The Orphan Nuclear Receptor RORα Restrains Adipocyte Differentiation through a Reduction of C/EBPβ Activity and Perilipin Gene Expression
The Orphan Nuclear Receptor RORα Restrains Adipocyte Differentiation through a Reduction of C/EBPβ Activity and Perilipin Gene Expression
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DOI：
10.1210/me.2008-0277
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发表时间：
2009-06-01
影响因子：
--
通讯作者：
Sato, Ryuichiro
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文献类型：
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作者：
Ohoka, Nobumichi;Kato, Shogo;Sato, Ryuichiro
核受体类转录因子视黄酸受体相关孤儿受体α(RORα)是一种多功能分子，参与组织发育和细胞功能，如炎症、代谢和分化等，但其在脂肪细胞分化中的作用尚未完全清楚。在这里，我们发现RORα抑制CCAAT/增强子结合蛋白β(C/EBPβ)的转录活性，而不影响其表达，从而阻断PPARγ和C/EBPα的诱导，从而抑制C/EBPβ依赖的脂肪生成。RoRα与C/EBPα相互作用，从而抑制C/EBPβ-p300结合和C/EBPβ依赖的p300向染色质的募集。除了对C/EBPβ功能的抑制作用外，RoRα还通过其启动子的特定机制来阻止过氧体增殖物激活受体γ(PPAR Gamma)对脂滴包被蛋白基因Perilipin的表达。我们在Perilipin启动子中发现了一个与PPAR反应元件重叠的抑制ROR反应元件，并验证了RORα竞争性拮抗PPARγ的结合。RORα抑制PPARγ依赖的脂肪生成，同时抑制Perilipin的诱导。这些发现表明，RORα是一种新的脂肪细胞分化负调控因子，它通过双重机制发挥作用。(分子内分泌学23：759-771,2009)
The nuclear receptor-type transcription factor retinoic acid receptor-related orphan receptor alpha (ROR alpha) is a multifunctional molecule involved in tissue development and cellular function, such as inflammation, metabolism, and differentiation; however, the role of ROR alpha during adipocyte differentiation has not yet been fully understood. Here we show that ROR alpha inhibits the transcriptional activity of CCAAT/enhancer-binding protein beta (C/EBP beta) without affecting its expression, thereby blocking the induction of both PPAR gamma and C/EBP alpha, resulting in the suppression of C/EBP beta-dependent adipogenesis. ROR alpha interacted with C/EBP alpha so as to repress both the C/EBP beta-p300 association and the C/EBP beta-dependent recruitment of p300 to chromatin. In addition to the inhibitory effect on C/EBP beta function, ROR alpha also prevents the expression of the lipid droplet coating protein gene perilipin by peroxisome proliferators-activated receptor gamma (PPAR gamma), acting through the specific mechanism of its promoter. We identified a suppressive ROR-responsive element overlapping the PPAR-responsive element in the perilipin promoter and verified that ROR alpha competitively antagonizes the binding of PPAR gamma. ROR alpha inhibits PPAR gamma-dependent adipogenesis along with the repression of perilipin induction. These findings suggest that ROR alpha is a novel negative regulator of adipocyte differentiation that acts through dual mechanisms. (Molecular Endocrinology 23: 759-771, 2009)