Regulation mechanism of lipid metabolism related gene by estrogen β

雌激素β对脂质代谢相关基因的调控机制

• 批准号: 12671598
• 负责人: TASAKA Keiichi
• 金额: $ 2.5万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671598/
• 关键词: Estrogen; lipoprotein lipase; ER-α; matrix metalloproteinase; マトリツクスメタロプロテイネース; マトリックスメタロプロテイネー; 肥満; 動脈硬化; LPL

Many reports described that estrogen replacement therapy is effective for preventing postmenopausal women against hyperlipidemia and atherosclerosis. We studied the mechanism underlying this estrogen-dependent lipid metabolism by lipoprotein lipase (LPL) gene promoter analyzes using mouse 3T3-L1 cells. We identified a novel (not consensus) estrogen responsive element, which is located -1856/-1850 of LPL promoter lesion by employing a set of 5 -deletion mutants of LPL-CAT reporter. We also confirmed that this repressive effect of estrogen is mainly mediated by estrogen receptor (ER)-α by co-transfection experiments, whereas ER-β, another estrogen receptor, showed only marginal effect. Next, we investigated effects of estrogen on matrix metalloproteinase activity that has an important role for forming atherosclerotic plaque using human umbilical vein endothelial cells. Zymography demonstrated that six-hour treatment of estrogen inhibited MMP2 activity in a dose-dependent manner. These results suggest that estrogen inhibits hyperlipidemia and atherosclerosis by various mechanisms.

雌激素替代治疗对绝经后妇女高脂血症和动脉粥样硬化的预防作用已被广泛报道。我们利用小鼠3 T3-L1细胞，通过脂蛋白脂酶（LPL）基因启动子分析研究了这种雌激素依赖性脂质代谢的机制。我们利用一组LPL-CAT报告基因的5 -缺失突变体，鉴定了一个新的（非共有的）雌激素反应元件，它位于LPL启动子损伤的-1856/-1850。我们还通过共转染实验证实了雌激素的这种抑制作用主要是由雌激素受体（ER）-α介导的，而另一种雌激素受体ER-β仅表现出边缘效应。接下来，我们研究了雌激素对基质金属蛋白酶活性的影响，基质金属蛋白酶活性对人脐静脉内皮细胞形成动脉粥样硬化斑块具有重要作用。酶谱分析表明，6小时的雌激素治疗抑制MMP 2的活性在剂量依赖性的方式。这些结果表明，雌激素通过多种机制抑制高脂血症和动脉粥样硬化。

项目成果

Homma, H., et al.: "Estrogen suppresses transcription of lipoprotein lipase gene"J Biol Chem. 275. 11404-11411 (2000)

Homma，H.，等人：“雌激素抑制脂蛋白脂肪酶基因的转录”J Biol Chem。