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FASEB J. 2016 Aug;30(8):2684-97. doi: 10.1096/fj.201500094R. Epub 2016 Apr 21.

On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury.

Author information

1
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
2
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom;
3
Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom; and.
4
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
5
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; kieran.clarke@dpag.ox.ac.uk.

Abstract

The role of peroxisome proliferator-activated receptor α (PPARα)-mediated metabolic remodeling in cardiac adaptation to hypoxia has yet to be defined. Here, mice were housed in hypoxia for 3 wk before in vivo contractile function was measured using cine MRI. In isolated, perfused hearts, energetics were measured using (31)P magnetic resonance spectroscopy (MRS), and glycolysis and fatty acid oxidation were measured using [(3)H] labeling. Compared with a normoxic, chow-fed control mouse heart, hypoxia decreased PPARα expression, fatty acid oxidation, and mitochondrial uncoupling protein 3 (UCP3) levels, while increasing glycolysis, all of which served to maintain normal ATP concentrations ([ATP]) and thereby, ejection fractions. A high-fat diet increased cardiac PPARα expression, fatty acid oxidation, and UCP3 levels with decreased glycolysis. Hypoxia was unable to alter the high PPARα expression or reverse the metabolic changes caused by the high-fat diet, with the result that [ATP] and contractile function decreased significantly. The adaptive metabolic changes caused by hypoxia in control mouse hearts were found to have occurred already in PPARα-deficient (PPARα(-/-)) mouse hearts and sustained function in hypoxia despite an inability for further metabolic remodeling. We conclude that decreased cardiac PPARα expression is essential for adaptive metabolic remodeling in hypoxia, but is prevented by dietary fat.-Cole, M. A., Abd Jamil, A. H., Heather, L. C., Murray, A. J., Sutton, E. R., Slingo, M., Sebag-Montefiore, L., Tan, S. C., Aksentijević, D., Gildea, O. S., Stuckey, D. J., Yeoh, K. K., Carr, C. A., Evans, R. D., Aasum, E., Schofield, C. J., Ratcliffe, P. J., Neubauer, S., Robbins, P. A., Clarke, K. On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury.

KEYWORDS:

31P MRS; HIF; cardiac contractile function; myocardial energy metabolism; substrate metabolism

PMID:
27103577
PMCID:
PMC5072355
DOI:
10.1096/fj.201500094R
[Indexed for MEDLINE]
Free PMC Article

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