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.
Toxicol Lett. 2012 Jan 25;208(2):185-91. doi: 10.1016/j.toxlet.2011.11.003. Epub 2011 Nov 11.
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.
苯巴比妥治疗长期以来一直被认为会影响啮齿动物和人类的血清和肝脏胆固醇水平。组成型雄烷受体（CAR）是核受体超家族的成员，介导苯巴比妥的各种生物学作用。因此，我们研究了 CAR 是否在肝脏中转激活胆固醇生成基因。CAR 在小鼠肝脏和培养的人肝细胞中的激活增加了编码胆固醇生物合成最后一步的 24-脱氢胆固醇还原酶（DHCR24）的小鼠 Dhcr24 和人 DHCR24 的 mRNA 水平。CAR 在培养的肝癌细胞中的报告基因检测中可转激活这些基因的表达。此外，我们已经确定了人 DHCR24 远端启动子中的 DR4（直接重复序列，间隔 4 个核苷酸）基序是 CAR/视黄酸受体α（RXRα）异二聚体的结合位点。我们还证明了孕烷 X 受体（PXR）/RXRα 的异二聚体结合到 DR4 基序上，并且人 DHCR24 报告基因可被配体激活的 PXR 转激活。这些结果表明，外源响应核受体 CAR，以及可能的 PXR，在小鼠和人类肝脏中的胆固醇生物合成中起作用。
