A second class of nuclear receptors for oxysterols: Regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol).
A second class of nuclear receptors for oxysterols: Regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol).
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DOI：
10.1016/j.bbalip.2010.02.012
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发表时间：
2010-08
期刊：
影响因子：
--
通讯作者：
Burris TP
中科院分区：
文献类型：
--
作者：
Wang Y;Kumar N;Crumbley C;Griffin PR;Burris TP
视黄酸受体相关的孤儿受体α和γ(RoRα[NR1F1]和RoRγ[NR1F3])是核激素受体超家族的成员。这两种受体调节许多生理过程，包括发育、新陈代谢和免疫。我们最近发现，某些氧合甾醇，即7-取代氧合甾醇，高亲和力地结合在RORα和RORγ的配体结合域上，改变了配体结合域的构象，减少了辅活化子的结合，从而抑制了这两种受体的结构性转录活性。在这里，我们证明了另一种氧固醇，24S-羟基胆固醇(24S-OHC)，也是RoRα和RoRγ(Ki∼25 nM)的高亲和力配体。24S-OHC也被称为脑固醇，因为它在大脑中含量很高，在中枢神经系统中作为胆固醇清除的中间体发挥着重要作用。在共转染实验中，24S-OHC作为一种RoRα/γ反向激动剂，抑制这些受体的结构性转录活性。此外，24S-OHC还以一种依赖于RoR的方式抑制了几个RoRα靶基因的表达，包括BMAL1和REV-ERBα。我们还证明了当24S-OHC与BMAL1启动子结合时，RoRα招募辅活化子SRC-2的能力降低。我们还注意到，24(S)，25-环氧胆固醇选择性地抑制了RoRγ的活性。这些数据表明，RoRα和RoRγ可能是氧甾醇的传感器。因此，RoRα和RoRγ与另一类氧固醇核受体-肝脏X受体(LXRα[NR1H3]和LXRβ[NR1H2])显示出重叠的配基偏好。
The retinoic acid receptor-related orphan receptor 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]).
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DOI：
10.1621/nrs.07003
发表时间：
2009
期刊：
Nuclear receptor signaling
影响因子：
--
作者：
Jetten AM
通讯作者：
Jetten AM
影响因子：
168.9
作者：
Jick, H;Zornberg, GL;Drachman, DA
通讯作者：
Drachman, DA
影响因子：
3.5
作者：
Riddell, David R.;Zhou, Hua;Jacobsen, J. Steve
通讯作者：
Jacobsen, J. Steve
DOI：
10.1073/pnas.96.1.266
发表时间：
1999-01-05
影响因子：
11.1
作者：
Janowski, BA;Grogan, MJ;Mangelsdorf, DJ
通讯作者：
Mangelsdorf, DJ
影响因子：
4.7
作者：
Liang, Y;Lin, SZ;Paul, SM
通讯作者：
Paul, SM