title: Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH.
abstract: Bile acids concentration in liver is tightly regulated to prevent cell damage. Previous studies have demonstrated that deregulation of bile acid homeostasis can lead to cholestatic liver disease. Recently, we have shown that ER-bound transcription factor Crebh is a downstream effector of hepatic Cb1r signaling pathway. In this study, we have investigated the effect of alcohol exposure on hepatic bile acid homeostasis and elucidated the mediatory roles of Cb1r and Crebh in this process. We found that alcohol exposure or Cb1r-agonist 2-AG treatment increases hepatic bile acid synthesis and serum ALT, AST levels in vivo alongwith significant increase in Crebh gene expression and activation. Alcohol exposure activated Cb1r, Crebh, and perturbed bile acid homeostasis. Overexpression of Crebh increased the expression of key bile acid synthesis enzyme genes via direct binding of Crebh to their promoters, whereas Cb1r knockout and Crebh-knockdown mice were protected against alcohol-induced perturbation of bile acid homeostasis. Interestingly, insulin treatment protected against Cb1r-mediated Crebh-induced disruption of bile acid homeostasis. Furthermore, Crebh expression and activation was found to be markedly increased in insulin resistance conditions and Crebh knockdown in diabetic mice model (db/db) significantly reversed alcohol-induced disruption of bile acid homeostasis. Overall, our study demonstrates a novel regulatory mechanism of hepatic bile acid metabolism by alcohol via Cb1r-mediated activation of Crebh, and suggests that targeting Crebh can be of therapeutic potential in ameliorating alcohol-induced perturbation of bile acid homeostasis.
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chanda
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Tiangang
authors.initials: T
authors.lastname: Li
authors.forename: Jagannath
authors.initials: J
authors.lastname: Misra
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Jung Ran
authors.initials: JR
authors.lastname: Kim
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwon
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Park
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency / Q000378:metabolism*; D063388:Endocannabinoids / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D056945:Hep G2 Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000172:deficiency / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D001647:Bile Acids and Salts; D017362:Cyclic AMP Response Element-Binding Protein; D063388:Endocannabinoids; D007328:Insulin; D043884:Receptor, Cannabinoid, CB1; D000431:Ethanol
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