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PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation
Ni-Huiping Son1, Shuiqing Yu, Joseph Tuinei
1Division of Preventive Medicine and Nutrition, Columbia University, New York, New York 10032, USA.
Abstract:
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.
Insights
Excess lipid accumulation in the heart impairs function, but a new study shows enhanced fatty acid metabolism can preserve heart function. This research suggests acylcarnitines, not just lipids, may cause heart toxicity.
Area of Science:
- Cardiology
- Metabolic Syndrome
- Molecular Biology
Background:
- Excessive lipid accumulation in the heart is linked to reduced cardiac function.
- This dysfunction is often attributed to toxic lipid effects or excessive fatty acid oxidation (FAO).
- PPARγ activation is implicated in heart failure, particularly in metabolic syndrome.
Purpose of the Study:
- To investigate the effects of modulating PPARγ and PPARα expression on cardiac lipid metabolism and function.
- To explore the mechanisms underlying cardiotoxicity in the context of altered lipid handling.
Main Methods:
- Mice with dilated cardiomyopathy (due to cardiomyocyte PPARγ overexpression) were crossed with PPARα-deficient mice.
- Analysis of PPAR-regulated gene expression, fatty acid uptake and oxidation, and triacylglycerol synthesis.
- Assessment of cardiac lipid levels (triglyceride, diacylglycerol, ceramide), long-chain fatty acyl-CoA, and acylcarnitine content.
- Evaluation of protein kinase C (PKC) activation, apoptosis, reactive oxygen species (ROS) levels, and endoplasmic reticulum stress.
Main Results:
- The cross resulted in enhanced expression of genes involved in fatty acid uptake, oxidation, and triacylglycerol synthesis.
- Despite increased fatty acid oxidation and triacylglycerol droplet size, cardiac function was preserved and survival improved.
- Cardiac triglyceride, diacylglycerol, and ceramide levels were not significantly decreased.
- Increased long-chain fatty acyl-CoA and decreased acylcarnitine levels were observed.
- Reduced activation of PKCα and PKCδ, apoptosis, ROS, and endoplasmic reticulum stress were noted.
Conclusions:
- Partitioning of lipids towards storage and oxidation can reverse cardiotoxicity, even with elevated diacylglycerol and ceramide.
- Acylcarnitines, rather than diacylglycerol or ceramide, may play a critical role in lipid-induced cardiotoxicity.
- This study offers new insights into managing heart conditions associated with metabolic dysfunction.
