Reduction of plasma triglycerides in apolipoprotein C-II transgenic mice overexpressing lipoprotein lipase in muscle

Leslie K. Pulawa, Dalan R. Jensen, Alison Coates¹ and Robert H. Eckel²

Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, CO

Published, JLR Papers in Press, October 3, 2006.

^¹ Present address of A. Coates: Nutritional Physiology ResearchCentre, School of Health Sciences, University of South Australia,Adelaide, South Australia, Australia.

^² To whom correspondence should be addressed. e-mail: robert.eckel{at}uchsc.edu

LPL and its specific physiological activator, apolipoproteinC-II (apoC-II), regulate the hydrolysis of triglycerides (TGs)from circulating TG-rich lipoproteins. Previously, we developeda skeletal muscle-specific LPL transgenic mouse that had lowerplasma TG levels. ApoC-II transgenic mice develop hypertriglyceridemiaattributed to delayed clearance. To investigate whether overexpressionof LPL could correct this apoC-II-induced hypertriglyceridemia,mice with overexpression of human apoC-II (CII) were cross-bredwith mice with two levels of muscle-specific human LPL overexpression(LPL-L or LPL-H). Plasma TG levels were 319 ± 39 mg/dlin CII mice and 39 ± 5 mg/dl in wild-type mice. Comparedwith CII mice, apoC-II transgenic mice with the higher levelof LPL overexpression (CIILPL-H) had a 50% reduction in plasmaTG levels (P = 0.013). Heart LPL activity was reduced by $~$ 30%in mice with the human apoC-II transgene, which accompanieda more modest 10% decrease in total LPL protein. Overexpressionof human LPL in skeletal muscle resulted in dose-dependent reductionof plasma TGs in apoC-II transgenic mice. Along with plasmaapoC-II concentrations, heart and skeletal muscle LPL activitieswere predictors of plasma TGs. These data suggest that micewith the human apoC-II transgene may have alterations in theexpression/activity of endogenous LPL in the heart. Furthermore,the decrease of LPL activity in the heart, along with the inhibitoryeffects of excess apoC-II, may contribute to the hypertriglyceridemiaobserved in apoC-II transgenic mice.

Supplementary key words hypertriglyceridemia • lipid metabolism • heparin-releasable lipoprotein lipase activity • heart • fasting

Abbreviations: apoC-II, apolipoprotein C-II; HSPG, heparan sulfate proteoglycan; TG, triglyceride; WT, wild-type

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