Copyright
©2014 Baishideng Publishing Group Inc.
World J Gastroenterol. Dec 28, 2014; 20(48): 18070-18091
Published online Dec 28, 2014. doi: 10.3748/wjg.v20.i48.18070
Published online Dec 28, 2014. doi: 10.3748/wjg.v20.i48.18070
Study | Finding | Ref. |
Human | Adiponectin 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] | |
Animal | Adiponectin 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 vitro | Adiponectin 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] |
Study | Finding | Ref. |
Human | Leptin 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] | |
Animal | Mice 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 vitro | Fibrogenic effect of leptin accomplished through hepatic stellate cells, leptin a potent mitogen and apoptosis inhibitor | [23] |
Study | Finding | Ref. |
Human | AG 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 vitro | Adipocytes 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] |
Adipocytokines | Finding | Ref. |
Resistin | Resistin 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] | |
Visfatin | Secretion 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 4 | Serum 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] |
Study | Finding | Ref. |
Human | Healthy 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] | |
Animal | Prolonged 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 vitro | JNK2-/- 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] |
Study | Finding | Ref. |
Human | Increased 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] | |
Animal | Chronic 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 vitro | LPS 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] |
Cytokines | Finding | Ref. |
IL-1α | Acute treatment of 3T3-L1 adipocytes with IL-1α led to transient IR at IRS-1 level, mediated by its serine phosphorylation | [254] |
IL-1β | ||
Human | Weight 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] | |
Animal | Hepatic 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 vitro | IL-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-1Ra | IL-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-18 | In 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] |
- 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
- URL: https://www.wjgnet.com/1007-9327/full/v20/i48/18070.htm
- DOI: https://dx.doi.org/10.3748/wjg.v20.i48.18070