OVEREXPRESSION OF HUMAN LIPOPROTEIN-LIPASE IN TRANSGENIC MICE - RESISTANCE TO DIET-INDUCED HYPERTRIGLYCERIDEMIA AND HYPERCHOLESTEROLEMIA

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyce ride-rich lipoproteins. To determine the role of LPL in lipoprotein me tabolism, we established three transgenic mouse lines overexpressing t he human LPL gene; the highest expressor line, which transcribed human LPL mRNA in the heart, skeletal muscles, and adipose tissue, was used in this study. The transgenic mice had 5- and 1.7-fold higher LPL act ivity in adipose tissue and post-heparin plasma, respectively. Plasma triglyceride levels in transgenic mice were 24.2% of that in control m ice, and gel filtration chromatography showed that very low density li poprotein (VLDL) triglycerides were much reduced in transgenic mice. I n the chemical analysis of plasma lipoproteins isolated by ultracentri fugation, we found that LDL particles were cholesterol-rich and HDL2 c holesterol was increased 1.4-fold in transgenic mice as compared to co ntrol mice. When we injected I-125-VLDL intravenously into transgenic mice, the clearance of I-125-VLDL and the conversion of VLDL to LDL wa s markedly enhanced as compared to control mice. Furthermore, the clea rance of chylomicrons, estimated by both the fat loading and retinyl p almitate loading tests, was significantly enhanced in transgenic mice. After sucrose feeding, no increase in VLDL was observed in transgenic mice. When fed a high cholesterol diet, the development of hyperchole sterolemia was suppressed in transgenic mice. These results suggested that LPL determined not only hydrolysis of triglyceride-rich lipoprote ins but also lipolytic conversion, and that overexpression of LPL acte d to protect against diet-induced hypertriglyceridemia as well as hype rcholesterolemia.