal levels of IL-6 have a significantly higher relative risk of developing T2DM[222-226]. Experimental models confirmed the role of IL-6 in this manner, but are characterized with conflicting findings regarding peripheral IR. In vitro studies showed that IL-6 promotes overall IR via several mechanisms[227-230]. However, in the majority of animal models this effect was only shown in hepatic IR[231-233]. The contribution of IL-6 signaling in obesity-induced inflammation also remains controversial because some studies have reported a hepatoprotective and hepatoproliferative role of short-term exposure to IL-6[234,235]. Since NAFLD is characterized by chronic necroinflammatory activity, results of short-term liver exposure to IL-6 are not entirely applicable. Chronic exposure to IL-6 led to liver injury, although there were studies that concluded it had a protective role against the progression of hepatic steatosis and paradoxically a hepatoprotective role in advanced stages of NAFLD[236-238]. Certain polymorphisms of the IL-6 gene were associated with development of NAFLD[239]. When compared to other chronic liver diseases, such as chronic hepatitis B, IL-6 levels were significantly higher among NAFLD patients, especially with advanced histopathology findings[240]. Although numerous human studies have shown a correlation between IL-6 levels and NAFLD, data concerning its relationship with stages of the disease are contradictory[189,241-247]. IL-6 as a single noninvasive marker for predicting the presence of NASH is not sufficient, therefore pathophysiological-based non-invasive panels of serological biomarkers are intensively investigated. A combination of IL-6, total cytokeratin-18 (M65 - a marker of necrosis and apoptosis) and adiponectin gave a good predictive value[248]. Several therapeutic options, including vitamin E and dietary quercetin showed a significant decrease in IL-6 levels in NAFLD subjects[249,250]. Tocilizumab, a humanized IL-6 receptor antibody, is yet to be investigated as a therapeutic choice in this manner[251].

In conclusion, IL-6 is a proinflammatory cytokine associated with the development of IR, but its exact role in the pathogenesis of NAFLD is still waiting to be determined.

INTERLEUKIN-1 AND NAFLD

IL-1 family cytokine members are produced by macrophages, endothelial cells and fibroblasts. IL-1 family members can be divided into potentially proinflammatory cytokines such as IL-1β or IL-18, and into antiinflammatory cytokines such as IL-1Ra[252,253]. IL-1α, acutely administrated in vitro, transiently causes IR, promotes inflammation and liver fibrosis[254]. IL-1α and IL-1β were shown to have a role in the transformation of steatosis to steatohepatitis and liver fibrosis[255].

IL-1β is a member of the IL-1 family most commonly investigated in the pathogenesis of NAFLD. Major generators of IL-1β are Kupffer cells and macrophages in which FoxO1, through NF-κB, induces its production[256]. LPS, saturated fatty acids, and others, induce production of pro-IL-1β through TLR in Kupffer cells, which is cleaved by caspase-1 to a mature biologically active form[257,258]. In vivo and in vitro, it was shown that IL-1β in many ways contributes to development of IR-derived NAFLD[259-261]. Inhibition of IL-1β decreases the severity of atherosclerosis and hyperglycemia in diet-induced obesity[262,263]. IL-1 serum levels were significantly higher among NAFLD patients compared to other chronic liver diseases, with remarkably high levels in advanced stage of fibrosis[240]. In experimental models it was shown that IL-1β promotes liver steatosis and fibrosis[264-267]. Several treatment options for NAFLD, mediated through reduction of IL-1β action, were investigated[268]. The previously mentioned studies that investigated IL-1 actions are displayed in Table 7.

Table 7 Studies and their findings on interleukin-1α, interleukin-1β, interleukin-1Ra and interleukin-18.
CytokinesFindingRef.
IL-1αAcute treatment of 3T3-L1 adipocytes with IL-1α led to transient IR at IRS-1 level, mediated by its serine phosphorylation[254]
IL-1β
HumanWeight loss in severely obese patients led to decreased IL-1β in subcutaneous adipose tissue and in liver without effect on adipose IL-1α IL-1β was significantly higher in subcutaneous/visceral adipose tissue than in liver[253]
IL1-β genetic variants in Japanese population associated with NASH[259]
AnimalHepatic IL-1α and IL-1β increased in NASH animal models Mice deficient in either cytokine not prone to NASH and fibrosis development[255]
In experimental models TLR2 and palmitic acid activated inflammasome in Kupffer cells and produced IL-1α and IL-1β[257]
IL-1β/ApoE-deficient mice had less pronounced atherosclerosis[262]
Treatment with an IL-1β antibody improved glycemic control and β cell function in diet-induced obese mice[263]
Animal NASH model showed increased macrophage infiltration in adipose tissue as well as in liver accompanied with increased expression of IL-1β[264]
Hepatic steatosis partially mediated by Kupffer cells that produced IL-1β which suppressed PPAR-α[266]
In diet induced NASH mice probiotics decreased hepatic IL-1β mRNA[268]
In vitroIL-1β inhibited insulin-induced phosphorylation of the insulin receptor beta subunit, IRS1, protein kinase B and extracellular regulated kinase 1/2 in murine and human adipocytes that lead to IR and inhibition of lipogenesis IL-1β decreased adiponectin[260]
IL-1β promoted hepatic fibrosis by upregulating TIMMP-1 in rat HSC mediated by p38 mitogen-activated protein kinases and JNK[267]
IL-1RaIL-1Ra decreased glucose uptake in muscle and was upregulated in WAT of diet-induce obese mice[270]
Atherogenic diet in IL-1Ra deficient mice caused severe liver steatosis, inflammation and portal fibrosis[272]
IL-18In obese women IL-18 positively correlated with body weight and visceral fat[275]
In T2DM patients and non-diabetic controls IL-18 plasma levels positively correlated with HOMA-IR[276]
In male patients with NAFLD, IL-18 alone in the absence of metabolic risks cannot contribute to evolution of NAFLD[278]
IL-18 enhanced cytokine production by stimulating TNF-α synthesis in immune cells[279]
Il-18 administrated with IL-12 induced mouse fatty liver in an IFN-γ dependent manner[280]
Rosiglitazone in NAFLD rat model reduced IL-18 and caspase-1 in liver as well as improved histology[277]
INTERLEUKIN-1 RECEPTOR ANTAGONIST AND NAFLD

IL-1Ra binds to IL-1 receptor competitively with IL-1α and IL-1β, thus blocking their activity. It has been shown in vivo and in vitro that IL-1β and IL-6 increase its plasma levels[269]. IL-1Ra is overexpressed in serum and WAT of obese patients and animal models, where it correlates with BMI and IR[270]. A correlation was found between IL-1Ra and the degree of hepatic lobular inflammation, while animal studies suggested that IL-1Ra may have a protective role against NAFLD development[271,272].

INTERLEUKIN-18 AND NAFLD

IL-18, previously called interferon-γ inducing factor, with structural properties of the IL-1 family, is primarily synthesized as a precursor protein, pro-IL-18, which requires activation by caspase-1 cleavage into a bioactive mature form[273]. Produced by macrophages, Kupffer cells and endothelial cells, it induces production of chemokines, adhesion molecules and proinflammatory cytokines. IL-18 binding protein, an inhibitor that binds on the same receptor as IL-18, enhances its negative feedback mechanism enabling cell protection from accelerated proinflammatory activity such as NASH.

Early studies showed a positive correlation of IL-18 with IR and obesity, but a reduction in plasma IL-18 was influenced only by changes in IR[274-277]. In NAFLD, higher levels of IL-18 and caspase-1 were found when compared to controls if components of MS were present[274,277,278]. Several possible mechanisms of IL-18 involvement in NAFLD were investigated[279,280]. Rosiglitazone treatment of NAFLD was investigated because of its inhibitory effect on hepatic IL-18 production[277]. Li et al[281] has shown that IL-18 itself, as well as its ratio with IL-18 binding protein, was significantly higher in a NAFLD group as compared to controls, implying that IL-18 binding protein should be included in future studies.

In conclusion, IL-18 could be involved in the development of IR-derived NAFLD and exact mechanisms are still waiting to be elucidated. Studies on IL-18 that were mentioned in this review are reported in Table 7.

CONCLUSION

The pathogenesis of NAFLD is still an unfinished book that needs further experimental and clinical research to fulfill all the pages. On the basis of previous and recent published data, key characters could be proinflammatory cytokines and chemokines that are products of adipose tissue, namely inflammatory cells infiltrating the adipose tissue. Although a definite conclusion on the effect of cytokines described in this review is a highly complex one, we could summarize that adiponectin, des-acyl ghrelin and leptin are adipokines that decrease, while TNF-α and IL-6 are cytokines that enhance IR and subsequently NAFLD. Acting on these premises, new therapeutic possibilities emerge; however, much of the work remains to be done, especially on identifying selective targets for future treatment.

Footnotes

P- Reviewer: de Oliveira CPMS, Lonardo A, Mach th, Miura K, Sebastiani G, Suda T S- Editor: Ma YJ L- Editor: Logan S E- Editor: Zhang DN

References
1.  Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592-1609.  [PubMed]  [DOI]
2.  Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274-285.  [PubMed]  [DOI]
3.  Basaranoglu M, Basaranoglu G, Sentürk H. From fatty liver to fibrosis: a tale of “second hit”. World J Gastroenterol. 2013;19:1158-1165.  [PubMed]  [DOI]
4.  Lonardo A, Lombardini S, Ricchi M, Scaglioni F, Loria P. Review article: hepatic steatosis and insulin resistance. Aliment Pharmacol Ther. 2005;22 Suppl 2:64-70.  [PubMed]  [DOI]
5.  Thomas LV, Ockhuizen T. New insights into the impact of the intestinal microbiota on health and disease: a symposium report. Br J Nutr. 2012;107 Suppl 1:S1-13.  [PubMed]  [DOI]
6.  Harris K, Kassis A, Major G, Chou CJ. Is the gut microbiota a new factor contributing to obesity and its metabolic disorders? J Obes. 2012;2012:879151.  [PubMed]  [DOI]
7.  Serino M, Luche E, Gres S, Baylac A, Bergé M, Cenac C, Waget A, Klopp P, Iacovoni J, Klopp C. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut. 2012;61:543-553.  [PubMed]  [DOI]
8.  Aron-Wisnewsky J, Gaborit B, Dutour A, Clement K. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect. 2013;19:338-348.  [PubMed]  [DOI]
9.  Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev. 2001;81:1031-1064.  [PubMed]  [DOI]
10.  Noverr MC, Huffnagle GB. Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 2004;12:562-568.  [PubMed]  [DOI]
11.  Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Mascianà R, Forgione A, Gabrieli ML, Perotti G. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877-1887.  [PubMed]  [DOI]
12.  Zeisel SH, Wishnok JS, Blusztajn JK. Formation of methylamines from ingested choline and lecithin. J Pharmacol Exp Ther. 1983;225:320-324.  [PubMed]  [DOI]
13.  Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature. 2012;487:104-108.  [PubMed]  [DOI]
14.  Dawes EA, Foster SM. The formation of ethanol in Escherichia coli. Biochim Biophys Acta. 1956;22:253-265.  [PubMed]  [DOI]
15.  Takahashi Y, Soejima Y, Fukusato T. Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2012;18:2300-2308.  [PubMed]  [DOI]
16.  Asaoka Y, Terai S, Sakaida I, Nishina H. The expanding role of fish models in understanding non-alcoholic fatty liver disease. Dis Model Mech. 2013;6:905-914.  [PubMed]  [DOI]
17.  Nagarajan P, Mahesh Kumar MJ, Venkatesan R, Majundar SS, Juyal RC. Genetically modified mouse models for the study of nonalcoholic fatty liver disease. World J Gastroenterol. 2012;18:1141-1153.  [PubMed]  [DOI]
18.  Tsochatzis EA, Papatheodoridis GV, Archimandritis AJ. Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy. Mediators Inflamm. 2009;2009:831670.  [PubMed]  [DOI]
19.  Copaci I, Micu L, Voiculescu M. The role of cytokines in non-alcoholic steatohepatitis. A review. J Gastrointestin Liver Dis. 2006;15:363-373.  [PubMed]  [DOI]
20.  Braunersreuther V, Viviani GL, Mach F, Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J Gastroenterol. 2012;18:727-735.  [PubMed]  [DOI]
21.  Asrih M, Jornayvaz FR. Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance. J Endocrinol. 2013;218:R25-R36.  [PubMed]  [DOI]
22.  Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42:987-1000.  [PubMed]  [DOI]
23.  Hui E, Xu A, Bo Yang H, Lam KS. Obesity as the common soil of non-alcoholic fatty liver disease and diabetes: Role of adipokines. J Diabetes Investig. 2013;4:413-425.  [PubMed]  [DOI]
24.  Tsochatzis E, Papatheodoridis GV, Archimandritis AJ. The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol. 2006;101:2629-2640.  [PubMed]  [DOI]
25.  Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257:79-83.  [PubMed]  [DOI]
26.  Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1). 1996. Biochem Biophys Res Commun. 2012;425:556-559.  [PubMed]  [DOI]
27.  Wang Y, Lam KS, Yau MH, Xu A. Post-translational modifications of adiponectin: mechanisms and functional implications. Biochem J. 2008;409:623-633.  [PubMed]  [DOI]
28.  Neumeier M, Weigert J, Schäffler A, Wehrwein G, Müller-Ladner U, Schölmerich J, Wrede C, Buechler C. Different effects of adiponectin isoforms in human monocytic cells. J Leukoc Biol. 2006;79:803-808.  [PubMed]  [DOI]
29.  Schober F, Neumeier M, Weigert J, Wurm S, Wanninger J, Schäffler A, Dada A, Liebisch G, Schmitz G, Aslanidis C. Low molecular weight adiponectin negatively correlates with the waist circumference and monocytic IL-6 release. Biochem Biophys Res Commun. 2007;361:968-973.  [PubMed]  [DOI]
30.  Silva TE, Colombo G, Schiavon LL. Adiponectin: A multitasking player in the field of liver diseases. Diabetes Metab. 2014;40:95-107.  [PubMed]  [DOI]
31.  Shetty S, Kusminski CM, Scherer PE. Adiponectin in health and disease: evaluation of adiponectin-targeted drug development strategies. Trends Pharmacol Sci. 2009;30:234-239.  [PubMed]  [DOI]
32.  Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003;423:762-769.  [PubMed]  [DOI]
33.  Neumeier M, Weigert J, Schäffler A, Weiss T, Kirchner S, Laberer S, Schölmerich J, Buechler C. Regulation of adiponectin receptor 1 in human hepatocytes by agonists of nuclear receptors. Biochem Biophys Res Commun. 2005;334:924-929.  [PubMed]  [DOI]
34.  Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem. 1996;271:10697-10703.  [PubMed]  [DOI]
35.  Stefan N, Bunt JC, Salbe AD, Funahashi T, Matsuzawa Y, Tataranni PA. Plasma adiponectin concentrations in children: relationships with obesity and insulinemia. J Clin Endocrinol Metab. 2002;87:4652-4656.  [PubMed]  [DOI]
36.  Ostrowska L, Fiedorczuk J, Adamska E. Effect of diet and other factors on serum adiponectin concentrations in patients with type 2 diabetes. Rocz Panstw Zakl Hig. 2013;64:61-66.  [PubMed]  [DOI]
37.  Yatagai T, Nagasaka S, Taniguchi A, Fukushima M, Nakamura T, Kuroe A, Nakai Y, Ishibashi S. Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Metabolism. 2003;52:1274-1278.  [PubMed]  [DOI]
38.  Bidulescu A, Liu J, Hickson DA, Hairston KG, Fox ER, Arnett DK, Sumner AE, Taylor HA, Gibbons GH. Gender differences in the association of visceral and subcutaneous adiposity with adiponectin in African Americans: the Jackson Heart Study. BMC Cardiovasc Disord. 2013;13:9.  [PubMed]  [DOI]
39.  Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001;50:2094-2099.  [PubMed]  [DOI]
40.  Statnick MA, Beavers LS, Conner LJ, Corominola H, Johnson D, Hammond CD, Rafaeloff-Phail R, Seng T, Suter TM, Sluka JP. Decreased expression of apM1 in omental and subcutaneous adipose tissue of humans with type 2 diabetes. Int J Exp Diabetes Res. 2000;1:81-88.  [PubMed]  [DOI]
41.  Ozcelik F, Yuksel C, Arslan E, Genc S, Omer B, Serdar MA. Relationship between visceral adipose tissue and adiponectin, inflammatory markers and thyroid hormones in obese males with hepatosteatosis and insulin resistance. Arch Med Res. 2013;44:273-280.  [PubMed]  [DOI]
42.  Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86:1930-1935.  [PubMed]  [DOI]
43.  Spranger J, Kroke A, Möhlig M, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF. Adiponectin and protection against type 2 diabetes mellitus. Lancet. 2003;361:226-228.  [PubMed]  [DOI]
44.  Vega GL, Grundy SM. Metabolic risk susceptibility in men is partially related to adiponectin/leptin ratio. J Obes. 2013;2013:409679.  [PubMed]  [DOI]
45.  Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem. 2002;277:25863-25866.  [PubMed]  [DOI]
46.  Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, Okada-Iwabu M, Kawamoto S, Kubota N, Kubota T. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13:332-339.  [PubMed]  [DOI]
47.  Shklyaev S, Aslanidi G, Tennant M, Prima V, Kohlbrenner E, Kroutov V, Campbell-Thompson M, Crawford J, Shek EW, Scarpace PJ. Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats. Proc Natl Acad Sci USA. 2003;100:14217-14222.  [PubMed]  [DOI]
48.  Mackawy AM. Association of the + 45T& gt; G adiponectin gene polymorphism with insulin resistance in non-diabetic Saudi women. Gene. 2013;530:158-163.  [PubMed]  [DOI]
49.  Ramya K, Ayyappa KA, Ghosh S, Mohan V, Radha V. Genetic association of ADIPOQ gene variants with type 2 diabetes, obesity and serum adiponectin levels in south Indian population. Gene. 2013;532:253-262.  [PubMed]  [DOI]
50.  Ryo M, Nakamura T, Kihara S, Kumada M, Shibazaki S, Takahashi M, Nagai M, Matsuzawa Y, Funahashi T. Adiponectin as a biomarker of the metabolic syndrome. Circ J. 2004;68:975-981.  [PubMed]  [DOI]
51.  Matsuzawa Y. Adiponectin: a key player in obesity related disorders. Curr Pharm Des. 2010;16:1896-1901.  [PubMed]  [DOI]
52.  Nannipieri M, Cecchetti F, Anselmino M, Mancini E, Marchetti G, Bonotti A, Baldi S, Solito B, Giannetti M, Pinchera A. Pattern of expression of adiponectin receptors in human liver and its relation to nonalcoholic steatohepatitis. Obes Surg. 2009;19:467-474.  [PubMed]  [DOI]
53.  Ma H, Gomez V, Lu L, Yang X, Wu X, Xiao SY. Expression of adiponectin and its receptors in livers of morbidly obese patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2009;24:233-237.  [PubMed]  [DOI]
54.  Uribe M, Zamora-Valdés D, Moreno-Portillo M, Bermejo-Martínez L, Pichardo-Bahena R, Baptista-González HA, Ponciano-Rodríguez G, Uribe MH, Medina-Santillán R, Méndez-Sánchez N. Hepatic expression of ghrelin and adiponectin and their receptors in patients with nonalcoholic fatty liver disease. Ann Hepatol. 2008;7:67-71.  [PubMed]  [DOI]
55.  Kaser S, Moschen A, Cayon A, Kaser A, Crespo J, Pons-Romero F, Ebenbichler CF, Patsch JR, Tilg H. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut. 2005;54:117-121.  [PubMed]  [DOI]
56.  Lemoine M, Ratziu V, Kim M, Maachi M, Wendum D, Paye F, Bastard JP, Poupon R, Housset C, Capeau J. Serum adipokine levels predictive of liver injury in non-alcoholic fatty liver disease. Liver Int. 2009;29:1431-1438.  [PubMed]  [DOI]
57.  Kamada Y, Matsumoto H, Tamura S, Fukushima J, Kiso S, Fukui K, Igura T, Maeda N, Kihara S, Funahashi T. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol. 2007;47:556-564.  [PubMed]  [DOI]
58.  Anania FA. Adiponectin and alcoholic fatty liver: Is it, after all, about what you eat? Hepatology. 2005;42:530-532.  [PubMed]  [DOI]
59.  You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology. 2005;42:568-577.  [PubMed]  [DOI]
60.  Awazawa M, Ueki K, Inabe K, Yamauchi T, Kaneko K, Okazaki Y, Bardeesy N, Ohnishi S, Nagai R, Kadowaki T. Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway. Biochem Biophys Res Commun. 2009;382:51-56.  [PubMed]  [DOI]
61.  Weigert J, Neumeier M, Wanninger J, Wurm S, Kopp A, Schober F, Filarsky M, Schäffler A, Zeitoun M, Aslanidis C. Reduced response to adiponectin and lower abundance of adiponectin receptor proteins in type 2 diabetic monocytes. FEBS Lett. 2008;582:1777-1782.  [PubMed]  [DOI]
62.  Inukai K, Nakashima Y, Watanabe M, Takata N, Sawa T, Kurihara S, Awata T, Katayama S. Regulation of adiponectin receptor gene expression in diabetic mice. Am J Physiol Endocrinol Metab. 2005;288:E876-E882.  [PubMed]  [DOI]
63.  Matsumoto H, Tamura S, Kamada Y, Kiso S, Fukushima J, Wada A, Maeda N, Kihara S, Funahashi T, Matsuzawa Y. Adiponectin deficiency exacerbates lipopolysaccharide/D-galactosamine-induced liver injury in mice. World J Gastroenterol. 2006;12:3352-3358.  [PubMed]  [DOI]
64.  Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, Yoshimatsu H. Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice. Hepatology. 2004;40:177-184.  [PubMed]  [DOI]
65.  Wolf AM, Wolf D, Avila MA, Moschen AR, Berasain C, Enrich B, Rumpold H, Tilg H. Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice. J Hepatol. 2006;44:537-543.  [PubMed]  [DOI]
66.  Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation. 1999;100:2473-2476.  [PubMed]  [DOI]
67.  Tsao TS, Murrey HE, Hug C, Lee DH, Lodish HF. Oligomerization state-dependent activation of NF-kappa B signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J Biol Chem. 2002;277:29359-29362.  [PubMed]  [DOI]
68.  Rovin BH, Song H. Chemokine induction by the adipocyte-derived cytokine adiponectin. Clin Immunol. 2006;120:99-105.  [PubMed]  [DOI]
69.  Wang Y, Lam KS, Xu JY, Lu G, Xu LY, Cooper GJ, Xu A. Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner. J Biol Chem. 2005;280:18341-18347.  [PubMed]  [DOI]
70.  Musso G, Gambino R, Biroli G, Carello M, Fagà E, Pacini G, De Michieli F, Cassader M, Durazzo M, Rizzetto M. Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic Beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2005;100:2438-2446.  [PubMed]  [DOI]
71.  Polyzos SA, Toulis KA, Goulis DG, Zavos C, Kountouras J. Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Metabolism. 2011;60:313-326.  [PubMed]  [DOI]
72.  Finelli C, Tarantino G. What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J Gastroenterol. 2013;19:802-812.  [PubMed]  [DOI]
73.  Handy JA, Saxena NK, Fu P, Lin S, Mells JE, Gupta NA, Anania FA. Adiponectin activation of AMPK disrupts leptin-mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS-3). J Cell Biochem. 2010;110:1195-1207.  [PubMed]  [DOI]
74.  Alsaleh A, Crepostnaia D, Maniou Z, Lewis FJ, Hall WL, Sanders TA, O’Dell SD. Adiponectin gene variant interacts with fish oil supplementation to influence serum adiponectin in older individuals. J Nutr. 2013;143:1021-1027.  [PubMed]  [DOI]
75.  Vrachnis N, Belitsos P, Sifakis S, Dafopoulos K, Siristatidis C, Pappa KI, Iliodromiti Z. Role of adipokines and other inflammatory mediators in gestational diabetes mellitus and previous gestational diabetes mellitus. Int J Endocrinol. 2012;2012:549748.  [PubMed]  [DOI]
76.  Polak J, Kovacova Z, Holst C, Verdich C, Astrup A, Blaak E, Patel K, Oppert JM, Langin D, Martinez JA. Total adiponectin and adiponectin multimeric complexes in relation to weight loss-induced improvements in insulin sensitivity in obese women: the NUGENOB study. Eur J Endocrinol. 2008;158:533-541.  [PubMed]  [DOI]
77.  Salani B, Briatore L, Andraghetti G, Adami GF, Maggi D, Cordera R. High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects. Obesity (Silver Spring). 2006;14:1511-1514.  [PubMed]  [DOI]
78.  Hage MP, Safadi B, Salti I, Nasrallah M. Role of Gut-Related Peptides and Other Hormones in the Amelioration of Type 2 Diabetes after Roux-en-Y Gastric Bypass Surgery. ISRN Endocrinol. 2012;2012:504756.  [PubMed]  [DOI]
79.  Stenvinkel P, Lönnqvist F, Schalling M. Molecular studies of leptin: implications for renal disease. Nephrol Dial Transplant. 1999;14:1103-1112.  [PubMed]  [DOI]
80.  Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale J, Becker GW, Bowsher RR, Stephens TW, Caro JF. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest. 1996;98:1277-1282.  [PubMed]  [DOI]
81.  Brabant G, Nave H, Mayr B, Behrend M, van Harmelen V, Arner P. Secretion of free and protein-bound leptin from subcutaneous adipose tissue of lean and obese women. J Clin Endocrinol Metab. 2002;87:3966-3970.  [PubMed]  [DOI]
82.  Zimmet P, Hodge A, Nicolson M, Staten M, de Courten M, Moore J, Morawiecki A, Lubina J, Collier G, Alberti G. Serum leptin concentration, obesity, and insulin resistance in Western Samoans: cross sectional study. BMJ. 1996;313:965-969.  [PubMed]  [DOI]
83.  Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF. Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro. Diabetes. 1996;45:699-701.  [PubMed]  [DOI]
84.  Zuo H, Shi Z, Yuan B, Dai Y, Wu G, Hussain A. Association between serum leptin concentrations and insulin resistance: a population-based study from China. PLoS One. 2013;8:e54615.  [PubMed]  [DOI]
85.  Ko BJ, Lee M, Park HS, Han K, Cho GJ, Hwang TG, Kim JH, Lee SH, Lee HY, Kim SM. Elevated vaspin and leptin levels are associated with obesity in prepubertal Korean children. Endocr J. 2013;60:609-616.  [PubMed]  [DOI]
86.  El-Wakkad A, Hassan Nel-M, Sibaii H, El-Zayat SR. Proinflammatory, anti-inflammatory cytokines and adiponkines in students with central obesity. Cytokine. 2013;61:682-687.  [PubMed]  [DOI]
87.  Seufert J, Kieffer TJ, Leech CA, Holz GG, Moritz W, Ricordi C, Habener JF. Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. J Clin Endocrinol Metab. 1999;84:670-676.  [PubMed]  [DOI]
88.  Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature. 1999;401:73-76.  [PubMed]  [DOI]
89.  Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570-578.  [PubMed]  [DOI]
90.  Scarpace PJ, Zhang Y. Leptin resistance: a prediposing factor for diet-induced obesity. Am J Physiol Regul Integr Comp Physiol. 2009;296:R493-R500.  [PubMed]  [DOI]
91.  Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia. 1978;14:141-148.  [PubMed]  [DOI]
92.  Nagao K, Inoue N, Ujino Y, Higa K, Shirouchi B, Wang YM, Yanagita T. Effect of leptin infusion on insulin sensitivity and lipid metabolism in diet-induced lipodystrophy model mice. Lipids Health Dis. 2008;7:8.  [PubMed]  [DOI]
93.  Huynh FK, Levi J, Denroche HC, Gray SL, Voshol PJ, Neumann UH, Speck M, Chua SC, Covey SD, Kieffer TJ. Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance. Diabetes. 2010;59:3032-3040.  [PubMed]  [DOI]
94.  Kakuma T, Lee Y, Higa M, Wang Zw, Pan W, Shimomura I, Unger RH. Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc Natl Acad Sci USA. 2000;97:8536-8541.  [PubMed]  [DOI]
95.  Münzberg H, Flier JS, Bjørbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology. 2004;145:4880-4889.  [PubMed]  [DOI]
96.  Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, Billes SK, Glavas MM, Grayson BE, Perello M, Nillni EA. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab. 2007;5:181-194.  [PubMed]  [DOI]
97.  El-Haschimi K, Pierroz DD, Hileman SM, Bjørbaek C, Flier JS. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest. 2000;105:1827-1832.  [PubMed]  [DOI]
98.  Lin S, Thomas TC, Storlien LH, Huang XF. Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. Int J Obes Relat Metab Disord. 2000;24:639-646.  [PubMed]  [DOI]
99.  Knight ZA, Hannan KS, Greenberg ML, Friedman JM. Hyperleptinemia is required for the development of leptin resistance. PLoS One. 2010;5:e11376.  [PubMed]  [DOI]
100.  Koch CE, Lowe C, Pretz D, Steger J, Williams LM, Tups A. High-fat diet induces leptin resistance in leptin-deficient mice. J Neuroendocrinol. 2014;26:58-67.  [PubMed]  [DOI]
101.  Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei Y, Sato N. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34:288-297.  [PubMed]  [DOI]
102.  Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, Lang T, Fukuda T, Yamashina S, Kitamura T. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology. 2002;122:1399-1410.  [PubMed]  [DOI]
103.  Saxena NK, Ikeda K, Rockey DC, Friedman SL, Anania FA. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology. 2002;35:762-771.  [PubMed]  [DOI]
104.  Saad MF, Damani S, Gingerich RL, Riad-Gabriel MG, Khan A, Boyadjian R, Jinagouda SD, el-Tawil K, Rude RK, Kamdar V. Sexual dimorphism in plasma leptin concentration. J Clin Endocrinol Metab. 1997;82:579-584.  [PubMed]  [DOI]
105.  Hassink SG, Sheslow DV, de Lancey E, Opentanova I, Considine RV, Caro JF. Serum leptin in children with obesity: relationship to gender and development. Pediatrics. 1996;98:201-203.  [PubMed]  [DOI]
106.  Hube F, Lietz U, Igel M, Jensen PB, Tornqvist H, Joost HG, Hauner H. Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Horm Metab Res. 1996;28:690-693.  [PubMed]  [DOI]
107.  Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F, Leibel RL. Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab. 1996;81:3424-3427.  [PubMed]  [DOI]
108.  Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol. 2010;314:1-16.  [PubMed]  [DOI]
109.  Paz-Filho G, Mastronardi C, Franco CB, Wang KB, Wong ML, Licinio J. Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications. Arq Bras Endocrinol Metabol. 2012;56:597-607.  [PubMed]  [DOI]
110.  Segal KR, Landt M, Klein S. Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes. 1996;45:988-991.  [PubMed]  [DOI]
111.  Lilja M, Rolandsson O, Norberg M, Söderberg S. The impact of leptin and adiponectin on incident type 2 diabetes is modified by sex and insulin resistance. Metab Syndr Relat Disord. 2012;10:143-151.  [PubMed]  [DOI]
112.  Dagogo-Jack S, Fanelli C, Paramore D, Brothers J, Landt M. Plasma leptin and insulin relationships in obese and nonobese humans. Diabetes. 1996;45:695-698.  [PubMed]  [DOI]
113.  Boumaiza I, Omezzine A, Rejeb J, Rebhi L, Ouedrani A, Ben Rejeb N, Nabli N, Ben Abdelaziz A, Bouslama A. Relationship between leptin G2548A and leptin receptor Q223R gene polymorphisms and obesity and metabolic syndrome risk in Tunisian volunteers. Genet Test Mol Biomarkers. 2012;16:726-733.  [PubMed]  [DOI]
114.  Ren W, Zhang SH, Wu J, Ni YX. Polymorphism of the leptin gene promoter in pedigrees of type 2 diabetes mellitus in Chongqing, China. Chin Med J (Engl). 2004;117:558-561.  [PubMed]  [DOI]
115.  Devalaraja-Narashimha K, Padanilam BJ. PARP1 deficiency exacerbates diet-induced obesity in mice. J Endocrinol. 2010;205:243-252.  [PubMed]  [DOI]
116.  Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C, Liddle C, Samarasinghe D, George J. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology. 2002;36:403-409.  [PubMed]  [DOI]
117.  Uygun A, Kadayifci A, Yesilova Z, Erdil A, Yaman H, Saka M, Deveci MS, Bagci S, Gulsen M, Karaeren N. Serum leptin levels in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2000;95:3584-3589.  [PubMed]  [DOI]
118.  Tsochatzis E, Papatheodoridis GV, Hadziyannis E, Georgiou A, Kafiri G, Tiniakos DG, Manesis EK, Archimandritis AJ. Serum adipokine levels in chronic liver diseases: association of resistin levels with fibrosis severity. Scand J Gastroenterol. 2008;43:1128-1136.  [PubMed]  [DOI]
119.  Singh DK, Sakhuja P, Rastogi A, Singh A, Gondal R, Sarin SK. Serum leptin levels correlate with body mass index but not with histologic disease severity in Indian patients with non-alcoholic steatohepatitis: a pilot study. Indian J Med Res. 2013;137:986-987.  [PubMed]  [DOI]
120.  Angulo P, Alba LM, Petrovic LM, Adams LA, Lindor KD, Jensen MD. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. J Hepatol. 2004;41:943-949.  [PubMed]  [DOI]
121.  Musso G, Gambino R, Durazzo M, Biroli G, Carello M, Fagà E, Pacini G, De Michieli F, Rabbione L, Premoli A. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005;42:1175-1183.  [PubMed]  [DOI]
122.  Medici V, Ali MR, Seo S, Aoki CA, Rossaro L, Kim K, Fuller WD, Vidovszky TJ, Smith W, Jiang JX. Increased soluble leptin receptor levels in morbidly obese patients with insulin resistance and nonalcoholic fatty liver disease. Obesity (Silver Spring). 2010;18:2268-2273.  [PubMed]  [DOI]
123.  Lanthier N, Horsmans Y, Leclercq IA. The metabolic syndrome: how it may influence hepatic stellate cell activation and hepatic fibrosis. Curr Opin Clin Nutr Metab Care. 2009;12:404-411.  [PubMed]  [DOI]
124.  Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656-660.  [PubMed]  [DOI]
125.  Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194-198.  [PubMed]  [DOI]
126.  Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132:387-396.  [PubMed]  [DOI]
127.  Gauna C, van der Lely AJ. Somatostatin, cortistatin, ghrelin and glucose metabolism. J Endocrinol Invest. 2005;28:127-131.  [PubMed]  [DOI]
128.  Pacifico L, Poggiogalle E, Costantino F, Anania C, Ferraro F, Chiarelli F, Chiesa C. Acylated and nonacylated ghrelin levels and their associations with insulin resistance in obese and normal weight children with metabolic syndrome. Eur J Endocrinol. 2009;161:861-870.  [PubMed]  [DOI]
129.  St-Pierre DH, Karelis AD, Coderre L, Malita F, Fontaine J, Mignault D, Brochu M, Bastard JP, Cianflone K, Doucet E. Association of acylated and nonacylated ghrelin with insulin sensitivity in overweight and obese postmenopausal women. J Clin Endocrinol Metab. 2007;92:264-269.  [PubMed]  [DOI]
130.  Barazzoni R, Zanetti M, Ferreira C, Vinci P, Pirulli A, Mucci M, Dore F, Fonda M, Ciocchi B, Cattin L. Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome. J Clin Endocrinol Metab. 2007;92:3935-3940.  [PubMed]  [DOI]
131.  Marchesini G, Pagotto U, Bugianesi E, De Iasio R, Manini R, Vanni E, Pasquali R, Melchionda N, Rizzetto M. Low ghrelin concentrations in nonalcoholic fatty liver disease are related to insulin resistance. J Clin Endocrinol Metab. 2003;88:5674-5679.  [PubMed]  [DOI]
132.  Estep M, Abawi M, Jarrar M, Wang L, Stepanova M, Elariny H, Moazez A, Goodman Z, Chandhoke V, Baranova A. Association of obestatin, ghrelin, and inflammatory cytokines in obese patients with non-alcoholic fatty liver disease. Obes Surg. 2011;21:1750-1757.  [PubMed]  [DOI]
133.  Rodríguez A, Gómez-Ambrosi J, Catalán V, Gil MJ, Becerril S, Sáinz N, Silva C, Salvador J, Colina I, Frühbeck G. Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Int J Obes (Lond). 2009;33:541-552.  [PubMed]  [DOI]
134.  Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, Hawley SA, Hardie DG, Grossman AB. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. 2005;280:25196-25201.  [PubMed]  [DOI]
135.  Li Y, Hai J, Li L, Chen X, Peng H, Cao M, Zhang Q. Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non-alcoholic fatty liver disease development. Endocrine. 2013;43:376-386.  [PubMed]  [DOI]
136.  Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 2000;19:4046-4055.  [PubMed]  [DOI]
137.  Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature. 2001;409:307-312.  [PubMed]  [DOI]
138.  Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee RR, Dai CY, Enders GH, Silberg DG, Wen X, Wu GD. A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci USA. 2001;98:502-506.  [PubMed]  [DOI]
139.  Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L. Disulfide-dependent multimeric assembly of resistin family hormones. Science. 2004;304:1154-1158.  [PubMed]  [DOI]
140.  Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O’Rahilly S. Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes. 2001;50:2199-2202.  [PubMed]  [DOI]
141.  Vendrell J, Broch M, Vilarrasa N, Molina A, Gómez JM, Gutiérrez C, Simón I, Soler J, Richart C. Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity. Obes Res. 2004;12:962-971.  [PubMed]  [DOI]
142.  Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q, Considine RV. Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab. 2003;88:5452-5455.  [PubMed]  [DOI]
143.  Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab. 2003;88:4848-4856.  [PubMed]  [DOI]
144.  McTernan PG, Fisher FM, Valsamakis G, Chetty R, Harte A, McTernan CL, Clark PM, Smith SA, Barnett AH, Kumar S. Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes. J Clin Endocrinol Metab. 2003;88:6098-6106.  [PubMed]  [DOI]
145.  Pfützner A, Langenfeld M, Kunt T, Löbig M, Forst T. Evaluation of human resistin assays with serum from patients with type 2 diabetes and different degrees of insulin resistance. Clin Lab. 2003;49:571-576.  [PubMed]  [DOI]
146.  Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol. 2003;149:331-335.  [PubMed]  [DOI]
147.  Youn BS, Yu KY, Park HJ, Lee NS, Min SS, Youn MY, Cho YM, Park YJ, Kim SY, Lee HK. Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2004;89:150-156.  [PubMed]  [DOI]
148.  Smith SR, Bai F, Charbonneau C, Janderová L, Argyropoulos G. A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes. 2003;52:1611-1618.  [PubMed]  [DOI]
149.  Wong VW, Hui AY, Tsang SW, Chan JL, Tse AM, Chan KF, So WY, Cheng AY, Ng WF, Wong GL. Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006;4:1154-1161.  [PubMed]  [DOI]
150.  Pagano C, Soardo G, Pilon C, Milocco C, Basan L, Milan G, Donnini D, Faggian D, Mussap M, Plebani M. Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J Clin Endocrinol Metab. 2006;91:1081-1086.  [PubMed]  [DOI]
151.  Zou CC, Liang L, Hong F, Fu JF, Zhao ZY. Serum adiponectin, resistin levels and non-alcoholic fatty liver disease in obese children. Endocr J. 2005;52:519-524.  [PubMed]  [DOI]
152.  Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR. Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun. 2003;309:286-290.  [PubMed]  [DOI]
153.  Haider DG, Schaller G, Kapiotis S, Maier C, Luger A, Wolzt M. The release of the adipocytokine visfatin is regulated by glucose and insulin. Diabetologia. 2006;49:1909-1914.  [PubMed]  [DOI]
154.  Chen MP, Chung FM, Chang DM, Tsai JC, Huang HF, Shin SJ, Lee YJ. Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2006;91:295-299.  [PubMed]  [DOI]
155.  Haider DG, Schindler K, Schaller G, Prager G, Wolzt M, Ludvik B. Increased plasma visfatin concentrations in morbidly obese subjects are reduced after gastric banding. J Clin Endocrinol Metab. 2006;91:1578-1581.  [PubMed]  [DOI]
156.  Filippatos TD, Derdemezis CS, Gazi IF, Lagos K, Kiortsis DN, Tselepis AD, Elisaf MS. Increased plasma visfatin levels in subjects with the metabolic syndrome. Eur J Clin Invest. 2008;38:71-72.  [PubMed]  [DOI]
157.  Berndt J, Klöting N, Kralisch S, Kovacs P, Fasshauer M, Schön MR, Stumvoll M, Blüher M. Plasma visfatin concentrations and fat depot-specific mRNA expression in humans. Diabetes. 2005;54:2911-2916.  [PubMed]  [DOI]
158.  Pagano C, Pilon C, Olivieri M, Mason P, Fabris R, Serra R, Milan G, Rossato M, Federspil G, Vettor R. Reduced plasma visfatin/pre-B cell colony-enhancing factor in obesity is not related to insulin resistance in humans. J Clin Endocrinol Metab. 2006;91:3165-3170.  [PubMed]  [DOI]
159.  Jarrar MH, Baranova A, Collantes R, Ranard B, Stepanova M, Bennett C, Fang Y, Elariny H, Goodman Z, Chandhoke V. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;27:412-421.  [PubMed]  [DOI]
160.  Aller R, de Luis DA, Izaola O, Sagrado MG, Conde R, Velasco MC, Alvarez T, Pacheco D, González JM. Influence of visfatin on histopathological changes of non-alcoholic fatty liver disease. Dig Dis Sci. 2009;54:1772-1777.  [PubMed]  [DOI]
161.  Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436:356-362.  [PubMed]  [DOI]
162.  Graham TE, Yang Q, Blüher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;354:2552-2563.  [PubMed]  [DOI]
163.  Klöting N, Graham TE, Berndt J, Kralisch S, Kovacs P, Wason CJ, Fasshauer M, Schön MR, Stumvoll M, Blüher M. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 2007;6:79-87.  [PubMed]  [DOI]
164.  Aeberli I, Biebinger R, Lehmann R, L’allemand D, Spinas GA, Zimmermann MB. Serum retinol-binding protein 4 concentration and its ratio to serum retinol are associated with obesity and metabolic syndrome components in children. J Clin Endocrinol Metab. 2007;92:4359-4365.  [PubMed]  [DOI]
165.  Möhlig M, Weickert MO, Ghadamgahi E, Arafat AM, Spranger J, Pfeiffer AF, Schöfl C. Retinol-binding protein 4 is associated with insulin resistance, but appears unsuited for metabolic screening in women with polycystic ovary syndrome. Eur J Endocrinol. 2008;158:517-523.  [PubMed]  [DOI]
166.  Qi Q, Yu Z, Ye X, Zhao F, Huang P, Hu FB, Franco OH, Wang J, Li H, Liu Y. Elevated retinol-binding protein 4 levels are associated with metabolic syndrome in Chinese people. J Clin Endocrinol Metab. 2007;92:4827-4834.  [PubMed]  [DOI]
167.  Janke J, Engeli S, Boschmann M, Adams F, Böhnke J, Luft FC, Sharma AM, Jordan J. Retinol-binding protein 4 in human obesity. Diabetes. 2006;55:2805-2810.  [PubMed]  [DOI]
168.  Yao-Borengasser A, Varma V, Bodles AM, Rasouli N, Phanavanh B, Lee MJ, Starks T, Kern LM, Spencer HJ, Rashidi AA. Retinol binding protein 4 expression in humans: relationship to insulin resistance, inflammation, and response to pioglitazone. J Clin Endocrinol Metab. 2007;92:2590-2597.  [PubMed]  [DOI]
169.  Broch M, Vendrell J, Ricart W, Richart C, Fernández-Real JM. Circulating retinol-binding protein-4, insulin sensitivity, insulin secretion, and insulin disposition index in obese and nonobese subjects. Diabetes Care. 2007;30:1802-1806.  [PubMed]  [DOI]
170.  von Eynatten M, Lepper PM, Liu D, Lang K, Baumann M, Nawroth PP, Bierhaus A, Dugi KA, Heemann U, Allolio B. Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease. Diabetologia. 2007;50:1930-1937.  [PubMed]  [DOI]
171.  Silha JV, Nyomba BL, Leslie WD, Murphy LJ. Ethnicity, insulin resistance, and inflammatory adipokines in women at high and low risk for vascular disease. Diabetes Care. 2007;30:286-291.  [PubMed]  [DOI]
172.  Balagopal P, Graham TE, Kahn BB, Altomare A, Funanage V, George D. Reduction of elevated serum retinol binding protein in obese children by lifestyle intervention: association with subclinical inflammation. J Clin Endocrinol Metab. 2007;92:1971-1974.  [PubMed]  [DOI]
173.  Terra X, Auguet T, Broch M, Sabench F, Hernández M, Pastor RM, Quesada IM, Luna A, Aguilar C, del Castillo D. Retinol binding protein-4 circulating levels were higher in nonalcoholic fatty liver disease vs. histologically normal liver from morbidly obese women. Obesity (Silver Spring). 2013;21:170-177.  [PubMed]  [DOI]
174.  Petta S, Tripodo C, Grimaudo S, Cabibi D, Cammà C, Di Cristina A, Di Marco V, Di Vita G, Ingrao S, Mazzola A. High liver RBP4 protein content is associated with histological features in patients with genotype 1 chronic hepatitis C and with nonalcoholic steatohepatitis. Dig Liver Dis. 2011;43:404-410.  [PubMed]  [DOI]
175.  Schina M, Koskinas J, Tiniakos D, Hadziyannis E, Savvas S, Karamanos B, Manesis E, Archimandritis A. Circulating and liver tissue levels of retinol-binding protein-4 in non-alcoholic fatty liver disease. Hepatol Res. 2009;39:972-978.  [PubMed]  [DOI]
176.  Cengiz C, Ardicoglu Y, Bulut S, Boyacioglu S. Serum retinol-binding protein 4 in patients with nonalcoholic fatty liver disease: does it have a significant impact on pathogenesis? Eur J Gastroenterol Hepatol. 2010;22:813-819.  [PubMed]  [DOI]
177.  Alkhouri N, Lopez R, Berk M, Feldstein AE. Serum retinol-binding protein 4 levels in patients with nonalcoholic fatty liver disease. J Clin Gastroenterol. 2009;43:985-989.  [PubMed]  [DOI]
178.  Lang CH, Dobrescu C, Bagby GJ. Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology. 1992;130:43-52.  [PubMed]  [DOI]
179.  Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389:610-614.  [PubMed]  [DOI]
180.  Seo YY, Cho YK, Bae JC, Seo MH, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Lee WY. Tumor Necrosis Factor-α as a Predictor for the Development of Nonalcoholic Fatty Liver Disease: A 4-Year Follow-Up Study. Endocrinol Metab (Seoul). 2013;28:41-45.  [PubMed]  [DOI]
181.  Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes. 2005;54:2939-2945.  [PubMed]  [DOI]
182.  Basaranoglu M, Basaranoglu G, Sabuncu T, Sentürk H. Fructose as a key player in the development of fatty liver disease. World J Gastroenterol. 2013;19:1166-1172.  [PubMed]  [DOI]
183.  Kodama Y, Taura K, Miura K, Schnabl B, Osawa Y, Brenner DA. Antiapoptotic effect of c-Jun N-terminal Kinase-1 through Mcl-1 stabilization in TNF-induced hepatocyte apoptosis. Gastroenterology. 2009;136:1423-1434.  [PubMed]  [DOI]
184.  Polyzos SA, Kountouras J, Zavos Ch. The multi-hit process and the antagonistic roles of tumor necrosis factor-alpha and adiponectin in non alcoholic fatty liver disease. Hippokratia. 2009;13:127; author reply 128.  [PubMed]  [DOI]
185.  Videla LA, Tapia G, Rodrigo R, Pettinelli P, Haim D, Santibañez C, Araya AV, Smok G, Csendes A, Gutierrez L. Liver NF-kappaB and AP-1 DNA binding in obese patients. Obesity (Silver Spring). 2009;17:973-979.  [PubMed]  [DOI]
186.  Dela Peña A, Leclercq I, Field J, George J, Jones B, Farrell G. NF-kappaB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis. Gastroenterology. 2005;129:1663-1674.  [PubMed]  [DOI]
187.  Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40:46-54.  [PubMed]  [DOI]
188.  Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol. 2007;46:1104-1110.  [PubMed]  [DOI]
189.  Abiru S, Migita K, Maeda Y, Daikoku M, Ito M, Ohata K, Nagaoka S, Matsumoto T, Takii Y, Kusumoto K. Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int. 2006;26:39-45.  [PubMed]  [DOI]
190.  Crespo J, Cayón A, Fernández-Gil P, Hernández-Guerra M, Mayorga M, Domínguez-Díez A, Fernández-Escalante JC, Pons-Romero F. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 2001;34:1158-1163.  [PubMed]  [DOI]
191.  Manco M, Marcellini M, Giannone G, Nobili V. Correlation of serum TNF-alpha levels and histologic liver injury scores in pediatric nonalcoholic fatty liver disease. Am J Clin Pathol. 2007;127:954-960.  [PubMed]  [DOI]
192.  Alaaeddine N, Sidaoui J, Hilal G, Serhal R, Abedelrahman A, Khoury S. TNF-α messenger ribonucleic acid (mRNA) in patients with nonalcoholic steatohepatitis. Eur Cytokine Netw. 2012;23:107-111.  [PubMed]  [DOI]
193.  Tomita K, Tamiya G, Ando S, Ohsumi K, Chiyo T, Mizutani A, Kitamura N, Toda K, Kaneko T, Horie Y. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut. 2006;55:415-424.  [PubMed]  [DOI]
194.  Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology. 2009;50:1094-1104.  [PubMed]  [DOI]
195.  Haub S, Kanuri G, Volynets V, Brune T, Bischoff SC, Bergheim I. Serotonin reuptake transporter (SERT) plays a critical role in the onset of fructose-induced hepatic steatosis in mice. Am J Physiol Gastrointest Liver Physiol. 2010;298:G335-G344.  [PubMed]  [DOI]
196.  Volynets V, Spruss A, Kanuri G, Wagnerberger S, Bischoff SC, Bergheim I. Protective effect of bile acids on the onset of fructose-induced hepatic steatosis in mice. J Lipid Res. 2010;51:3414-3424.  [PubMed]  [DOI]
197.  Bergheim I, Weber S, Vos M, Krämer S, Volynets V, Kaserouni S, McClain CJ, Bischoff SC. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol. 2008;48:983-992.  [PubMed]  [DOI]
198.  Kanuri G, Spruss A, Wagnerberger S, Bischoff SC, Bergheim I. Role of tumor necrosis factor α (TNFα) in the onset of fructose-induced nonalcoholic fatty liver disease in mice. J Nutr Biochem. 2011;22:527-534.  [PubMed]  [DOI]
199.  Alisi A, Manco M, Devito R, Piemonte F, Nobili V. Endotoxin and plasminogen activator inhibitor-1 serum levels associated with nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2010;50:645-649.  [PubMed]  [DOI]
200.  Ruiz AG, Casafont F, Crespo J, Cayón A, Mayorga M, Estebanez A, Fernadez-Escalante JC, Pons-Romero F. Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obes Surg. 2007;17:1374-1380.  [PubMed]  [DOI]
201.  Endo M, Masaki T, Seike M, Yoshimatsu H. TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c). Exp Biol Med (Maywood). 2007;232:614-621.  [PubMed]  [DOI]
202.  Wang JK, Feng ZW, Li YC, Li QY, Tao XY. Association of tumor necrosis factor-α gene promoter polymorphism at sites -308 and -238 with non-alcoholic fatty liver disease: a meta-analysis. J Gastroenterol Hepatol. 2012;27:670-676.  [PubMed]  [DOI]
203.  Hu ZW, Luo HB, Xu YM, Guo JW, Deng XL, Tong YW, Tang X. Tumor necrosis factor--alpha gene promoter polymorphisms in Chinese patients with nonalcoholic fatty liver diseases. Acta Gastroenterol Belg. 2009;72:215-221.  [PubMed]  [DOI]
204.  Satapathy SK, Garg S, Chauhan R, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99:1946-1952.  [PubMed]  [DOI]
205.  Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99:2365-2368.  [PubMed]  [DOI]
206.  Satapathy SK, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2007;22:634-638.  [PubMed]  [DOI]
207.  Duman DG, Ozdemir F, Birben E, Keskin O, Ekşioğlu-Demiralp E, Celikel C, Kalayci O, Kalayci C. Effects of pentoxifylline on TNF-alpha production by peripheral blood mononuclear cells in patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2007;52:2520-2524.  [PubMed]  [DOI]
208.  Ma YY, Li L, Yu CH, Shen Z, Chen LH, Li YM. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol. 2013;19:6911-6918.  [PubMed]  [DOI]
209.  Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, Song XY, Diehl AM. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37:343-350.  [PubMed]  [DOI]
210.  Barbuio R, Milanski M, Bertolo MB, Saad MJ, Velloso LA. Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet. J Endocrinol. 2007;194:539-550.  [PubMed]  [DOI]
211.  Solomon SS, Usdan LS, Palazzolo MR. Mechanisms involved in tumor necrosis factor-alpha induction of insulin resistance and its reversal by thiazolidinedione(s). Am J Med Sci. 2001;322:75-78.  [PubMed]  [DOI]
212.  Okada Y, Yamaguchi K, Nakajima T, Nishikawa T, Jo M, Mitsumoto Y, Kimura H, Nishimura T, Tochiki N, Yasui K. Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats. Liver Int. 2013;33:301-311.  [PubMed]  [DOI]
213.  Xu P, Zhang XG, Li YM, Yu CH, Xu L, Xu GY. Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats. J Zhejiang Univ Sci B. 2006;7:627-633.  [PubMed]  [DOI]
214.  Al-Gayyar MM, Shams ME, Barakat EA. Fish oil improves lipid metabolism and ameliorates inflammation in patients with metabolic syndrome: impact of nonalcoholic fatty liver disease. Pharm Biol. 2012;50:297-303.  [PubMed]  [DOI]
215.  Vidyashankar S, Sandeep Varma R, Patki PS. Quercetin ameliorate insulin resistance and up-regulates cellular antioxidants during oleic acid induced hepatic steatosis in HepG2 cells. Toxicol In Vitro. 2013;27:945-953.  [PubMed]  [DOI]
216.  Lee JY, Moon JH, Park JS, Lee BW, Kang ES, Ahn CW, Lee HC, Cha BS. Dietary oleate has beneficial effects on every step of non-alcoholic Fatty liver disease progression in a methionine- and choline-deficient diet-fed animal model. Diabetes Metab J. 2011;35:489-496.  [PubMed]  [DOI]
217.  Lin Z, Cai F, Lin N, Ye J, Zheng Q, Ding G. Effects of glutamine on oxidative stress and nuclear factor-κB expression in the livers of rats with nonalcoholic fatty liver disease. Exp Ther Med. 2014;7:365-370.  [PubMed]  [DOI]
218.  Pinto Lde F, Compri CM, Fornari JV, Bartchewsky W, Cintra DE, Trevisan M, Carvalho Pde O, Ribeiro ML, Velloso LA, Saad MJ. The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice. Liver Int. 2010;30:603-610.  [PubMed]  [DOI]
219.  Chung MY, Yeung SF, Park HJ, Volek JS, Bruno RS. Dietary α- and γ-tocopherol supplementation attenuates lipopolysaccharide-induced oxidative stress and inflammatory-related responses in an obese mouse model of nonalcoholic steatohepatitis. J Nutr Biochem. 2010;21:1200-1206.  [PubMed]  [DOI]
220.  Yamashita A, Soga Y, Iwamoto Y, Yoshizawa S, Iwata H, Kokeguchi S, Takashiba S, Nishimura F. Macrophage-adipocyte interaction: marked interleukin-6 production by lipopolysaccharide. Obesity (Silver Spring). 2007;15:2549-2552.  [PubMed]  [DOI]
221.  Tarantino G, Finelli C. Pathogenesis of hepatic steatosis: the link between hypercortisolism and non-alcoholic fatty liver disease. World J Gastroenterol. 2013;19:6735-6743.  [PubMed]  [DOI]
222.  Pickup JC, Chusney GD, Thomas SM, Burt D. Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci. 2000;67:291-300.  [PubMed]  [DOI]
223.  Tsigos C, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS, Chrousos GP. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J Clin Endocrinol Metab. 1997;82:4167-4170.  [PubMed]  [DOI]
224.  Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327-334.  [PubMed]  [DOI]
225.  Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar E, Roka R, Schernthaner G. Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients. Arterioscler Thromb Vasc Biol. 2003;23:1042-1047.  [PubMed]  [DOI]
226.  Felipo V, Urios A, García-Torres ML, El Mlili N, del Olmo JA, Civera M, Ortega J, Ferrandez A, Martínez-Valls J, Cassinello N. Alterations in adipocytokines and cGMP homeostasis in morbid obesity patients reverse after bariatric surgery. Obesity (Silver Spring). 2013;21:229-237.  [PubMed]  [DOI]
227.  Kanemaki T, Kitade H, Kaibori M, Sakitani K, Hiramatsu Y, Kamiyama Y, Ito S, Okumura T. Interleukin 1beta and interleukin 6, but not tumor necrosis factor alpha, inhibit insulin-stimulated glycogen synthesis in rat hepatocytes. Hepatology. 1998;27:1296-1303.  [PubMed]  [DOI]
228.  Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes. 2002;51:3391-3399.  [PubMed]  [DOI]
229.  Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem. 2003;278:45777-45784.  [PubMed]  [DOI]
230.  Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, Mooney RA. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem. 2003;278:13740-13746.  [PubMed]  [DOI]
231.  Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes. 2003;52:2784-2789.  [PubMed]  [DOI]
232.  Klover PJ, Clementi AH, Mooney RA. Interleukin-6 depletion selectively improves hepatic insulin action in obesity. Endocrinology. 2005;146:3417-3427.  [PubMed]  [DOI]
233.  Wunderlich FT, Ströhle P, Könner AC, Gruber S, Tovar S, Brönneke HS, Juntti-Berggren L, Li LS, van Rooijen N, Libert C. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 2010;12:237-249.  [PubMed]  [DOI]
234.  Teoh N, Field J, Farrell G. Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice. J Hepatol. 2006;45:20-27.  [PubMed]  [DOI]
235.  Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, Taub R. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379-1383.  [PubMed]  [DOI]
236.  Jin X, Zimmers TA, Perez EA, Pierce RH, Zhang Z, Koniaris LG. Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair. Hepatology. 2006;43:474-484.  [PubMed]  [DOI]
237.  Yamaguchi K, Itoh Y, Yokomizo C, Nishimura T, Niimi T, Fujii H, Okanoue T, Yoshikawa T. Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice. Lab Invest. 2010;90:1169-1178.  [PubMed]  [DOI]
238.  Yamaguchi K, Itoh Y, Yokomizo C, Nishimura T, Niimi T, Umemura A, Fujii H, Okanoue T, Yoshikawa T. Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-fed db/db mice. Lab Invest. 2011;91:609-618.  [PubMed]  [DOI]
239.  Carulli L, Canedi I, Rondinella S, Lombardini S, Ganazzi D, Fargion S, De Palma M, Lonardo A, Ricchi M, Bertolotti M. Genetic polymorphisms in non-alcoholic fatty liver disease: interleukin-6-174G/C polymorphism is associated with non-alcoholic steatohepatitis. Dig Liver Dis. 2009;41:823-828.  [PubMed]  [DOI]
240.  Kumar R, Prakash S, Chhabra S, Singla V, Madan K, Gupta SD, Panda SK, Khanal S, Acharya SK. Association of pro-inflammatory cytokines, adipokines & oxidative stress with insulin resistance & non-alcoholic fatty liver disease. Indian J Med Res. 2012;136:229-236.  [PubMed]  [DOI]
241.  Haukeland JW, Damås JK, Konopski Z, Løberg EM, Haaland T, Goverud I, Torjesen PA, Birkeland K, Bjøro K, Aukrust P. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol. 2006;44:1167-1174.  [PubMed]  [DOI]
242.  Leite NC, Salles GF, Cardoso CR, Villela-Nogueira CA. Serum biomarkers in type 2 diabetic patients with non-alcoholic steatohepatitis and advanced fibrosis. Hepatol Res. 2013;43:508-515.  [PubMed]  [DOI]
243.  Yoneda M, Mawatari H, Fujita K, Iida H, Yonemitsu K, Kato S, Takahashi H, Kirikoshi H, Inamori M, Nozaki Y. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH. J Gastroenterol. 2007;42:573-582.  [PubMed]  [DOI]
244.  Fitzpatrick E, Dew TK, Quaglia A, Sherwood RA, Mitry RR, Dhawan A. Analysis of adipokine concentrations in paediatric non-alcoholic fatty liver disease. Pediatr Obes. 2012;7:471-479.  [PubMed]  [DOI]
245.  García-Galiano D, Sánchez-Garrido MA, Espejo I, Montero JL, Costán G, Marchal T, Membrives A, Gallardo-Valverde JM, Muñoz-Castañeda JR, Arévalo E. IL-6 and IGF-1 are independent prognostic factors of liver steatosis and non-alcoholic steatohepatitis in morbidly obese patients. Obes Surg. 2007;17:493-503.  [PubMed]  [DOI]
246.  Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol. 2008;103:1372-1379.  [PubMed]  [DOI]
247.  Tarantino G, Conca P, Pasanisi F, Ariello M, Mastrolia M, Arena A, Tarantino M, Scopacasa F, Vecchione R. Could inflammatory markers help diagnose nonalcoholic steatohepatitis? Eur J Gastroenterol Hepatol. 2009;21:504-511.  [PubMed]  [DOI]
248.  Grigorescu M, Crisan D, Radu C, Grigorescu MD, Sparchez Z, Serban A. A novel pathophysiological-based panel of biomarkers for the diagnosis of nonalcoholic steatohepatitis. J Physiol Pharmacol. 2012;63:347-353.  [PubMed]  [DOI]
249.  Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003;38:413-419.  [PubMed]  [DOI]
250.  Ying HZ, Liu YH, Yu B, Wang ZY, Zang JN, Yu CH. Dietary quercetin ameliorates nonalcoholic steatohepatitis induced by a high-fat diet in gerbils. Food Chem Toxicol. 2013;52:53-60.  [PubMed]  [DOI]
251.  Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371:987-997.  [PubMed]  [DOI]
252.  Andrews AE, Barcham GJ, Brandon MR, Nash AD. Molecular cloning and characterization of ovine IL-1 alpha and IL-1 beta. Immunology. 1991;74:453-460.  [PubMed]  [DOI]
253.  Moschen AR, Molnar C, Enrich B, Geiger S, Ebenbichler CF, Tilg H. Adipose and liver expression of interleukin (IL)-1 family members in morbid obesity and effects of weight loss. Mol Med. 2011;17:840-845.  [PubMed]  [DOI]
254.  He J, Usui I, Ishizuka K, Kanatani Y, Hiratani K, Iwata M, Bukhari A, Haruta T, Sasaoka T, Kobayashi M. Interleukin-1alpha inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes. Mol Endocrinol. 2006;20:114-124.  [PubMed]  [DOI]
255.  Kamari Y, Shaish A, Vax E, Shemesh S, Kandel-Kfir M, Arbel Y, Olteanu S, Barshack I, Dotan S, Voronov E. Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. J Hepatol. 2011;55:1086-1094.  [PubMed]  [DOI]
256.  Liu Q, Bengmark S, Qu S. The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Lipids Health Dis. 2010;9:42.  [PubMed]  [DOI]
257.  Miura K, Yang L, van Rooijen N, Brenner DA, Ohnishi H, Seki E. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology. 2013;57:577-589.  [PubMed]  [DOI]
258.  Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T, Ohnishi H, Olefsky JM, Brenner DA, Seki E. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 2010;139:323-34.e7.  [PubMed]  [DOI]
259.  Nozaki Y, Saibara T, Nemoto Y, Ono M, Akisawa N, Iwasaki S, Hayashi Y, Hiroi M, Enzan H, Onishi S. Polymorphisms of interleukin-1 beta and beta 3-adrenergic receptor in Japanese patients with nonalcoholic steatohepatitis. Alcohol Clin Exp Res. 2004;28:106S-110S.  [PubMed]  [DOI]
260.  Lagathu C, Yvan-Charvet L, Bastard JP, Maachi M, Quignard-Boulangé A, Capeau J, Caron M. Long-term treatment with interleukin-1beta induces insulin resistance in murine and human adipocytes. Diabetologia. 2006;49:2162-2173.  [PubMed]  [DOI]
261.  Jager J, Grémeaux T, Cormont M, Le Marchand-Brustel Y, Tanti JF. Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology. 2007;148:241-251.  [PubMed]  [DOI]
262.  Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, Asano M, Moriwaki H, Seishima M. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2003;23:656-660.  [PubMed]  [DOI]
263.  Osborn O, Brownell SE, Sanchez-Alavez M, Salomon D, Gram H, Bartfai T. Treatment with an Interleukin 1 beta antibody improves glycemic control in diet-induced obesity. Cytokine. 2008;44:141-148.  [PubMed]  [DOI]
264.  Stanton MC, Chen SC, Jackson JV, Rojas-Triana A, Kinsley D, Cui L, Fine JS, Greenfeder S, Bober LA, Jenh CH. Inflammatory Signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice. J Inflamm (Lond). 2011;8:8.  [PubMed]  [DOI]
265.  Ma KL, Ruan XZ, Powis SH, Chen Y, Moorhead JF, Varghese Z. Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology. 2008;48:770-781.  [PubMed]  [DOI]
266.  Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N, Staels B, Kersten S, Müller M. Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology. 2010;51:511-522.  [PubMed]  [DOI]
267.  Zhang YP, Yao XX, Zhao X. Interleukin-1 beta up-regulates tissue inhibitor of matrix metalloproteinase-1 mRNA and phosphorylation of c-jun N-terminal kinase and p38 in hepatic stellate cells. World J Gastroenterol. 2006;12:1392-1396.  [PubMed]  [DOI]
268.  Ritze Y, Bárdos G, Claus A, Ehrmann V, Bergheim I, Schwiertz A, Bischoff SC. Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice. PLoS One. 2014;9:e80169.  [PubMed]  [DOI]
269.  Gabay C, Smith MF, Eidlen D, Arend WP. Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein. J Clin Invest. 1997;99:2930-2940.  [PubMed]  [DOI]
270.  Somm E, Cettour-Rose P, Asensio C, Charollais A, Klein M, Theander-Carrillo C, Juge-Aubry CE, Dayer JM, Nicklin MJ, Meda P. Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents. Diabetologia. 2006;49:387-393.  [PubMed]  [DOI]
271.  Pihlajamäki J, Kuulasmaa T, Kaminska D, Simonen M, Kärjä V, Grönlund S, Käkelä P, Pääkkönen M, Kainulainen S, Punnonen K. Serum interleukin 1 receptor antagonist as an independent marker of non-alcoholic steatohepatitis in humans. J Hepatol. 2012;56:663-670.  [PubMed]  [DOI]
272.  Isoda K, Sawada S, Ayaori M, Matsuki T, Horai R, Kagata Y, Miyazaki K, Kusuhara M, Okazaki M, Matsubara O. Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice. J Biol Chem. 2005;280:7002-7009.  [PubMed]  [DOI]
273.  Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, Quintal L, Sekut L, Talanian R, Paskind M. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature. 1997;386:619-623.  [PubMed]  [DOI]
274.  López-Bermejo A, Bosch M, Recasens M, Biarnés J, Esteve E, Casamitjana R, Vendrell J, Ricart W, Fernández-Real JM. Potential role of interleukin-18 in liver disease associated with insulin resistance. Obes Res. 2005;13:1925-1931.  [PubMed]  [DOI]
275.  Esposito K, Pontillo A, Ciotola M, Di Palo C, Grella E, Nicoletti G, Giugliano D. Weight loss reduces interleukin-18 levels in obese women. J Clin Endocrinol Metab. 2002;87:3864-3866.  [PubMed]  [DOI]
276.  Fischer CP, Perstrup LB, Berntsen A, Eskildsen P, Pedersen BK. Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans. Clin Immunol. 2005;117:152-160.  [PubMed]  [DOI]
277.  Wang HN, Wang YR, Liu GQ, Liu Z, Wu PX, Wei XL, Hong TP. Inhibition of hepatic interleukin-18 production by rosiglitazone in a rat model of nonalcoholic fatty liver disease. World J Gastroenterol. 2008;14:7240-7246.  [PubMed]  [DOI]
278.  Tapan S, Dogru T, Kara M, Ercin CN, Kilciler G, Genc H, Sertoglu E, Acikel C, Kilic S, Karslioglu Y. Circulating levels of interleukin-18 in patients with non-alcoholic fatty liver disease. Scand J Clin Lab Invest. 2010;70:399-403.  [PubMed]  [DOI]
279.  Puren AJ, Fantuzzi G, Gu Y, Su MS, Dinarello CA. Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells. J Clin Invest. 1998;101:711-721.  [PubMed]  [DOI]
280.  Chikano S, Sawada K, Shimoyama T, Kashiwamura SI, Sugihara A, Sekikawa K, Terada N, Nakanishi K, Okamura H. IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner. Gut. 2000;47:779-786.  [PubMed]  [DOI]
281.  Li Y, Li-Li Z, Qin L, Ying W. Plasma interleukin-18/interleukin-18 binding protein ratio in Chinese with NAFLD. Hepatogastroenterology. 2010;57:103-106.  [PubMed]  [DOI]