Gene targeting study on mechanisms for cholesterol accumulation in the artery

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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.