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

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 wildtype 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. Heart and skeletal muscle are among the lowest cholesterol biosynthetic tissues of the body (1) and, as for many tissues, circulating lipoproteins probably supply muscle cholesterol needs. Although this could occur via LDL receptor uptake, a curious aspect of the regulation of the fibroblast LDL receptor is that the receptor is half maximally saturated by subphysiologic levels (30 mg/ml) of LDL cholesterol (2). Thus, if the fibroblast is representative of muscles, the LDL receptor should be downregulated and an alternative process must lead to the acquisition of plasma LDL. Such a conclusion is consistent with studies showing that heart and skeletal muscle take up very little LDL from the circulation (3, 4).There are likely to be other pathways mediating cellular cholesterol uptake by heart and skeletal muscle. These pathways could involve the uptake of cholesterol from lipoproteins other than LDL or could include the selective uptake of LDL cholesterol (i.e., acquisition of lipid exclusive of whole particles). In the case of HDL, selective uptake of lipoprotein lipids occurs via scavenger receptors (5). 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.Cells must modulate cholesterol content to prevent lipid intoxication. The liver eliminates excess cholesterol into the bile; adipose tissue can store excess cholesterol within lipid droplets. Muscles might need to more finely regulate cholesterol uptake. Inappropriate upregulation of LDL receptors leading to excess cellular cholesterol could be pathologic (8). Similarly, receptor-mediated increased muscle uptake of lipoproteins could lead to potentially toxic levels of phospholipids, TGs, and fatty acids.Previously, we created mice that develo...

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“…It has also been found that skeletal muscle LDL‐C uptake is increased in statin‐treated mice overexpressing lipoprotein lipase (LPL) in skeletal muscle (Yokoyama et al. 2007). These data suggest that LPL [the primary enzyme for intravascular hydrolysis of triglyceride (TG)], could also be an important mediator of skeletal muscle cholesterol uptake.…”

New Aspects of Cellular Cholesterol Regulation on Blood Glucose Control—Review and Perspective on the Impact of Statin Medications on Metabolic Health

“…It has also been found that skeletal muscle LDL-C uptake is increased in statin-treated mice overexpressing LPL in skeletal muscle. 47 These data suggest that LPL (the primary enzyme for intravascular hydrolysis of triglyceride [TG]), could also be an important mediator of skeletal muscle cholesterol uptake by increasing the availability of LDLC from VLDL/IDL conversion. Notably, statins increase LPL serum mass and activity in T2D.…”

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“…10,14 In rat cardiomyocytes, HMGCR activity has been suggested to account for the intracellular cholesterol levels, 18,19 although cardiomyocytes may acquire cholesterol from the circulation. 20 Recent metabolites profile studies using mass spectrometry-based analysis combined with high-temperature gas chromatography show an 7-fold increase in cholesterol levels in hypertrophic cardiac tissues. 21 However, in our studies, mice fed chow supplemented with ≤1.5% cholesterol for 15 days did not exhibit significant differences in the magnitude of cardiac hypertrophy induced by Ang II (unpublished observations).…”