Activation of the GP130-STAT3 axis and its potential implications in nonalcoholic fatty liver disease

American Journal of Physiology. Gastrointestinal and Liver Physiology
Hae-Ki MinArun J Sanyal

Abstract

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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Citations

Feb 2, 2016·Journal of Hepatology·Ludger Scheja, Joerg Heeren
May 24, 2015·Biochemical and Biophysical Research Communications·Nana XiaShiwei Cui
Aug 25, 2016·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hae-Ki MinArun J Sanyal
Jul 28, 2016·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Josiah E HardestyMatthew C Cave
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Sep 20, 2018·Canadian Journal of Gastroenterology & Hepatology·Ozlem KutluEbru Ozer
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Jul 24, 2020·Annals of Hepatology·Jie ZhaoYan-Rong Yu
Nov 26, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Xin HouHua Wang

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