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

Table 6 Studies and their findings on interleukin-6

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]

IL-6: Interleukin 6; T2DM: Type 2 diabetes mellitus; IR: Insulin resistance; NASH: Nonalcoholic steatohepatitis; NAFLD: Non-alcoholic fatty liver disease; STAT3: Signal transducer and activator of transcription 3; LPS: Lipopolysaccharide; TLR: Toll-like receptor; IRS-1: Insulin receptor substrate 1; Akt: Protein kinase B; GLUT4: Glucose transporter type 4; PPAR-γ: Peroxisome proliferator-activated receptor gamma.