Roles of fatty acids in pathogenesis of insulin resisitance and atherosclerosis

脂肪酸在胰岛素抵抗和动脉粥样硬化发病机制中的作用

• 批准号: 11470231
• 负责人: YAMADA Nobuhiro
• 金额: $ 9.34万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470231/
• 关键词: SREBP; atherosclerosis; insulin resistance; fatty acid; transcription

The main purpose of this project is to manipulate the fatty acid synthesis in a tissue specific manner and to investigate the effects of changes in fatty acids on glucose-lipid metabolism, insulin resistance, and atherosclerosis. In the previous fiscal year, we showed that SREBP-1 plays a crucial role in regulation of synthesis of fatty acids and triglycerides through the analyses of SREBP-1 transgenic and knockout mice. It is also suggested that this transcription factor regulates lipid synthesis by changing its own amount and mediates the action of insulin and glucose. This year, we performed analysis of SREBP-1 expression in a hepatic cell line, and reported that increasing concentrations of glucose in the media can induce the expression of SREBP-1 in the cells showing that glucose can be a signal to SREBP-1 induction as well as a substrate for lipid synthesis (reference 1). To elucidate the mechanism by which excess amount of energy induces SREBP-1 expression as a lipogenic signal, we sequenced and analyzed the SREBP-1c promoter (reference 2). We found a sterol regulatory element (SRE) near upsream of the transcription start site. The presence of SRE in the SREBP-1c gene promoter can explain for the overshooting phenomenon in physiological regulations of SREBP-1c and target lipogenic genes in a context of autoloop regulation. We also found an oxysterol-inducible element upsream of the SRE.This element suggests that a new link between fatty acid and cholesterol metabolism and we are in the middle of analyzing this element.

本项目的主要目的是在组织特异性的方式下操纵脂肪酸合成，并研究脂肪酸的变化对糖脂代谢、胰岛素抵抗和动脉粥样硬化的影响。在上一财年，我们通过对SREBP-1转基因小鼠和敲除小鼠的分析表明，SREBP-1在脂肪酸和甘油三酯合成的调控中起着至关重要的作用。也提示该转录因子通过改变自身数量调节脂质合成，并介导胰岛素和葡萄糖的作用。今年，我们对肝细胞系中SREBP-1的表达进行了分析，并报道了培养基中葡萄糖浓度的增加可以诱导细胞中SREBP-1的表达，这表明葡萄糖可以作为SREBP-1诱导的信号以及脂质合成的底物（文献1）。为了阐明过量能量诱导SREBP-1作为脂肪生成信号表达的机制，我们对SREBP-1c启动子进行了测序和分析（文献2）。我们在转录起始位点上游附近发现了一个甾醇调控元件（SRE）。SRE在SREBP-1c基因启动子中的存在，可以解释SREBP-1c和靶脂肪基因在自动循环调节背景下的生理调控超调现象。我们还在SRE上游发现了一个氧甾醇诱导因子。这个元素表明脂肪酸和胆固醇代谢之间有新的联系，我们正在分析这个元素。

项目成果

Gotoda T: "Complex connection between CD36 and atherosclerosis, lipid metabolism, and insulin resistance syndromes."Current Atherosclerosis Reports. 2. 453-4 (2000)

Gotoda T：“CD36 与动脉粥样硬化、脂质代谢和胰岛素抵抗综合征之间的复杂联系。”当前动脉粥样硬化报告。

島野仁、山田信博 他: "Sterol Regulatory Element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes."J. Biol. Chem.. 274. 35832-35839 (1999)

Hitoshi Shimano、Nobuhiro Yamada 等人：“甾醇调节元件结合蛋白-1 作为脂肪生成酶基因营养诱导的关键转录因子。J. Biol. 274. 35832-35839 (1999)

横山郁夫、山田信博 他: "Improvement of impaired myocardial vasodilation due to diffuse coronary atherosclerosis in hypercholesterolemics after lipid lowering therapy."Circulation. 100. 117-122 (1999)

Ikuo Yokoyama、Nobuhiro Yamada 等人：“降脂治疗后高胆固醇血症患者因弥漫性冠状动脉粥样硬化而导致的心肌血管舒张受损的改善”。循环。100。117-122 (1999)

大橋,山田 他: "Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia."J Lipid Res.. 41(8). 1199-1204 (2000)

Ohashi, Yamada 等人：“微粒体甘油三酯转移蛋白基因的新突变导致无β脂蛋白血症。”J Lipid Res. 1199-1204 (2000)。

Hasty AH,山田 他: "Sterol Regulatory Element-binding Protein-1 Is Regulated by Glucose at the Transcriptional Level."J Biol Chem.. 275(40). 31069-31077 (2000)

Hasty AH, Yamada 等人：“甾醇调节元件结合蛋白-1 在转录水平上受葡萄糖调节。”J Biol Chem. 275(40) (2000)。