Excessive bile acid activated NF-kappa B and promoted the development of alcoholic steatohepatitis in farnesoid X receptor deficient mice

Wei-Bin Wu, Yuan-Yuan Chen, Bo Zhu, Xiao-Min Peng, Song-Wen Zhang, Mei-Ling Zhou
Biochimie 2015, 115: 86-92
Chronic and excessive alcohol consumption can lead to alcoholic liver disease (ALD), which is characterized by a spectrum of liver disorders, including fatty liver, alcoholic steatohepatitis (ASH), fibrosis/cirrhosis and hepatocellular carcinoma (HCC). The mechanism of the progression from alcoholic steatosis to steatohepatitis and fibrosis is still not fully understood. As a nuclear receptor, farnesoid X receptor (FXR) plays a critical role in maintaining hepatic lipid and bile acid homeostasis. To clarify the role of FXR in the progression of steatohepatitis, we studied the effect of ethanol feeding on FXR-deficient mice. Wild-type and FXR-deficient mice were fed with Lieber-DeCarli ethanol liquid diet or an isocaloric control diet. We found that FXR-deficient mice fed with ethanol diet developed more severe liver injury and steatosis, even progressed to steatohepatitis and moderate fibrosis. Whereas, wild-type (WT) mice only developed mild level of steatosis, with rarely observed inflammatory foci and collagen accumulation. We also found that ethanol induced hepatic bile acid accumulation and NF-κB activation in FXR-deficient mice, which could be attenuated by ursodeoxycholic acid (UDCA). Thus, FXR deficient mice were more prone to develop alcoholic steatohepatitis and fibrosis upon ethanol diet feeding. Our results highlight the role of FXR in hepatoprotection during ALD development. Moreover, attenuating alcoholic liver cholestasis would be beneficial in preventing the progression of hepatic hepatitis in patients with ALD.

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