Constitutive androstane receptor transactivates the hepatic expression of mouse Dhcr24 and human DHCR24 encoding a cholesterogenic enzyme 24-dehydrocholesterol reductase

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.

► Treatment of mice with CAR ligand increased total cholesterol contents in livers.
► Treatment of mice with CAR ligand increased Dhcr24 mRNA levels in livers.
► CAR activation in cultured human hepatocytes increased DHCR24 mRNA levels.
► Both mouse and human DHCR24 genes were transactivated by CAR in hepatoma cells.
► CAR transactivates human DHCR24 gene through a DR4 motif in the distal promoter.