title: Constitutive androstane receptor transactivates the hepatic expression of mouse Dhcr24 and human DHCR24 encoding a cholesterogenic enzyme 24-dehydrocholesterol reductase.
abstract: 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 α (RXRα) heterodimer. We have also demonstrated that the heterodimer of pregnane X receptor (PXR)/ RXRα 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.
authors.affiliation: 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. yoshinari@m.tohoku.ac.jp
authors.forename: Kouichi
authors.initials: K
authors.lastname: Yoshinari
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohno
authors.forename: Satoshi
authors.initials: S
authors.lastname: Benoki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe
mesh_terms: D000818:Animals; D000090702:Constitutive Androstane Receptor; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000090702:Constitutive Androstane Receptor; D009419:Nerve Tissue Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human; C499056:Dhcr24 protein, mouse