Antrodia camphorata-Derived Antrodin C Inhibits Liver Fibrosis by Blocking TGF-Beta and PDGF Signaling Pathways
Xinyi Xu, Yan Geng, Haoxiang Xu, Yilin Ren, Dengyang Liu, Yong Mao
Abstract
Hepatic stellate cells (HSCs) play an essential role in the development of liver fibrosis. Antrodia camphorata ( A. camphorata ) is a medicinal fungus with hepatoprotective effect. This study investigated whether Antrodin C, an A. camphorata -fermented metabolite, could exert a protective role on liver fibrosis both in vitro and in vivo . The anti-fibrotic effect of Antrodin C was investigated in CFSC-8B cell (hepatic stellate cell) stimulated by transforming growth factor-β1 (TGF-β1) or platelet-derived growth factor-BB (PDGF-BB) in vitro and in CCl 4 induced liver fibrosis in mice. Antrodin C (50 μM) inhibited TGF-β1 or PDGF-BB stimulated CFSC-8B cell activation, migration and extracellular matrix (ECM) accumulation (all p < 0.05). Antrodin C (3, 6 mg/kg/d) oral administration reduced the degree of liver fibrosis induced by CCl 4 in mice. Antrodin C down-regulated the expression of α-smooth muscle actin (α-SMA) and collagen I in fibrotic livers. Furthermore, Antrodin C ameliorated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation in serum (all p < 0.05). Mechanistically, Antrodin C executes its anti-fibrotic activity through negatively modulate TGF-β1 downstream SMAD Family Member 2 (Smad2), AKT Serine/Threonine Kinase 1 (AKT), extracellular signal-regulated kinase (ERK), and P38 MAP Kinase (P38), as well as PDGF-BB downstream AKT and ERK signaling pathways. Antrodin C ameliorates the activation, migration, ECM production in HSCs and CCl 4 -induced liver fibrosis in mice, suggesting that Antrodin C could serve as a protective molecule against liver fibrosis.