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

本研究拟通过对细胞内脂质代谢的研究，探讨脂质在动脉壁和脂肪组织中蓄积的机制，以阐明动脉粥样硬化、肥胖、高脂血症和糖耐量等常见的病理生理机制。激素敏感脂肪酶（HSL）和中性胆固醇酯水解酶（NCEH）作为与动脉硬化、肥胖和高脂血症中常见的脂质积聚有关的胰岛素敏感基因的候选者，在调节细胞内胆固醇代谢和甘油三酯代谢方面可能是相同的，因此我们对其进行了研究。本研究试图通过HSL基因打靶来阐明动脉粥样硬化和肥胖的共同机制，我们已经成功地进行了HSL基因打靶，并建立了HSL基因敲除小鼠系列。当分析HSL基因敲除小鼠的表型时，识别出男性不育。说明HSL与精子发生有关。血浆游离脂肪酸水平没有明显下降，但血液游离脂肪酸水平下降，表明脂肪组织中存在除HSL外的新的中性脂肪降解酶。将检查该小鼠模型中肥胖、胰岛素抵抗和葡萄糖耐量的病理生理学。

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.