Cholesterol sulfotransferase (Sult2b1) inactivates oxysterol ligands of LXR

Sult2b1b catalyzes the sulfation of cholesterol, oxysterols, and dehydoepiandrosterone (DHEA). Oxysterols are ligands of the liver X receptor (LXR), a member of the nuclear receptors. We utilized in vitro and in vivo systems to show that over‐expression of Sult2b1b inactivates oxysterol ligands of LXR. In transfected HEK293 cells, oxysterols and a non‐sterol agonist of LXR (T0901317) stimulate the transcription of LXR‐responsive promoters. Co‐transfection of a cDNA encoding Sult2b1b led to partial inactivation of the stimulation mediated by the oxysterols 22‐hydroxylcholesterol and 24, 25‐epoxycholesterol but not that by T0901317. In stable cell lines expressing Sult2b1 from an inducible promoter, oxysterols and T0901317 induced the expression of an endogenous LXR target gene, ABCA1. Induction of Sult2b1b partially inactivated oxysterol but not T0901317 stimulation of ABCA1. In RAW macrophages, oxysterols and T0901317 induced two LXR target genes, ABCA1 and SREBP1c. Infection of these cells with an adenovirus expressing Sult2b1b inactivated stimulation by oxysterols but not that by T0901317. In primary rat hepatocytes, insulin and T0901317 stimulate expression of SREBP1c via LXR. Infection of these cells with the Sult2b1b adenovirus inactivated the insulin effect but not the T0901317 effect. Feeding mice a diet containing 1% cholesterol or T0901317 induced the expression of multiple LXR target genes, and the induction mediated by cholesterol but not that affected by T0901317 was inactivated by infection with the Sult2b1 expressing adenovirus. We conclude that oxysterols may be endogenous ligands for LXR and that their effects can be ameliorated by over‐expression of a catabolic enzyme. (This research was support by NIH grant AR51943).