Journal
TOXICOLOGY LETTERS
Volume 208, Issue 2, Pages 185-191Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2011.11.003
Keywords
Nuclear receptor; CAR; Cholesterol biosynthesis; Transcription; Hepatocyte; Phenobarbital
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Funding
- Ministry of Education, Culture, Sports, Sciences and Technology of Japan [22390027]
- Japan Chemical Industry Association (JCIA) Long-range Research Initiative (LRI)
- Grants-in-Aid for Scientific Research [22390027] Funding Source: KAKEN
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Phenobarbital treatment has long been known to influence serum and hepatic cholesterol levels in rodents and humans. 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 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 alpha (RXR alpha) heterodimer. We have also demonstrated that the heterodimer of pregnane X receptor (PXR)/ RXR alpha binds to the DR4 motif and that human DHCR24 reporter gene is transactivated by the ligand-activated PXR. These results suggest a role of xenobiotic-responsive nuclear receptor CAR, and also possibly PXR, in cholesterol biosynthesis in the liver of mice and humans. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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