Roles of fatty acids in pathogenesis of insulin resisitance and atherosclerosis

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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.