Journal article
PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation
The Journal of clinical investigation, Vol.120(10), pp.3443-3454
10/01/2010
DOI: 10.1172/JCI40905
PMID: 20852389
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.
Details
- Title: Subtitle
- PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation
- Creators
- Ni-Huiping Son - Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USAShuiqing Yu - Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USAJoseph Tuinei - Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USAKotaro Arai - Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USAHiroko Hamai - Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USAShunichi Homma - Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USAGerald I Shulman - Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USAE. Dale Abel - Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USAIra J Goldberg - Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.120(10), pp.3443-3454
- DOI
- 10.1172/JCI40905
- PMID
- 20852389
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Language
- English
- Date published
- 10/01/2010
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984025269702771
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