Nuclear receptor regulation of the human cholesterol 7 alpha-hydroxylase, sterol 27-hydroxylase and sterol 12 alpha-hydroxylase genes in bile acid synthesis
rat; biosynthesis; transcription factor; expression; hepatocytes; messenger-rna; pathway; activation; identification; cyp7a
Chiang J Y L; Chen W; Zhang M; Cowsley E; Yang Y Z
2001
2001
Book/Monograph
n/a
Hepatic Cannabinoid Receptor Type 1 Mediates Alcohol-Induced Regulation of Bile Acid Enzyme Genes Expression Via CREBH
metabolism; Ohio; mice; Signaling; Signal transduction; liver; Homeostasis; transcription factor; Genes; exposure; Acids; er stress; endoplasmic-reticulum stress; Science & Technology - Other Topics; insulin-resistance; cholesterol 7-alpha-hydroxylase; human hepatocytes; Rodents; Bile acids; alcohol; element-binding protein; gene-expression; endocannabinoid system; bound; cb1 receptors; leptin resistance; Liver diseases; Diabetes mellitus; insulin-resistance; insulin; Fatty liver; hepatocytes; Sciences: Comprehensive Works; Alcohols; Bile; activation; Damage prevention; Deregulation; Muridae; Regulatory mechanisms (biology); RNA extraction; Synthesis
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.
Chanda D; Kim Y H; Li T; Misra J; Kim D K; Kim J R; Kwon J; Jeong W I; Ahn S H; Park T S; Koo S H; Chiang J Y L; Lee C H; Choi H S
PLOS ONE
2013
2013-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1371/journal.pone.0068845" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0068845</a>
Regulation of aldo-keto reductases in human diseases.
aldo-keto reductase; human disease; regulation; response element; transcription factor
The aldo-keto reductases (AKRs) are a superfamily of NAD(P)H-linked oxidoreductases, which reduce aldehydes and ketones to their respective primary and secondary alcohols. AKR enzymes are increasingly being recognized to play an important role in the transformation and detoxification of aldehydes and ketones generated during drug detoxification and xenobiotic metabolism. Many transcription factors have been identified to regulate the expression of human AKR genes, which could have profound effects on the metabolism of endogenous mediators and detoxication of chemical carcinogens. This review summarizes the current knowledge on AKR regulation by transcription factors and other mediators in human diseases.
Chen Wei-Dong; Zhang Yanqiao
Frontiers in pharmacology
2012
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3389/fphar.2012.00035" target="_blank" rel="noreferrer noopener">10.3389/fphar.2012.00035</a>