Key result
Overexpression of human LPL in WHHL rabbits reduced total cholesterol by 64% and triglycerides by 91%, but resulted in a two-fold increase in aortic atherosclerosis compared to non-transgenic rabbits.
Why the study?
Does overexpression of human LPL affect plasma lipids and aortic atherosclerosis in LDL receptor-deficient WHHL rabbits?
Does overexpression of human LPL affect plasma lipids and aortic atherosclerosis in LDL receptor-deficient WHHL rabbits?
Answers are grounded in this paper and cite their sources.
In the setting of LDL receptor deficiency, increased LPL activity improves hyperlipidemia but paradoxically accelerates atherosclerosis by increasing the generation of atherogenic small dense LDL particles.
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.
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Koike et al. (2004) studied Atherosclerosis and hyperlipidemia. Overexpression of human lipoprotein lipase (LPL) vs. Non-transgenic WHHL rabbits was evaluated on Aortic atherosclerosis (2-fold increase). Overexpression of human LPL in WHHL rabbits reduced total cholesterol by 64% and triglycerides by 91%, but resulted in a two-fold increase in aortic atherosclerosis compared to non-transgenic rabbits.
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