title: Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease.
abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Wu
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: Xiaomin
authors.initials: X
authors.lastname: Peng
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: Meiling
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: jiadongwei@fudan.edu.cn.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Jia
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
mesh_terms: D000818:Animals; D001381:Azepines / Q000627:therapeutic use*; D002779:Cholestasis / Q000188:drug therapy* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy / Q000473:pathology; D007211:Indoles / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001381:Azepines; D019392:Cytochrome P-450 CYP2E1; D007211:Indoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C540004:WAY-362450
keywords: 4-HNE; 4-hydroxynonenal; 6ECDCA; 6α-ethyl-chenodeoxy-cholic acid; ADH; ALD; ALDH; ALT; AST; Alcoholic cholestasis; Alcoholic fatty liver; BSEP; CYP2E1; CYP7A1; CYP8B1; Co-IP; FXR; FXR deficient; FXR-/-; Farnesoid X receptor agonist; Lieber-DeCarli ethanol diet; MCP-1; OCT; RXRα; Retinoid X receptor α; SHP; SREBP-1c; TBARS; WAY-362450; alanine aminotransferase; alcohol dehydrogenase; alcoholic liver disease; aldehyde dehydrogenase; aspartate aminotransferase; bile salt export pump; cholesterol 7α-hydroxylase; co-immunoprecipitation; cytochrome P450 2E1 enzyme; farnesoid X receptor; monocyte chemotactic protein-1; optimal cutting temperature; small heterodimer partner; sterol 12α-hydroxylase; sterol regulatory element-binding protein 1c; thiobarbituric acid reactive substances