TY - JOUR
T1 - A second class of nuclear receptors for oxysterols
T2 - Regulation of RORα and RORγ activity by 24S-hydroxycholesterol (cerebrosterol)
AU - Wang, Yongjun
AU - Kumar, Naresh
AU - Crumbley, Christine
AU - Griffin, Patrick R.
AU - Burris, Thomas P.
N1 - Funding Information:
The efforts of P.R.G. were supported by the National Institutes of Health (NIH) Molecular Library Screening Center Network (MLSCN) grant U54MH074404 (Hugh Rosen, Principal Investigator). This work was also supported by NIH grants DK080201 , NS066417 , NS067589 (T.P.B.) and GM084041 (P.R.G).
PY - 2010/8
Y1 - 2010/8
N2 - The retinoic acid receptor-related orphan receptors α and γ (RORα [NR1F1] and RORγ [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 RORα and RORγ 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 RORα and RORγ (Ki ∼ 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 RORα/γ inverse agonist suppressing the constitutive transcriptional activity of these receptors in cotransfection assays. Additionally, 24S-OHC suppressed the expression of several RORα target genes including BMAL1 and REV-ERBα in a ROR-dependent manner. We also demonstrate that 24S-OHC decreases the ability of RORα 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 RORγ. These data indicate that RORα and RORγ may serve as sensors of oxsterols. Thus, RORα and RORγ display an overlapping ligand preference with another class of oxysterol nuclear receptors, the liver X receptors (LXRα [NR1H3] and LXRβ [NR1H2]).
AB - The retinoic acid receptor-related orphan receptors α and γ (RORα [NR1F1] and RORγ [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 RORα and RORγ 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 RORα and RORγ (Ki ∼ 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 RORα/γ inverse agonist suppressing the constitutive transcriptional activity of these receptors in cotransfection assays. Additionally, 24S-OHC suppressed the expression of several RORα target genes including BMAL1 and REV-ERBα in a ROR-dependent manner. We also demonstrate that 24S-OHC decreases the ability of RORα 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 RORγ. These data indicate that RORα and RORγ may serve as sensors of oxsterols. Thus, RORα and RORγ display an overlapping ligand preference with another class of oxysterol nuclear receptors, the liver X receptors (LXRα [NR1H3] and LXRβ [NR1H2]).
KW - Cholesterol
KW - Circadian
KW - LXR
KW - Lipid
KW - Orphan receptor
KW - REV-ERB
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UR - http://www.scopus.com/inward/citedby.url?scp=77953243855&partnerID=8YFLogxK
U2 - 10.1016/j.bbalip.2010.02.012
DO - 10.1016/j.bbalip.2010.02.012
M3 - Article
C2 - 20211758
AN - SCOPUS:77953243855
VL - 1801
SP - 917
EP - 923
JO - BBA - Specialised Section On Lipids and Related Subjects
JF - BBA - Specialised Section On Lipids and Related Subjects
SN - 1388-1981
IS - 8
ER -