| RRC ID |
38512
|
| 著者 |
Yoshinari K, Ohno H, Benoki S, Yamazoe Y.
|
| タイトル |
Constitutive androstane receptor transactivates the hepatic expression of mouse Dhcr24 and human DHCR24 encoding a cholesterogenic enzyme 24-dehydrocholesterol reductase.
|
| ジャーナル |
Toxicol Lett
|
| 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.
|
| 巻・号 |
208(2)
|
| ページ |
185-91
|
| 公開日 |
2012-1-25
|
| DOI |
10.1016/j.toxlet.2011.11.003
|
| PII |
S0378-4274(11)01603-1
|
| PMID |
22101211
|
| MeSH |
Animals
Constitutive Androstane Receptor
Enzyme Activation / drug effects
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation / drug effects
Genes, Reporter / genetics
Hepatocytes / drug effects
Hepatocytes / metabolism
Humans
Liver / drug effects*
Liver / enzymology
Liver / metabolism
Male
Mice
Mice, Inbred C57BL
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Oxidoreductases Acting on CH-CH Group Donors / genetics
Oxidoreductases Acting on CH-CH Group Donors / metabolism*
Receptors, Cytoplasmic and Nuclear / drug effects
Receptors, Cytoplasmic and Nuclear / physiology*
Transcriptional Activation / drug effects
|
| IF |
3.569
|
| 引用数 |
15
|
|
WOS 分野
|
TOXICOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
|
