Effects of lipoprotein lipase and statins on cholesterol uptake into heart and skeletal muscle

Yunying Hu,Toru Seo,Ni Huiping Son,Ira J Goldberg,Reeba K Vikramadithyan,Robert H Eckel,Masayoshi Yokoyama,Taesik Park,Ayanna S Augustus,Rajasekhar Ramakrishnan,Leslie K Pulawa,Hiroaki Yagyu

doi:10.1194/jlr.m600301-jlr200

Abstract

Regulation of cholesterol metabolism in cultured cells and in the liver is dependent on actions of the LDL receptor. However, nonhepatic tissues have multiple pathways of cholesterol uptake. One possible pathway is mediated by LPL, an enzyme that primarily hydrolyzes plasma triglyceride into fatty acids. In this study, LDL uptake and tissue cholesterol levels in heart and skeletal muscle of wild-type and transgenic mice with alterations in LPL expression were assessed. Overexpression of a myocyte-anchored form of LPL in heart muscle led to increased uptake of LDL and greater heart cholesterol levels. Loss of LDL receptors did not alter LDL uptake into heart or skeletal muscle. To induce LDL receptors, mice were treated with simvastatin. Statin treatment increased LDL receptor expression and LDL uptake by liver and skeletal muscle but not heart muscle. Plasma creatinine phosphokinase as well as muscle mitochondria, cholesterol, and lipid droplet levels were increased in statin-treated mice overexpressing LPL in skeletal muscle. Thus, pathways affecting cholesterol balance in heart and skeletal muscle differ.

Highlights

Regulation of cholesterol metabolism in cultured cells and in the liver is dependent on actions of the LDL receptor
We created mice that develop a dilated cardiomyopathy and excess cholesterol in the heart [9]. These mice express a transgene for a cardiomyocyte-anchored form of human LPL; they are denoted LPLGPI because the Abbreviations: CPK, creatine phosphokinase; HMG-CoA-R, hydroxymethyl glutaryl coenzyme A reductase; Ldlr2/2, low density lipoprotein receptor knockout; LPLGPI, glycosylphosphatidyl-inositolanchored lipoprotein lipase; MCK, muscle creatinine kinase; Sterol-regulatory element binding protein 2 (Srebp2), sterol-regulatory element binding protein 2; TC, tyramine cellobiose; TG, triglyceride
We studied the importance of LPL and its regulation on LDL uptake in cardiac and skeletal muscle using animals with tissue-specific expression of LPL

Summary

Introduction

Regulation of cholesterol metabolism in cultured cells and in the liver is dependent on actions of the LDL receptor. The selective uptake of cholesterol from LDL can be mediated by LPL [6, 7], the primary enzyme responsible for intravascular hydrolysis of triglyceride (TG) This process might be especially important in skeletal and heart muscle that have robust LPL expression. We created mice that develop a dilated cardiomyopathy and excess cholesterol in the heart [9] These mice express a transgene for a cardiomyocyte-anchored form of human LPL; they are denoted LPLGPI because the Abbreviations: CPK, creatine phosphokinase; HMG-CoA-R, hydroxymethyl glutaryl coenzyme A reductase; Ldlr2/2, low density lipoprotein receptor knockout; LPLGPI, glycosylphosphatidyl-inositolanchored lipoprotein lipase; MCK, muscle creatinine kinase; Srebp, sterol-regulatory element binding protein 2; TC, tyramine cellobiose; TG, triglyceride

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