title: The nuclear receptor CAR modulates alcohol-induced liver injury.
abstract: The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily and a sensor and detoxifier of both xenobiotics and endobiotics. Recent studies also show that CAR participates in metabolism of glucose and lipid, and has an important role in fatty liver disease and diabetes. In this study, we investigate the roles of CAR in chronic and acute alcohol-induced liver injuries. The results showed that absence of CAR in rodents led to significantly increased susceptibility to chronic alcohol-induced liver injury, which was accompanied with elevated hepatocyte apoptosis and fat accumulation. However, pre-activation of CAR by a CAR agonist, TCPOBOP, strongly enhanced the hepatic toxicity by both chronic and acute alcohol infusion in wild-type, but not in CAR(-/-) mice. Gene expression analyses indicated that CAR pre-activation and alcohol infusion synergistically decreased the expression of enzymes that metabolize the alcohol in liver. These results support a role of CAR in modulating alcoholic liver injury and imply a risk of synergistic liver toxicity induced by alcohol and CAR activation.
authors.affiliation: Division of Gene Regulation and Drug Discovery, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Chen
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Meng
authors.forename: Xiaoqiong
authors.initials: X
authors.lastname: Wang
authors.forename: Samuel
authors.initials: S
authors.lastname: Zeng
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012997:Solvents / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D000090702:Constitutive Androstane Receptor; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D012997:Solvents; D000431:Ethanol; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene