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 triglyceride-rich lipoproteins. To determine the role of LPL in lipoprotein metabolism, we established three transgenic mouse lines overexpressing the 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 activity in adipose tissue and post-heparin plasma, respectively. Plasma triglyceride levels in transgenic mice were 24.2% of that in control mice, and gel filtration chromatography showed that very low density lipoprotein (VLDL) triglycerides were much reduced in transgenic mice. In the chemical analysis of plasma lipoproteins isolated by ultracentrifugation, we found that LDL particles were cholesterol-rich and HDL2 cholesterol was increased 1.4-fold in transgenic mice as compared to control mice. When we injected 125I-VLDL intravenously into transgenic mice, the clearance of 125I-VLDL and the conversion of VLDL to LDL was markedly enhanced as compared to control mice. Furthermore, the clearance of chylomicrons, estimated by both the fat loading and retinyl palmitate 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 hypercholesterolemia was suppressed in transgenic mice. These results suggested that LPL determined not only hydrolysis of triglyceride-rich lipoproteins but also lipolytic conversion, and that overexpression of LPL acted to protect against diet-induced hypertriglyceridemia as well as hypercholesterolemia.
Shimada
M
M
Third Department of Internal Medicine, University of Tokyo, Japan.
Shimano
H
H
Gotoda
T
T
Yamamoto
K
K
Kawamura
M
M
Inaba
T
T
Yazaki
Y
Y
Yamada
N
N
D000199:Actins / Q000235:genetics; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015139:Blotting, Southern; D002645:Chickens; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D002850:Chromatography, Gel; D004041:Dietary Fats; D015870:Gene Expression; D006801:Humans; D006937:Hypercholesterolemia / Q000209:etiology / Q000517:prevention & control*; D015228:Hypertriglyceridemia / Q000209:etiology / Q000517:prevention & control*; D008071:Lipoprotein Lipase / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009132:Muscles / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D009838:Oligodeoxyribonucleotides; D009928:Organ Specificity; D010743:Phospholipids / Q000097:blood; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism*; D012016:Reference Values; D015183:Restriction Mapping; D014280:Triglycerides / Q000097:blood
D000199:Actins; D002788:Cholesterol Esters; D004041:Dietary Fats; D008074:Lipoproteins; D009838:Oligodeoxyribonucleotides; D010743:Phospholipids; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase