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On the pivotal role of PPARa in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury
Author(s) -
Cole Mark A.,
Jamil Amira H. Abd,
Heather Lisa C.,
Murray Andrew J.,
Sutton Elizabeth R.,
Slingo Mary,
SebagMontefiore Liam,
Tan Suat Cheng,
Aksentijević Dunja,
Gildea Ottilie S.,
Stuckey Daniel J.,
Yeoh Kar Kheng,
Carr Carolyn A.,
Evans Rhys D.,
Aasum Ellen,
Schofield Christopher J.,
Ratcliffe Peter J.,
Neubauer Stefan,
Robbins Peter A.,
Clarke Kieran
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201500094r
Subject(s) - ucp3 , endocrinology , hypoxia (environmental) , medicine , glycolysis , uncoupling protein , beta oxidation , peroxisome proliferator activated receptor , peroxisome , biology , fatty acid , receptor , metabolism , chemistry , biochemistry , oxygen , adipose tissue , organic chemistry , brown adipose tissue
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 PPARa 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. Ahigh‐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 PPARa‐deficient (PPARa ‐/‐ ) 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. FASEB J. 30, 2684‐2697 (2016). www.fasebj.org