Excess lipid accumulation in the heart is associated with decreased cardiac function in humans and in animal models. The reasons are unclear, but this is generally believed to result from either toxic effects of intracellular lipids or excessive fatty acid oxidation (FAO). PPARγ expression is increased in the hearts of humans with metabolic syndrome, and use of PPARγ agonists is associated with heart failure. Here, mice with dilated cardiomyopathy due to cardiomyocyte PPARγ overexpression were crossed with PPARα-deficient mice. Surprisingly, this cross led to enhanced expression of several PPAR-regulated genes that mediate fatty acid (FA) uptake/oxidation and triacylglycerol (TAG) synthesis. Although FA oxidation and TAG droplet size were increased, heart function was preserved and survival improved. There was no marked decrease in cardiac levels of triglyceride or the potentially toxic lipids diacylglycerol (DAG) and ceramide. However, long-chain FA coenzyme A (LCCoA) levels were increased, and acylcarnitine content was decreased. Activation of PKCα and PKCδ, apoptosis, ROS levels, and evidence of endoplasmic reticulum stress were also reduced. Thus, partitioning of lipid to storage and oxidation can reverse cardiolipotoxicity despite increased DAG and ceramide levels, suggesting a role for other toxic intermediates such as acylcarnitines in the toxic effects of lipid accumulation in the heart.
Objective There are several pathways that mediate the aberrant metabolism of glucose and that might induce greater vascular damage in the setting of diabetes. The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be anti-atherogenic. Methods and Results Atherosclerosis development was quantified in two lines of transgenic mice expressing human AR (hAR) crossed on the apoE knockout (apoE−/−) background. The transgenes were used to increase the normally low levels of this enzyme in wild type mice. Both generalized hAR overexpression and hAR expression via the Tie 2 promoter increased lesion size in streptozotocin (STZ) diabetic mice. In addition, pharmacologic inhibition of AR reduced lesion size. Conclusion Although in some settings AR expression might reduce levels of toxic aldehydes, transgenic expression of this enzyme within the artery wall leads to greater atherosclerosis.
Background: Lipoprotein lipase (LpL) is rate-limiting for plasma triglyceride lipolysis, but its importance in adipose development is uncertain. Results: Adipocyte LpL knock-out affected brown but not white fat composition. White fat was reduced when muscle LpL expression was increased. Conclusion: LpL distribution and adipose metabolism affect adipogenesis. Significance: All fat depots are not equally dependent on triglyceride uptake.
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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