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，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。最近，已经建立了过表达或缺乏特定基因的转基因小鼠或敲除小鼠的各种品系，并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，可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水解。酶的活动是在急性神经元和激素的控制。儿茶酚胺和其他脂解激素通过环腺苷3 '，5'-单磷酸（cAMP）依赖性蛋白激酶（PKA）可逆磷酸化丝氨酸来刺激其活性。相反，胰岛素，一种抗脂解激素，通过阻止磷酸化来抑制其活性。HSL-1<-1->小鼠表现出适度的肥胖、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中胆固醇酯水解的缺陷。出乎意料的是，我们发现HSL是饥饿时生存所必需的。在HSL-1小鼠中完全不存在响应于禁食的血浆游离脂肪酸（FFA）水平的正常升高<-1->。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，我们认为HSL是作为一种适应饥饿所需的分子进化而来的，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.