Antrodia camphorata-Derived Antrodin C Inhibits Liver Fibrosis by Blocking TGF-Beta and PDGF Signaling Pathways.

Xin-Yi Xu,Yilin Ren,Deng-Yang Liu,Yan Geng,Hao-Xiang Xu,Yong Mao

doi:10.3389/fmolb.2022.835508

Xin-Yi Xu, Yilin Ren + Show 4 more

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https://doi.org/10.3389/fmolb.2022.835508

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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 CCl4 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 CCl4 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 CCl4-induced liver fibrosis in mice, suggesting that Antrodin C could serve as a protective molecule against liver fibrosis.

Highlights

Organ fibrosis refers to the excessive deposition of extracellular matrix (ECM) in response to chronic tissue injury (Caligiuri et al, 2021)
The data showed that Antrodin C is able to reduce the proliferation of Hepatic stellate cells (HSCs), and because we found that the concentrations below 50 μM of Antrodin C do not have significant cytotoxic effects on CFSC-8B cells, we used these concentrations (12, 25, 50 μM) in the following experiments
Antrodin C treatment dose dependently inhibit transforming growth factor-β1 (TGF-β1) induced phosphorylation of AKT, extracellular signal-regulated kinase (ERK), and P38 (Figure 3). These results suggest that Antrodin C inhibits the classical TGF-β1 pathway, and suppresses non-classical TGF-β1 signaling in HSCs activation, which is characterized by decreased TGF-β1 induced phosphorylation level of SMAD Family Member 2 (Smad2), AKT, ERK, and P38

Summary

Introduction

Organ fibrosis refers to the excessive deposition of extracellular matrix (ECM) in response to chronic tissue injury (Caligiuri et al, 2021). Hepatic fibrosis is caused by various factors, such as genomic mutations, toxic chemicals, hepatitis B/C, excessive alcohol consumption, and nonalcoholic steatohepatitis (Guerra et al, 2016; George et al, 2019). Aging has been considered as a risk factor for progression of fibrosis in hepatitis C and for poor outcome in alcoholic hepatitis (Goldstein et al, 2005; David and George, 2008). It has been suggested that aging increases the susceptibility of liver fibrosis. Recent studies suggest that hepatic fibrosis could be reversible, its underlying mechanism remains uncertain and efficient antifibrotic drugs are urgently needed (Tan et al, 2021)

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