Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH.
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 Cb1...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3718807?pdf=render |
| _version_ | 1819100276830765056 |
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| author | Dipanjan Chanda Yong-Hoon Kim Tiangang Li Jagannath Misra Don-Kyu Kim Jung Ran Kim Joseph Kwon Won-Il Jeong Sung-Hoon Ahn Tae-Sik Park Seung-Hoi Koo John Y L Chiang Chul-Ho Lee Hueng-Sik Choi |
| author_facet | Dipanjan Chanda Yong-Hoon Kim Tiangang Li Jagannath Misra Don-Kyu Kim Jung Ran Kim Joseph Kwon Won-Il Jeong Sung-Hoon Ahn Tae-Sik Park Seung-Hoi Koo John Y L Chiang Chul-Ho Lee Hueng-Sik Choi |
| author_sort | Dipanjan Chanda |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T01:00:12Z |
| format | Article |
| id | doaj.art-bbd54b9e0aa64dd0b96b06b9da7d7b41 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T01:00:12Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-bbd54b9e0aa64dd0b96b06b9da7d7b412022-12-21T18:44:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0187e6884510.1371/journal.pone.0068845Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH.Dipanjan ChandaYong-Hoon KimTiangang LiJagannath MisraDon-Kyu KimJung Ran KimJoseph KwonWon-Il JeongSung-Hoon AhnTae-Sik ParkSeung-Hoi KooJohn Y L ChiangChul-Ho LeeHueng-Sik ChoiBile 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.http://europepmc.org/articles/PMC3718807?pdf=render |
| spellingShingle | Dipanjan Chanda Yong-Hoon Kim Tiangang Li Jagannath Misra Don-Kyu Kim Jung Ran Kim Joseph Kwon Won-Il Jeong Sung-Hoon Ahn Tae-Sik Park Seung-Hoi Koo John Y L Chiang Chul-Ho Lee Hueng-Sik Choi Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. PLoS ONE |
| title | Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. |
| title_full | Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. |
| title_fullStr | Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. |
| title_full_unstemmed | Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. |
| title_short | Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. |
| title_sort | hepatic cannabinoid receptor type 1 mediates alcohol induced regulation of bile acid enzyme genes expression via crebh |
| url | http://europepmc.org/articles/PMC3718807?pdf=render |
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