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Title 

Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH

Authors 

D ChandaYong Hoon KimT LiJ MisraD K KimJ R KimJ KwonW I JeongS H AhnT S ParkS H KooJ Y L ChiangChul Ho LeeH S Choi

Publisher 

Public Library of Science

Issue Date 

2013

Citation 

Plos One, vol. 8, no. 7, pp. e68845-e68845

Abstract 

h Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea i Drug Discovery Platform Technology Team, Korea Research Institute of Chemical Technology, Daejeon, South Korea j Department of Molecular Genetics, Maastricht University, Maastricht, Netherlands View additional affiliations Retrieving additional affiliations... -------------------------------------------------------------------------------- View references (43) 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.

ISSN 

1932-6203

Link 

http://dx.doi.org/10.1371/journal.pone.0068845

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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