Overexpression of lipoprotein lipase in transgenic rabbits inhibits diet-induced hypercholesterolemia and atherosclerosis

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of TG-rich lipop roteins. To elucidate the physiological roles of LPL in lipid and lipoprote in metabolism, we generated transgenic rabbits expressing human LPL. In pos theparinized plasma of transgenic rabbits, the human LPL protein levels wer e about 650 ng/ml, and LPL enzymatic activity was found at levels up to 4-f old greater than that in nontransgenic littermates. Increased LPL activity in transgenic rabbits was associated with as much as an 80% decrease in pla sma triglycerides and a 59% decrease in high density lipoprotein-cholestero l. Analysis of the lipoprotein density fractions revealed that increased ex pression of the LPL transgene resulted in a remarkable reduction in the lev el of very low density lipoproteins as well as in the level of intermediate density lipoproteins. In addition, LDL cholesterol levels in transgenic ra bbits were significantly increased. When transgenic rabbits were fed a chol esterol-rich diet, the development of hypercholesterolemia and aortic ather osclerosis was dramatically suppressed in transgenic rabbits. These results demonstrate that systemically increased LPL activity functions in the meta bolism of all classes of lipoproteins, thereby playing a crucial role in pl asma triglyceride hydrolysis and lipoprotein conversion, and that overexpre ssion of LPL protects against diet-induced hypercholesterolemia and atheros clerosis.