Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease

Table 5 Studies and their findings on tumor necrosis factor alpha

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]

TNF-α: Tumor necrosis factor alpha; NAFLD: Non-alcoholic fatty liver disease; BMI: Body mass index; IRS-1: Insulin receptor substrate 1; GLUT4: Glucose transporter type 4; IR: Insulin resistance; NASH: Nonalcoholic steatohepatitis; TNFR1: Tumor necrosis factor receptor 1; IL-6: Interleukin 6; LPS: Lipopolysaccharide; HFD: High-fat diet; JNK: c-Jun N-terminal kinase; MS: Metabolic syndrome; MCD: Methionine and choline deficient diet; HSC: Hepatic stellate cells; TNFR2: Tumor-necrosis factor receptor 2; AMPK: AMP-activated protein kinase; SOCS-3: Suppressors of cytokine signaling-3; Akt: Protein kinase B; SREBP-1: Sterol regulatory element-binding protein 1; FAS: Fatty acid synthase; RBP4: Retinol binding protein 4; IKK-B: Inhibitor of nuclear factor kappa-B kinase subunit beta; STAT3: Signal transducer and activator of transcription 3.