title: Excessive bile acid activated NF-kappa B and promoted the development of alcoholic steatohepatitis in farnesoid X receptor deficient mice.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Departments of Bio-Bank, The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address: wuweibin01@gmail.com.
authors.forename: Wei-Bin
authors.initials: WB
authors.lastname: Wu
authors.affiliation: Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Peng
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Song-Wen
authors.initials: SW
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Zhongshan Hospital of Fudan University and Shanghai Institute of Medical Imaging, Shanghai 200032, China. Electronic address: meilingzhou2012@gmail.com.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000009:adverse effects*; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D000431:Ethanol / Q000009:adverse effects; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D055786:Gene Knockout Techniques; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D003094:Collagen; D000431:Ethanol; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated
keywords: Alcoholic liver disease; Alcoholic steatohepatitis; Farnesoid X receptor; Lieber-DeCarli ethanol diet