A second class of nuclear receptors for oxysterols: Regulation of ROR alpha and ROR gamma activity by 24S-hydroxycholesterol (cerebrosterol)

作者：Wang Yongjun; Kumar Naresh; Crumbley Christine; Griffin Patrick R; Burris Thomas P^*

来源：Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 2010, 1801(8): 917-923.

DOI：10.1016/j.bbalip.2010.02.012

• Cholesterol
• LXR
• Lipid
• REV-ERB
• Circadian
• Orphan receptor

The retinoic acid receptor-related orphan receptors alpha and gamma (ROR alpha [NR1F1] and ROR gamma [NR1F3]) are members of the nuclear hormone receptor superfamily. These 2 receptors regulate many physiological processes including development, metabolism and immunity. We recently found that certain oxysterols, namely the 7-substituted oxysterols, bound to the ligand binding domains (LBDs) of ROR alpha and ROR gamma with high affinity, altered the LBD conformation and reduced coactivator binding resulting in suppression of the constitutive transcriptional activity of these two receptors. Here, we show that another oxysterol, 24S-hydroxycholesterol (24S-OHC), is also a high affinity ligand for ROR alpha and ROR gamma (Ki similar to 25 nM). 24S-OHC is also known as cerebrosterol due to its high level in the brain where it plays an essential role as an intermediate in cholesterol elimination from the CNS. 24S-OHC functions as a ROR alpha/gamma inverse agonist suppressing the constitutive transcriptional activity of these receptors in cotransfection assays. Additionally, 24S-OHC suppressed the expression of several ROR alpha target genes including BMAL1 and REV-ERB alpha in a ROR-dependent manner. We also demonstrate that 24S-OHC decreases the ability of ROR alpha to recruit the coactivator SRC-2 when bound to the BMAL1 promoter. We also noted that 24(S), 25-epoxycholesterol selectively suppressed the activity of ROR gamma. These data indicate that ROR alpha and ROR gamma may serve as sensors of oxsterols. Thus, ROR alpha and ROR gamma display an overlapping ligand preference with another class of oxysterol nuclear receptors, the liver X receptors (LXR alpha [NR1H3] and LXR beta [NR1H2]).

• 出版日期2010-8