Distinct regulation of adiponutrin/PNPLA3 gene expression by the transcription factors ChREBP and SREBP1c in mouse and human hepatocytes
Distinct regulation of adiponutrin/PNPLA3 gene expression by the transcription factors ChREBP and SREBP1c in mouse and human hepatocytes
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DOI：
10.1016/j.jhep.2010.10.024
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发表时间：
2011-07-01
影响因子：
25.7
通讯作者：
Moldes, Marthe
中科院分区：
文献类型：
--
作者：
Dubuquoy, Celine;Robichon, Celine;Moldes, Marthe
背景和目的：adiponutrin/PNPLA3（含patatin样磷脂酶结构域的蛋白3）变体1148M最近已成为人类脂肪肝疾病的重要标志物。为了了解 Adiponutrin/PNPLA3 蛋白的作用，我们研究了其在人和小鼠肝细胞中表达的调节。方法：通过实时 PCR 分析，在小鼠肝脏的体内以及小鼠肝细胞和人肝细胞的体外分析中测定 Adiponutrin/PNPLA3 和脂肪生成酶的表达。 结果：我们发现，在小鼠肝脏中，adiponutrin/PNPLA3 基因表达受到 ChREBP（碳水化合物反应元件结合蛋白）和 SREBP1c（甾醇调节元件结合蛋白 1c）的直接转录控制，以响应葡萄糖和胰岛素， 分别。硅胶分析揭示了小鼠脂联素/PNPLA3 基因启动子上存在 ChoRE（碳水化合物反应元件）和 SRE（甾醇反应元件）结合位点。报告基因测定中的点突变分析确定了小鼠脂联素/PNPLA3启动子中这两个结合位点的功能反应。相比之下，在人永生化肝细胞和 HepG2 肝癌细胞中，只有 SREBP1c 能够诱导 adiponutrin/PNPLA3 表达，而 ChREBP 无法调节其表达。结论：总而言之，我们的结果表明 adiponutrin/PNPLA3 受到糖酵解和脂肪生成途径的两个关键因素的调节，提高 它在碳水化合物和脂质代谢中的影响问题。 (C) 2010 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background & Aims: The adiponutrin/PNPLA3 (patatin-like phospholipase domain-containing protein 3) variant 1148M has recently emerged as an important marker of human fatty liver disease. In order to understand the role of the adiponutrin/PNPLA3 protein, we investigated the regulation of its expression in both human and mouse hepatocytes.Methods: Adiponutrin/PNPLA3 and lipogenic enzyme expression was determined by real-time PCR analysis in a wide panel of analysis in vivo in the mouse liver and in vitro in murine hepatocytes and human hepatocyte cell lines infected with ChREBP or SREBP1c-expressing adenoviruses.Results: We show that in the mouse liver, adiponutrin/PNPLA3 gene expression is under the direct transcriptional control of ChREBP (carbohydrate-response element-binding protein) and SREBP1c (sterol regulatory element binding protein1c) in response to glucose and insulin, respectively. In silica analysis revealed the presence of a ChoRE (carbohydrate response element) and of a SRE (sterol response element) binding site on the mouse adiponutrin/PNPLA3 gene promoter. Point mutation analysis in reporter gene assays identified the functional response of these two binding sites in the mouse adiponutrin/PNPLA3 promoter. In contrast, in human immortalized hepatocytes and in HepG2 hepatoma cells, only SREBP1c was able to induce adiponutrin/PNPLA3 expression, whereas ChREBP was unable to modulate its expression.Conclusions: All together, our results suggest that adiponutrin/PNPLA3 is regulated by two key factors of the glycolytic and lipogenic pathways, raising the question of its implication in the metabolism of carbohydrates and lipids. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.