Overexpression of lipoprotein lipase in transgenic Watanabe heritable hyperlipidemic rabbits improves hyperlipidemia and obesity.
Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of the triglyceride-rich lipoproteins and plays a critical role in lipoprotein and free fatty acid metabolism. Genetic manipulation of LPL may be beneficial in the treatment of hypertriglyceridemias, but it is unknown whether increased LPL activity may be effective in lowering plasma cholesterol and improving insulin resistance in familial hypercholesterolemic patients. To test the hypothesis that stimulation of LPL expression may be used as an adjunctive therapy for treatment of homozygous familial hypercholesterolemia, we have generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits that overexpress the human LPL transgene and compared their plasma lipid levels, glucose metabolism, and body fat accumulation with those of non-Tg WHHL rabbits. Overexpression of LPL dramatically ameliorated hypertriglyceridemia in Tg WHHL rabbits. Furthermore, increased LPL activity in male Tg WHHL rabbits also corrected hypercholesterolemia (544 +/- 52 in non-Tg versus 227 +/- 29 mg/dl in Tg, p < 0.01) and reduced body fat accumulation by 61% (323 +/- 27 in non-Tg versus 125 +/- 21ginTg, p < 0.01), suggesting that LPL plays an important role in mediating plasma cholesterol homeostasis and adipose accumulation. In addition, overexpression of LPL significantly suppressed high fat diet-induced obesity and insulin resistance in Tg WHHL rabbits. These results imply that systemic elevation of LPL expression may be potentially useful for the treatment of hyperlipidemias, obesity, and insulin resistance.
Koike
Tomonari
T
Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
Liang
Jingyan
J
Wang
Xiaofei
X
Ichikawa
Tomonaga
T
Shiomi
Masashi
M
Liu
George
G
Sun
Huijun
H
Kitajima
Shuji
S
Morimoto
Masatoshi
M
Watanabe
Teruo
T
Yamada
Nobuhiro
N
Fan
Jianglin
J
D000273:Adipose Tissue / Q000648:ultrastructure; D000818:Animals; D030801:Animals, Genetically Modified; D001786:Blood Glucose / Q000032:analysis; D015152:Blotting, Northern; D001823:Body Composition; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005951:Glucose Tolerance Test; D006801:Humans; D006949:Hyperlipidemias / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008071:Lipoprotein Lipase / Q000235:genetics*; D008297:Male; D008855:Microscopy, Electron, Scanning; D009765:Obesity / Q000201:enzymology / Q000628:therapy*; D016133:Polymerase Chain Reaction; D011817:Rabbits; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase