Peroxisome Proliferator-activated Receptor γ Regulates Expression of the Anti-lipolytic G-protein-coupled Receptor 81 (GPR81/Gpr81)
Peroxisome Proliferator-activated Receptor γ Regulates Expression of the Anti-lipolytic G-protein-coupled Receptor 81 (GPR81/Gpr81)
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过氧化物酶体增殖物激活受体γ调控抗脂解G蛋白偶联受体81（GPR81/Gpr81）的表达
DOI：
10.1074/jbc.m109.040741
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发表时间：
2009-09-25
影响因子：
4.8
通讯作者：
Kalkhoven, Eric
中科院分区：
文献类型：
--
作者：
Jeninga, Ellen H.;Bugge, Anne;Kalkhoven, Eric
配体诱导型核受体过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor gamma，PPARgamma）在脂肪细胞的分化、维持和功能中起着关键作用，是胰岛素增敏噻唑烷二酮类药物（thiazoledinediones，TZDs）的分子靶点。虽然已经鉴定了可能有助于TZD治疗后循环游离脂肪酸减少的许多PPAR γ靶基因，但可能发挥TZD抗脂解作用的相关PPAR γ靶基因尚不清楚。在这里，我们确定了抗脂肪分解的人类G蛋白偶联受体81（GPR 81）、GPR 109 A和（人类特异性）GPR 109 B基因以及小鼠Gpr 81和Gpr 109 A基因是成熟脂肪细胞中新的TZD诱导基因。GPR 81/Gpr 81是一种直接的PPAR γ靶基因，因为在罗格列酮刺激后，GPR 81/Gpr 81（和GPR 109 A/Gpr 109 A）的mRNA表达在成熟的人和鼠脂肪细胞中以及在小鼠附睾脂肪垫中增加，而在分化的3 T3-L1脂肪细胞中，小干扰RNA介导的PPAR γ敲低显示Gpr 81蛋白表达显著降低。此外，在分化的3 T3-L1细胞染色质免疫沉淀测序分析揭示了一个保守的PPAR：类维生素A X受体结合位点的近端启动子的Gpr 81基因，这被证明是功能性的电迁移率变动测定和报告分析。重要的是，小干扰RNA介导的Gpr 81敲低部分逆转了TZDs对3 T3-L1脂肪细胞脂解的抑制作用。PPAR γ介导的GPR 81/Gpr 81和GPR 109 A/Gpr 109 A基因（以及人类中的GPR 109 B）的协调调节提出了一种新的机制，通过该机制，TZD可以降低循环游离脂肪酸水平，并可能改善肥胖患者的胰岛素抵抗。
The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a key role in the differentiation, maintenance, and function of adipocytes and is the molecular target for the insulin-sensitizing thiazoledinediones (TZDs). Although a number of PPAR gamma target genes that may contribute to the reduction of circulating free fatty acids after TZD treatment have been identified, the relevant PPAR gamma target genes that may exert the anti-lipolytic effect of TZDs are unknown. Here we identified the anti-lipolytic human G-protein-coupled receptor 81 (GPR81), GPR109A, and the (human-specific) GPR109B genes as well as the mouse Gpr81 and Gpr109A genes as novel TZD-induced genes in mature adipocytes. GPR81/Gpr81 is a direct PPAR gamma target gene, because mRNA expression of GPR81/Gpr81 (and GPR109A/Gpr109A) increased in mature human and murine adipocytes as well as in vivo in epididymal fat pads of mice upon rosiglitazone stimulation, whereas small interfering RNA-mediated knockdown of PPAR gamma in differentiated 3T3-L1 adipocytes showed a significant decrease in Gpr81 protein expression. In addition, chromatin immunoprecipitation sequencing analysis in differentiated 3T3-L1 cells revealed a conserved PPAR: retinoid X receptor-binding site in the proximal promoter of the Gpr81 gene, which was proven to be functional by electromobility shift assay and reporter assays. Importantly, small interfering RNA-mediated knockdown of Gpr81 partly reversed the inhibitory effect of TZDs on lipolysis in 3T3-L1 adipocytes. The coordinated PPAR gamma-mediated regulation of the GPR81/Gpr81 and GPR109A/Gpr109A genes (and GPR109B in humans) presents a novel mechanism by which TZDs may reduce circulating free fatty acid levels and perhaps ameliorate insulin resistance in obese patients.