Down-Regulation of Hepatic HNF4α Gene Expression during Hyperinsulinemia via SREBPs
Down-Regulation of Hepatic HNF4α Gene Expression during Hyperinsulinemia via SREBPs
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DOI：
10.1210/me.2007-0531
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发表时间：
2009-04-01
影响因子：
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通讯作者：
Sladek, Frances M.
中科院分区：
文献类型：
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作者：
Xie, Xuefen;Liao, Hailing;Sladek, Frances M.
已知肝细胞核因子4 α（HNF 4 α）编码区及其驱动胰腺表达的上游启动子（P2）的突变会导致年轻人成熟型糖尿病1（MODY 1）。HNF 4 α还控制肝脏中的脂质代谢和脂质生成，其中近端启动子（P1）占主导地位。然而，关于肝HNF 4 α在糖尿病中的作用知之甚少。在这里，我们研究了两种糖尿病小鼠模型，db/db小鼠（2型，胰岛素抵抗）和链脲佐菌素治疗的小鼠（1型，胰岛素缺乏）的肝脏HNF 4 α的表达。我们发现db/db小鼠肝脏中HNF 4 α蛋白和mRNA的水平降低，但链脲佐菌素治疗的小鼠肝脏中HNF 4 α蛋白和mRNA的水平升高。由于胰岛素增加了固醇调节元件结合蛋白（SREBP）-1c和-2的活性，我们还研究了SREBP对肝脏HNF 4 α基因表达的影响，发现与胰岛素一样，SREBP的异位表达降低了体外原代肝细胞和体内C57 BL/6小鼠肝脏中肝脏HNF 4 α蛋白和mRNA的水平。最后，我们使用凝胶位移，染色质免疫沉淀，小干扰RNA和报告基因分析表明，SREBP 2结合人类HNF 4 α P1启动子和负调控其表达。这些数据表明，高胰岛素血症通过上调SREBP下调肝脏中的HNF 4 α，从而在调节肝脏中脂质和葡萄糖代谢的这两个关键转录因子途径之间建立联系。这些发现也为糖尿病相关并发症如脂肪肝提供了新的见解。（分子内分泌学23：434-443，2009）
Mutations in the coding region of hepatocyte nuclear factor 4 alpha (HNF4 alpha), and its upstream promoter (P2) that drives expression in the pancreas, are known to lead to maturity-onset diabetes of the young 1 (MODY1). HNF4 alpha also controls gluconeogenesis and lipid metabolism in the liver, where the proximal promoter (P1) predominates. However, very little is known about the role of hepatic HNF4 alpha in diabetes. Here, we examine the expression of hepatic HNF4 alpha in two diabetic mouse models, db/db mice (type 2, insulin resistant) and streptozotocin-treated mice (type 1, insulin deficient). We found that the level of HNF4 alpha protein and mRNA was decreased in the liver of db/db mice but increased in streptozotocin-treated mice. Because insulin increases the activity of sterol regulatory element-binding proteins (SREBP)-1c and -2, we also examined the effect of SREBPs on hepatic HNF4 alpha gene expression and found that, like insulin, ectopic expression of SREBPs decreases the level of hepatic HNF4 alpha protein and mRNA both in vitro in primary hepatocytes and in vivo in the liver of C57BL/6 mice. Finally, we use gel shift, chromatin immunoprecipitation, small interfering RNA, and reporter gene analysis to show that SREBP2 binds the human HNF4 alpha P1 promoter and negatively regulates its expression. These data indicate that hyperinsulinemia down-regulates HNF4 alpha in the liver through the up-regulation of SREBPs, thereby establishing a link between these two critical transcription factor pathways that regulate lipid and glucose metabolism in the liver. These findings also provide new insights into diabetes-associated complications such as fatty liver disease. (Molecular Endocrinology 23: 434-443, 2009)