Development of animal models for atherosclerosis and obesity, and molecular mechanism of the common pathway

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We intend to study the mechanism of lipid accumulation in arterial wall and fat tissue by studying intracellular lipid metabolism, to clarify the common pathophysiology of atherosclerosis, obesity, hyperlipidemia, and glucose tolerance. As a candidate of insulin-sensitive gene concerning the lipid accumulation which is commonly observed in arteriosclerosis, obesity, and hyperlipidemia, we paid attention to hormone sensitive lipase(HSL)and neutral cholesterol ester hydrolase(NCEH)which may be identical in the regulation of intracellular cholesterol metabolism and triglyceride metabolim. In this study, we try to clarify the common mechanism for atherosclerosis and obesity by gene targeting of HSL.We had already succeeded in gene targeting of HSL, and the series of the HSL knockout mouse was established. The male infertility was recognized when the phenotype of the HSL knockout mouse was analyzed. It was indicated that HSL was related to the spermatogenesis. The obvious lowering of plasma FFA level was not recognized, though the blood FFA level decreased, indicating that novel neutral fat degrading enzyme except for HSL exists in fat tissue. The pathophysiology of obesity, insulin resistance, and glucose tolerance in this mouse model will be examined.