Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors
Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors
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DOI：
10.2337/diabetes.52.7.1655
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发表时间：
2003-07-01
期刊：
影响因子：
7.7
通讯作者：
Shimomura, I
中科院分区：
文献类型：
--
作者：
Iwaki, M;Matsuda, M;Shimomura, I
脂联素是一种脂肪来源的激素，具有抗糖尿病和抗动脉粥样硬化的特性。肥胖患者的低脂联素血症与胰岛素抵抗型糖尿病和动脉粥样硬化有关。噻唑烷二酮类，过氧化物酶体增殖激活受体- γ (ppar - γ)激动剂，已被证明通过转录诱导在脂肪组织中增加血浆脂联素水平。然而，这种作用的确切机制尚不清楚。在这项研究中，我们在人脂联素启动子中鉴定了一个功能性的ppar响应元件（PPRE）。ppar - γ /类视黄醇X受体（RXR）异源二聚体直接与PPRE结合并增加细胞中的启动子活性。在脂肪细胞中，PPRE的点突变显著降低了基础转录活性，完全阻断了噻唑烷二酮诱导的脂联素启动子的转激活。我们还在脂联素启动子中发现了另一个孤儿核受体的响应元件，肝受体同源物-1 （LRH-1）。LRH-1在3T3-L1细胞和大鼠脂肪细胞中表达。LRH-1特异性结合到已识别的应答元件（LRH-RE）上。LRH-1增强了ppar - γ诱导的脂联素启动子的转激活，LRH-RE的点突变显著降低了脂联素启动子的基础活性和噻唑烷二酮诱导的活性。我们的研究结果表明，ppar - γ和LRH-1通过PPRE及其启动子中的LRH-RE在脂联素基因的转录激活中发挥重要作用。
Adiponectin is a fat-derived hormone with antidiabetic and antiatherogenic properties. Hypoadiponectinemia seen in obesity is associated with insulin-resistant diabetes and atherosclerosis. Thiazolidinediones, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, have been shown to increase plasma adiponectin levels by the transcriptional induction in adipose tissues. However, the precise mechanism of such action is unknown. In this study, we have identified a functional PPAR-responsive element (PPRE) in human adiponectin promoter. PPAR-gamma/retinoid X receptor (RXR) heterodimer directly bound to the PPRE and increased the promoter activity in cells. In adipocytes, point mutation of the PPRE markedly reduced the basal transcriptional activity and completely blocked thiazolidinedione-induced transactivation of adiponectin promoter. We have also identified a responsive element of another orphan nuclear receptor, liver receptor homolog-1 (LRH-1), in adiponectin promoter. LRH-1 was expressed in 3T3-L1 cells and rat adipocytes. LRH-1 bound specifically to the identified responsive element (LRH-RE). LRH-1 augmented PPAR-gamma-induced transactivation of adiponectin promoter, and point mutation of the LRH-RE significantly decreased the basal and thiazolidinedione-induced activities of adiponectin promoter. Our results indicate that PPAR-gamma and LRH-1 play significant roles in the transcriptional activation of adiponectin gene via the PPRE and the LRH-RE in its promoter.