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| 在高胰岛素血症期间通过SREBPs下调肝的HNF-a基因表达 |
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| Down-regulation of Hepatic HNF4α Gene Expression during Hyperinsulinemia via SREBPs |
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| Xie X., Liao H., Dang H., Pang W., Guan Y., Wang X., Shyy J.Y.-J., Zhu Y., Sladek F.M. 2009/5/29 18:38:56 |
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Molecular Endocrinology, 2009, Volume 23, Issue 4
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| Mutations in the coding region of hepatocyte nuclear factor 4α (HNF4α), and its upstream promoter (P2) that drives expression in the pancreas, are known to lead to maturity-onset diabetes of the young 1 (MODY1). HNF4α 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 HNF4α in diabetes. Here, we examine the expression of hepatic HNF4α 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 HNF4α protein and mRNAwas 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 HNF4α gene expression and found that, like insulin, ectopic expression of SREBPs decreases the level of hepatic HNF4α 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 HNF4α P1 promoter and negatively regulates its expression. These data indicate that hyperinsulinemia down-regulates HNF4α 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) Copyright © 2009 by The Endocrine Society. |
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| Correspondence Address: Sladek, F. M.; Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, CA 92521; email: frances.sladek@ucr.edu |
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 疾病资源中心
摘自：《西氏内科学》，第23版
患者女性，21岁，因干咳、间歇性气促2个月到急诊科就诊。开始症状为上呼吸道感染引起的鼻塞、流涕和咳嗽。医生检查后开了抗生素。服药后鼻部症状缓解，但仍有轻微干咳和呼吸困难。其他症状包括疲劳和焦虑。否认发热、体重减轻、胸痛、端坐呼吸、气喘、鼻后滴漏、胃灼热以及神经系统症状。
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