Roles of fatty acids in pathogenesis of insulin resisitance and atherosclerosis

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。

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.