Gene targeting study on mechanisms for cholesterol accumulation in the artery

在转基因小鼠或基因敲除小鼠中，特定的基因可以被转导或缺失，以研究其功能及其与人类疾病的关系。近年来，各种过表达或缺乏特定基因的转基因小鼠或基因敲除小鼠已被建立，可用于研究人类疾病的病理生理学，包括动脉粥样硬化、糖尿病和高脂血症。激素敏感脂肪酶(HSL)是一种多功能酶，催化脂肪组织中储存的三酰甘油和动脉粥样硬化病变中的胆固醇酯的水解。酶活性受到急性神经元和激素的控制。儿茶酚胺和其他脂类激素通过环磷酸腺苷(CAMP)依赖的蛋白激酶(PKA)使丝氨酸可逆地磷酸化来刺激其活性。相反，胰岛素是一种抗脂类激素，通过阻止磷酸化来抑制其活性。HSL^&lt；-1-&gt；小鼠表现出中度肥胖、低脂血症和对饮食诱导的动脉粥样硬化的极端敏感性，这可能是由于主动脉病变中胆固醇酯水解的缺陷所致。出乎意料的是，我们发现HSL对于饥饿时的生存是必不可少的。在HSL^&lt；-1-gt；小鼠中，空腹引起的血浆游离脂肪酸(FFA)水平的正常升高是完全不存在的。我们推测，维持正常的心脏功能需要持续的FFA供应。因此，我们认为HSL被进化为一种适应饥饿所需的分子，并将肥胖与动脉粥样硬化联系起来。

In the transgenic mouse or knockout mouse, a specific gene can be transduced or deleted to study its function and relation to human diseases. Recently, various lines of transgenic mice or knockout mice which overexpress or lack a specific gene have been established and are available to study the pathophysiology of human diseases, including atherosclerosis, diabetes mellitus, and hyperlipidemia. Hormone-sensitive lipase (HSL) is a multi-functional enzyme which catalyzes the hydrolysis of triacylglycrol stored in adipose tissue and cholesterol esters in atherosclerotic lesions. The enzymatic activities are under acute neuronal and hormonal control. Catecholamines and other lipolytic hormones stimulate its activities through reversible phosphorylation of serine by cyclic adenosine 3', 5'-monophosphate (cAMP)-dependent protein kinase (PKA). Conversely, insulin, an anti-lipolytic hormone, suppresses its activities through preventing the phosphorylation. HSL^<-1-> mice exhibited modest obesity, hypolipidemia and extreme susceptibility to diet-induced atherosclerosis probably due to the defect in hydrolysis of cholesterol ester in the aortic lesions. Unexpectedly, we found that HSL is essential for survival upon starvation. Normal rise in plasma free fatty acids (FFA) levels in response to fasting is completely absent in HSL^<-1-> mice. We speculate that a continuous supply of FFA is required to sustain normal cardiac function. Thus, we propose that HSL is evolved as a molecule needed for adaptation to starvation and links obesity to atherosclerosis.