Regulation of peroxisome proliferator-activated receptor-gamma activity affects the hepatic stellate cell activation and
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ORIGINAL ARTICLE
Regulation of peroxisome proliferator-activated receptor-gamma activity affects the hepatic stellate cell activation and the progression of NASH via TGF-β1/Smad signaling pathway Xi-Xi Ni 1
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Xiao-Yun Li 1
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Qi Wang 1
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Jing Hua 1
Received: 13 August 2020 / Accepted: 10 November 2020 # University of Navarra 2020
Abstract Development of liver fibrosis is associated with activation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (activated HSCs), which produce excessive extracellular matrix. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) exerts protective effects on hepatic inflammation and fibrosis. The current study was to explore the function of PPAR-γ on HSC activation and progression of nonalcoholic steatohepatitis (NASH). Our study found that HSCs were gradually activated during the progression of methionine-choline-deficient (MCD) diet-induced NASH, accompanied by decreased PPAR-γ expression and activated TGF-β1/ Smad signaling pathway in the liver. PPAR-γ agonist was found to inhibit primary HSCs and NIH/3T3 fibroblast activation and reverted their phenotypical morphology induced by TGF-β1 in vitro. In addition to this, PPAR-γ agonist decreased expression of TGF-β1 and phosphorylation of Smad2/3 while increased expression of Smad7. In vivo, rosiglitazone, a PPAR-γ agonist, inhibited HSC activation and alleviated liver fibrosis and inflammation similarly via inhibiting the activation of TGF-β1/Smad signaling pathway. In parallel, rosiglitazone alleviated hepatic lipid accumulation and peroxidation, beneficial to reverse of NASH. From these findings, it can be concluded that the gradual activation of HSCs is crucial to the progression of NASH and modulating PPAR-γ expression can affect HSC activation via TGF-β1/Smad signaling pathway and thereby influence hepatic fibrogenesis. Keywords Hepatic stellate cell activation . Peroxisome proliferator-activated receptor-gamma . TGF-β1/Smad . Liver fibrosis . Nonalcoholic steatohepatitis
Introduction Nonalcoholic steatohepatitis (NASH) is a progressive subtype of nonalcoholic fatty liver disease (NAFLD), characterized by Xi-Xi Ni, Xiao-Yun Li and Qi Wang contributed equally to this work. Key Points • HSCs are activated gradually with decreased PPAR-γ expression in the liver from NASH. • PPAR-γ agonist inhibited HSC activation and reverted their phenotype. • PPAR-γ agonist alleviated excessive hepatic lipid accumulation and reduced oxidative stress. • HSC activation and liver fibrosis were reduced by PPAR-γ agonist via TGF-β1/Smad inhibition. * Jing Hua [email protected] 1
Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai 200127, People’s Republic of China
hepatic steatosis, inflammatory infiltration, and fibrosis, which can progress to liver cirrhosis and hepatocellular carcinoma (HCC) [9]. The two-hit theory and multiple parallel–hit hypothesis have bee
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