| Project/Area Number |
07457219
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
内分泌・代謝学
|
|---|
| Research Institution | University of Tokyo |
|---|
Principal Investigator |
YAMADA Nobuhiro University of Tokyo, Faculty of Medicine, Associate Prof., 医学部・附属病院, 助教授 (40200729)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OSUGA Jun-ichi University of Tokyo, Faculty of Medicine, Research Fellow, 医学部・附属病院, 医員
GOTODA Takanari University of Tokyo, Faculty of Medicine, Research Fellow, 医学部・附属病院, 医員
ISHIBASHI Shun University of Tokyo, Faculty of Medicine, Research Associate, 医学部・附属病院, 助手 (90212919)
|
|---|
| Project Period (FY) |
1995 – 1996
|
| Project Status |
Completed (Fiscal Year 1996)
|
| Budget Amount *help |
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1996: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1995: ¥4,300,000 (Direct Cost: ¥4,300,000)
|
|---|
| Keywords | Molecular engineering / ACAT / Gene targeting / Atheroscherosis / Hormone-sensitive lipase |
|---|
| Research Abstract |
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.
|
