| PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation. | |
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MedLine Citation:
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PMID: 20852389 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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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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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-09-13 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 120 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-05 Completed Date: 2010-11-10 Revised Date: 2012-03-23 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 3443-54 Citation Subset: AIM; IM |
Affiliation:
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Division of Preventive Medicine and Nutrition, Columbia University, New York, New York 10032, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis Fatty Acids / metabolism* Fatty Acids, Nonesterified / blood Lipid Metabolism Lipids / toxicity* Mice Mice, Inbred C57BL Mice, Inbred CBA Myocardium / metabolism* Myocytes, Cardiac / ultrastructure Oxidation-Reduction PPAR alpha / deficiency, physiology* PPAR gamma / physiology* Reactive Oxygen Species / metabolism Triglycerides / biosynthesis |
| Grant Support | |
ID/Acronym/Agency:
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HL45095/HL/NHLBI NIH HHS; HL73029/HL/NHLBI NIH HHS; P50 HL077113/HL/NHLBI NIH HHS; R01 HL045095-21/HL/NHLBI NIH HHS; R01 HL045095-22/HL/NHLBI NIH HHS; U01HL087947/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Fatty Acids; 0/Fatty Acids, Nonesterified; 0/Lipids; 0/PPAR alpha; 0/PPAR gamma; 0/Reactive Oxygen Species; 0/Triglycerides |
| Comments/Corrections | |
Comment In:
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Cell Metab. 2010 Dec 1;12(6):555-6
[PMID:
21109186
]
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Erratum In:
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J Clin Invest. 2010 Dec 1;120(12):4583 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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