Gene targeting study on mechanisms for cholesterol accumulation in the artery

在转基因小鼠或敲除小鼠中，可以转导或删除特定基因，以研究其功能及其与人类疾病的关系。近年来，已经建立了多种转基因小鼠或基因敲除小鼠，这些小鼠过度表达或缺乏特定基因，可用于研究人类疾病的病理生理，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，在动脉粥样硬化病变中催化储存在脂肪组织中的甘油三酯和胆固醇酯的水解。酶的活性受到神经元和激素的急性控制。儿茶酚胺和其他脂溶激素通过环腺苷3',5'-单磷酸（cAMP）依赖性蛋白激酶（PKA）对丝氨酸的可逆磷酸化来刺激其活性。相反，胰岛素，一种抗脂溶激素，通过阻止磷酸化抑制其活动。HSL^<-1->小鼠表现出适度肥胖、低血脂和对饮食诱导的动脉粥样硬化的极端易感性，这可能是由于主动脉病变处胆固醇酯水解缺陷所致。出乎意料的是，我们发现HSL是饥饿时生存所必需的。空腹后血浆游离脂肪酸（FFA）水平的正常升高在HSL^<-1->小鼠中完全不存在。我们推测FFA的持续供应是维持正常心脏功能所必需的。因此，我们提出HSL进化为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.