Regulation of Adipogenesis by Natural and Synthetic REV-ERB Ligands
Regulation of Adipogenesis by Natural and Synthetic REV-ERB Ligands
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DOI：
10.1210/en.2009-0800
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发表时间：
2010-07-01
期刊：
影响因子：
4.8
通讯作者：
Burris, Thomas P.
中科院分区：
文献类型：
--
作者：
Kumar, Naresh;Solt, Laura A.;Burris, Thomas P.
核激素受体REV-ERB在脂肪形成中起重要作用。在脂肪形成过程中，在3 T3-L1细胞中诱导Rev-erb α表达，并且该受体的过表达导致脂肪形成基因的表达。我们最近证明，卟啉血红素作为REV-ERB的配体，血红素的结合是受体活性所必需的。因此，我们假设REV-ERB配体可能在脂肪形成的调节中发挥作用。我们检测到在3 T3-L1脂肪形成过程中细胞内血红素水平的增加，这与诱导氨基乙酰丙酸合成酶1（Alas 1）表达相关，Alas 1是血红素生物合成的限速酶。如果Alas 1表达的增加被阻断，则脂肪形成严重减弱，这表明Alas 1表达的诱导和血红素合成的增加对于分化至关重要。在脂肪形成过程中血红素合成的抑制导致REV-ERB靶基因启动子的核受体辅阻遏物的募集减少，表明REV-ERB活性的改变。用合成的REV-ERB配体SR 6452处理3 T3-L1细胞，导致脂肪细胞分化的诱导程度与用过氧化物酶体增殖物激活受体-γ激动剂罗格列酮处理相似。SR 6452和罗格列酮的组合对脂肪细胞分化的刺激具有累加效应。这些结果表明，血红素，作为一个REV-ERB配体，是一个重要的信号分子诱导脂肪形成。此外，REV-ERB的合成小分子配体是脂肪形成的有效调节剂，并且可用于治疗代谢疾病。（内分泌学151：3015-3025，2010）
The nuclear hormone receptor, REV-ERB, plays an essential role in adipogenesis. Rev-erb alpha expression is induced in 3T3-L1 cells during adipogenesis, and overexpression of this receptor leads to expression of adipogenic genes. We recently demonstrated that the porphyrin heme functions as a ligand for REV-ERB, and binding of heme is required for the receptor's activity. We therefore hypothesized that REV-ERB ligands may play a role in regulation of adipogenesis. We detected an increase intracellular heme levels during 3T3-L1 adipogenesis that correlated with induction of aminolevulinic acid synthase 1 (Alas1) expression, the rate-limiting enzyme in heme biosynthesis. If the increase in Alas1 expression was blocked, adipogenesis was severely attenuated, indicating that induction of expression of Alas1 and the increase in heme synthesis is critical for differentiation. Inhibition of heme synthesis during adipogenesis leads to decreased recruitment of nuclear receptor corepressor to the promoter of a REV-ERB target gene, suggesting alteration of REV-ERB activity. Treatment of 3T3-L1 cells with a synthetic REV-ERB ligand, SR6452, resulted in induction of adipocyte differentiation to a similar extent as treatment with the peroxisomal proliferator-activated receptor-gamma agonist, rosiglitazone. Combination of SR6452 and rosiglitazone had an additive effect on stimulation of adipocyte differentiation. These results suggest that heme, functioning as a REV-ERB ligand, is an important signaling molecule for induction of adipogenesis. Moreover, synthetic small molecule ligands for REV-ERB are effective modulators of adipogenesis and may be useful for treatment of metabolic diseases. (Endocrinology 151: 3015-3025, 2010)