M. Shimada et al., OVEREXPRESSION OF HUMAN LIPOPROTEIN-LIPASE IN TRANSGENIC MICE - RESISTANCE TO DIET-INDUCED HYPERTRIGLYCERIDEMIA AND HYPERCHOLESTEROLEMIA, The Journal of biological chemistry, 268(24), 1993, pp. 17924-17929
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.