Endothelial lipase and HDL metabolism.
OBJECTIVE
In the past year, several laboratories taking independent approaches have provided compelling evidence that endothelial lipase, a relatively recent addition to the triglyceride lipase gene family, is a major determinant of HDL metabolism. This review summarizes recent findings from experiments in mice with altered levels of endothelial lipase, from an examination of endothelial lipase catalytic and non-catalytic functions in vitro, and from human genetic studies.


RESULTS
An analysis of lipids and lipoproteins in endothelial lipase knockout and transgenic mice and in mice with adenovirus-driven hepatic overexpression of endothelial lipase shows, without exception, that total cholesterol, phospholipid and HDL-cholesterol all vary inversely with the endothelial lipase gene dosage, and primarily depend on endothelial lipase catalytic activity. Endothelial lipase participates in HDL metabolism by promoting the turnover of HDL components and increasing the catabolism of apolipoprotein A-I. The measurement of lipase activity on lipoprotein substrates in vitro demonstrates that endothelial lipase is distinct from other triglyceride lipases in showing the highest activity on HDL. Endothelial lipase gene polymorphisms in humans appear to be associated with HDL-cholesterol or HDL3-cholesterol concentrations.


CONCLUSIONS
A low HDL-cholesterol level in humans is a risk factor for coronary heart disease. Although not yet demonstrated, it is possible that the action of endothelial lipase on HDL may promote atherogenesis, in which case endothelial lipase may represent an attractive target for pharmaceutical intervention.
Jaye
Michael
M
GlaxoSmithKline, Cardiovascular Center for Excellence in Drug Discovery, Vascular Biology and Thrombosis Department, King of Prussia, Pennsylvania 19406-0939, USA. michael.c.jaye@gsk.com
Krawiec
John
J
D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D008049:Lipase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011110:Polymorphism, Genetic
D008075:Lipoproteins, HDL; C410382:LIPG protein, human; D008049:Lipase; C498741:Lipg protein, mouse