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

Alison Coates,Robert H. Eckel,Dalan R. Jensen,Leslie K. Pulawa

doi:10.1194/jlr.m600384-jlr200

Abstract

LPL and its specific physiological activator, apolipoprotein C-II (apoC-II), regulate the hydrolysis of triglycerides (TGs) from circulating TG-rich lipoproteins. Previously, we developed a skeletal muscle-specific LPL transgenic mouse that had lower plasma TG levels. ApoC-II transgenic mice develop hypertriglyceridemia attributed to delayed clearance. To investigate whether overexpression of LPL could correct this apoC-II-induced hypertriglyceridemia, mice with overexpression of human apoC-II (CII) were cross-bred with mice with two levels of muscle-specific human LPL overexpression (LPL-L or LPL-H). Plasma TG levels were 319 +/- 39 mg/dl in CII mice and 39 +/- 5 mg/dl in wild-type mice. Compared with CII mice, apoC-II transgenic mice with the higher level of LPL overexpression (CIILPL-H) had a 50% reduction in plasma TG levels (P = 0.013). Heart LPL activity was reduced by approximately 30% in mice with the human apoC-II transgene, which accompanied a more modest 10% decrease in total LPL protein. Overexpression of human LPL in skeletal muscle resulted in dose-dependent reduction of plasma TGs in apoC-II transgenic mice. Along with plasma apoC-II concentrations, heart and skeletal muscle LPL activities were predictors of plasma TGs. These data suggest that mice with the human apoC-II transgene may have alterations in the expression/activity of endogenous LPL in the heart. Furthermore, the decrease of LPL activity in the heart, along with the inhibitory effects of excess apoC-II, may contribute to the hypertriglyceridemia observed in apoC-II transgenic mice.

Highlights

LPL and its specific physiological activator, apolipoprotein C-II, regulate the hydrolysis of triglycerides (TGs) from circulating TG-rich lipoproteins
To determine whether the reduction in LPL activity in heart of mice carrying the human apolipoprotein C-II (apoC-II) transgene was the result of decreased endogenous LPL expression, murine LPL mRNA levels were determined by real-time RT-PCR in mice from the CII3LPL-H cross
Contrary to the LPL activity results, mouse LPL mRNA was upregulated in heart of CII and CIILPL-H mice compared with WT and LPL mice (ANOVA; P 5 0.047), and when pairwise comparisons were performed, the increase in LPL mRNA of CIILPL-H compared with WT mice was just above the level set for significance (Tukey; P 5 0.051)

Summary

Introduction

LPL and its specific physiological activator, apolipoprotein C-II (apoC-II), regulate the hydrolysis of triglycerides (TGs) from circulating TG-rich lipoproteins. To investigate whether overexpression of LPL could correct this apoC-II-induced hypertriglyceridemia, mice with overexpression of human apoC-II (CII) were cross-bred with mice with two levels of muscle-specific human LPL overexpression (LPL-L or LPL-H). Overexpression of human LPL in skeletal muscle resulted in dose-dependent reduction of plasma TGs in apoC-II transgenic mice. Reduction of plasma triglycerides in apolipoprotein C-II transgenic mice overexpressing lipoprotein lipase in muscle. Overexpressing human apoC-II in mice resulted in hypertriglyceridemia attributed to the delayed clearance of VLDL TGs, and human apoC-II levels were highly correlated with plasma TGs [11]. Our laboratory has previously generated a transgenic mouse with muscle-specific LPL overexpression that results in a reduction of plasma TG levels [1, 2]. This article is available online at http://www.jlr.org

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Conclusion