Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our previous study revealed that blockade of interleukin-6 (IL-6)-STAT3 signaling ameliorated liver injury, although hepatic STAT3(-/-) or GP130(-/-) mice have been reported to develop severe liver injury, in a murine methionine choline deficient (MCD) diet-induced model of non-alcoholic steatohepatitis (NASH). In this study, to determine whether profound blockade of IL-6-STAT3 signaling may still ameliorate liver injury, we studied db/db mice, which have impaired leptin-mediated STAT3 activation, using the MCD diet-induced NASH model. Male lean and db/db mice (6 weeks old) were fed either control chow or an MCD diet for 8 or 12 weeks. Half of the mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor neutralizing antibody (MR16-1) intraperitoneally twice weekly, the remainder were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress and antiapoptotic gene expression were evaluated. Plasma IL-6 levels were elevated in all groups of db/db mice. Although hepatic IL-6/ GP130 signaling was activated in chow-fed db/db mice, this was suppressed in MCD diet-fed db/db mice, accompanied by downregulation of hepatic IL-6 receptor and GP130 mRNA expression. MR16-1 treatment of MCD diet-fed db/db mice further repressed STAT3 activities and expression of STAT3-related antiapoptotic genes, such as Bcl-2 and Ref-1, but increased plasma-free fatty acid and hepatic markers of lipid peroxidation/oxidant stress, leading to increased liver injury, hepatocyte apoptosis and liver fibrosis. Although 'moderate' blockade of enhanced IL-6-STAT3 signaling may be beneficial in NASH, as we reported previously, these findings demonstrate that a profound defect in STAT3 activation is detrimental in terms of liver injury, hepatocyte apoptosis and liver fibrosis, indicating the hepato-protective role of IL-6 signaling in this severe NASH model.
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PMID:Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-fed db/db mice. 2132 32

The status of the GP130-STAT3 signaling pathway in humans with nonalcoholic fatty liver disease (NAFLD) and its relevance to disease pathogenesis are unknown. The expression of the gp130-STAT3 axis and gp130 cytokine receptors were studied in subjects with varying phenotypes of NAFLD including nonalcoholic steatohepatitis (NASH) and compared with lean and weight-matched controls without NAFLD. Gp130 and its downstream signaling element (Tyk2 and STAT3) expression were inhibited in obese controls whereas they were increased in NAFLD. IL-6 levels were increased in NASH and correlated with gp130 expression (P < 0.01). Palmitate inhibited gp130-STAT3 expression and signaling. IL-6 and palmitate inhibited hepatic insulin signaling via STAT3-dependent and independent mechanisms, respectively. STAT3 overexpression reversed palmitate-induced lipotoxicity by increasing autophagy (ATG7) and decreasing endoplasmic reticulum stress. These data demonstrate that the STAT3 pathway is activated in NAFLD and can worsen insulin resistance while protecting against other lipotoxic mechanisms of disease pathogenesis.
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PMID:Activation of the GP130-STAT3 axis and its potential implications in nonalcoholic fatty liver disease. 2574 54