PPARγ-induced cardiolipotoxicity in mice is ameliorated by
PPARα deficiency despite increases in fatty acid
oxidation |
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Authors: | Ni-Huiping Son Shuiqing Yu Joseph Tuinei Kotaro Arai Hiroko Hamai Shunichi Homma Gerald I Shulman E Dale Abel Ira J Goldberg |
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Institution: | 1.Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USA. 2.Division of Endocrinology Metabolism and Diabetes and Program in Molecular Medicine, University of Utah, Salt Lake City, Utah, USA. 3.Division of Cardiology, Department of Medicine, and 4.Department of Pathology and Cell Biology, Columbia University, New York, New York, USA. 5.Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. |
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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. |
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