ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor α Expression in Pancreatic β-Cells
ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor α Expression in Pancreatic β-Cells
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DOI：
10.1074/jbc.m110.215467
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发表时间：
2011-04-15
影响因子：
4.8
通讯作者：
Mandrup, Susanne
中科院分区：
文献类型：
--
作者：
Boergesen, Michael;Poulsen, Lars la Cour;Mandrup, Susanne
长期暴露于葡萄糖和脂肪酸水平升高导致胰腺β细胞功能障碍，其机制仅部分了解。转录因子过氧化物酶体增殖物激活受体α (PPAR α)是参与脂肪酸代谢的基因的重要调节因子，并已被证明可以防止脂质诱导的β细胞功能障碍。我们和其他人之前已经表明，β细胞中PPAR α基因的表达会被葡萄糖迅速抑制。在这里，我们发现PPAR α基因从五个可选的转录起始位点转录，导致三个可选的第一外显子拼接到外显子2上。在胰岛素瘤细胞和分离的胰岛中，所有PPAR α转录本的表达都受到葡萄糖的抑制。观察到葡萄糖抑制PPAR α转录的动态与碳水化合物反应元件结合蛋白（carbon response element-binding protein, ChREBP）激活靶基因的动态非常相似，促使我们研究ChREBP在调控PPAR α表达中的潜在作用。我们发现缺乏n端结构域的组成活性ChREBP有效抑制胰岛素瘤细胞、啮齿动物和人类胰岛中PPAR α的表达。此外，我们证明了sirna介导的ChREBP敲低可消除胰岛素瘤细胞中葡萄糖对PPAR α表达的抑制以及诱导已建立的ChREBP靶基因。总之，本研究表明ChREBP是葡萄糖抑制胰腺β细胞PPAR α基因表达的关键和直接介质，表明ChREBP可能在葡萄糖抑制β细胞脂肪酸氧化能力中起重要作用。
Chronic exposure to elevated levels of glucose and fatty acids leads to dysfunction of pancreatic beta-cells by mechanisms that are only partly understood. The transcription factor peroxisome proliferator-activated receptor alpha (PPAR alpha) is an important regulator of genes involved in fatty acid metabolism and has been shown to protect against lipid-induced beta-cell dysfunction. We and others have previously shown that expression of the PPAR alpha gene in beta-cells is rapidly repressed by glucose. Here we show that the PPAR alpha gene is transcribed from five alternative transcription start sites, resulting in three alternative first exons that are spliced to exon 2. Expression of all PPAR alpha transcripts is repressed by glucose both in insulinoma cells and in isolated pancreatic islets. The observation that the dynamics of glucose repression of PPAR alpha transcription are very similar to those of glucose activation of target genes by the carbohydrate response element-binding protein (ChREBP) prompted us to investigate the potential role of ChREBP in the regulation of PPAR alpha expression. We show that a constitutively active ChREBP lacking the N-terminal domain efficiently represses PPAR alpha expression in insulinoma cells and in rodent and human islets. In addition, we demonstrate that siRNA-mediated knockdown of ChREBP abrogates glucose repression of PPAR alpha expression as well as induction of well established ChREBP target genes in insulinoma cells. In conclusion, this work shows that ChREBP is a critical and direct mediator of glucose repression of PPAR alpha gene expression in pancreatic beta-cells, suggesting that ChREBP may be important for glucose suppression of the fatty acid oxidation capacity of beta-cells.