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.

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.