Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase.
OBJECTIVE
This study was designed to address the effects of increased lipoprotein lipase (LPL) activity on atherosclerosis in the setting of LDL receptor deficiency.


METHODS
We generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits overexpressing human LPL and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL rabbits.


RESULTS
Increased expression of LPL significantly ameliorated hypertriglyceridemia and hypercholesterolemia in Tg WHHL rabbits [64% reduction in total cholesterol (TC) and 91% reduction in triglycerides (TG) vs. non-Tg]. In spite of this beneficial effect of LPL, Tg WHHL rabbits had two-fold greater aortic atherosclerosis than non-Tg WHHL rabbits. Analysis of plasma lipoprotein profiles revealed that increased LPL activity in Tg WHHL rabbits resulted in the dramatic reduction of large TG-rich lipoproteins (VLDL, d<1.006 g/ml and IDL, d=1.006-1.02) but concomitant increases in LDL fractions, especially those of small and dense LDL particles (d=1.04-1.06, 2.6-fold over non-Tg). Using apoB-containing lipoproteins, we found that small-sized LDL from Tg WHHL rabbits contained more oxidizable substrate and exhibited higher affinity to biglycan than large TG-rich LDL of non-Tg WHHL rabbits.


CONCLUSIONS
We conclude that in the absence of LDL receptor function, increased LPL activity accelerates the catabolism of large TG-rich VLDL (possibly via the LRP pathway) and subsequently improves hyperlipidemia. However, LPL may also enhance the generation and accumulation of small dense LDLs, which are more atherogenic.
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
Sun
Huijun
H
Watanabe
Teruo
T
Liu
George
G
Fan
Jianglin
J
D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D001055:Apolipoproteins B / Q000032:analysis; D001161:Arteriosclerosis / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000201:enzymology* / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D008071:Lipoprotein Lipase / Q000097:blood / Q000235:genetics*; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D011817:Rabbits; D014280:Triglycerides / Q000097:blood
D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase