Bruceine A ameliorates hepatic steatosis and oxidative stress in alcoholic liver disease by activating Farnesoid X receptor to upregulate forkhead box A2 expression

Bruceine A (BA) has a protective effect against alcoholic liver disease (ALD) in vivo and in vitro . • BA alleviated alcohol-induced hepatic steatosis and oxidative stress by activating FXR to up-regulate the expression of FOXA2. • FOXA2 and FXR are downregulated in ALD patients and experimental ethanol models and FXR had a regulatory effect on FOXA2. Background Alcoholic liver disease (ALD) represents a major risk that threatens human health worldwide and lacks effective therapies. Alcohol-induced inflammation and oxidative stress can trigger and aggravate liver steatosis and promote the development of diseases such as alcoholic liver fibrosis without effective treatment. Bruceine A (BA), a compound extracted from traditional Chinese medicine Brucea javanica , exhibits various activities in multiple diseases. Purpose This study aimed to investigate the hepatoprotective effect of BA and its underlying mechanism involving the farnesoid X receptor (FXR) / forkhead box A2 (FOXA2) pathway. Study design and Methods Here, a mouse model of ALD was established with a Lieber-DeCarli liquid diet including 5% ethanol (v/v). Molecular dynamics simulations and cellular thermal shift assay (CETSA) were performed to assess the binding of BA to FXR. Chromatin immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase reporter assays were performed to examine the transcriptional regulation of FOXA2 by FXR. Results The results showed that BA alleviated ethanol-induced liver injury and lipid accumulation, and reduced oxidative stress. BA exhibited affinity for FXR and attenuated ethanol-induced FXR inactivation. FXR bound to the promoter fragments of FOXA2 and enhanced its transcriptional activity and positively affected the expression level of FOXA2. Silencing FOXA2 attenuated the protective effect of BA against hepatic lipid deposition and oxidative stress in vitro . Conclusion We first demonstrated that RBA could alleviate ALD, and further verified that RBA exerted protective effects through modulating FXR-FOXA2-mediated lipid metabolism and oxidative stress in vivo and in vitro . Download: Download high-res image (153KB) Download: Download full-size image