Document Detail

Constitutive androstane receptor transactivates the hepatic expression of mouse Dhcr24 and human DHCR24 encoding a cholesterogenic enzyme 24-dehydrocholesterol reductase.
MedLine Citation:
PMID:  22101211     Owner:  NLM     Status:  Publisher    
Phenobarbital treatment has long been known to influence serum and hepatic cholesterol levels in rodents and humans (H). Constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, mediates various biological actions of phenobarbital. We have thus investigated whether CAR transactivates cholesterogenic genes in livers. Activation of CAR in mouse (M) livers and cultured human hepatocytes increased mRNA levels of mouse Dhcr24 and human DHCR24, both of which encode 24-dehydrocholesterol reductase (DHCR24) catalyzing the last step of cholesterol biosynthesis. CAR transactivated the expression of these genes in reporter assays with cultured hepatoma cells. Furthermore, we have identified a DR4 (direct repeat separated by 4 nucleotides) motif in the human DHCR24 distal promoter as a binding site of CAR/retinoid X receptor (RXR) heterodimer. We have also demonstrated that the heterodimer of pregnane X receptor (PXR)/retinoid X receptor binds to the DR4 motif and that human DHCR24 reporter gene is transactivated by the ligand-activated pregnane X receptor. These results suggest a role of xenobiotic-responsive nuclear receptor CAR, and also possibly pregnane X receptor, in cholesterol biosynthesis in the liver of mice and humans.
Kouichi Yoshinari; Hitoshi Ohno; Satoshi Benoki; Yasushi Yamazoe
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-11-11
Journal Detail:
Title:  Toxicology letters     Volume:  -     ISSN:  1879-3169     ISO Abbreviation:  -     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7709027     Medline TA:  Toxicol Lett     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Ireland Ltd.
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-aoba, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
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