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

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 31P magnetic resonance spectroscopy (MRS), and glycolysis and fatty acid oxidation were measured using [3H] 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.

Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration—probing the role of PPARα

“…This was indicated by a fall in CS-corrected respiration rates for fatty acid substrates and also by substrate control ratios expressing FAO as a proportion of maximal oxphos or in relation to pyruvate-supported oxphos. This effect of hypoxia was seen in the hearts of WT but not Ppara −/− mice, indicating that the hypoxic suppression of FAO is primarily driven by decreased PPARα activity, as suggested previously (8). There was no specific effect on CPT1-supported FAO (with palmitoyl CoA plus malate) compared with CPT1-independent respiration (with palmitoyl carnitine plus malate), indicating that although CPT1 activity may be down-regulated, there are also effects of a similar magnitude downstream, probably on β-oxidation capacity, although in agreement with our previous work (9) HADH activity was unaltered by hypoxia.…”

“…Decreased PPARα transcriptional activity appears to be a key aspect of the cardiac metabolic response to hypoxia (8, 9), so here we sought to understand whether PPARα plays a role in mediating the protective effect of NO 3 − in the hypoxic heart.…”

“…In the hypoxic rodent heart, the transcriptional activity of PPARα is down-regulated in association with a suppression of FAO (8, 9) and an increase in glycolysis (8). As such, the cardiac metabolic phenotype of hypoxic mice resembles that of mice without PPAR receptor ( Ppara −/− ), and notably, no further suppression of FAO occurs in Ppara −/− mice following exposure to hypoxia (8).…”

“…As such, the cardiac metabolic phenotype of hypoxic mice resembles that of mice without PPAR receptor ( Ppara −/− ), and notably, no further suppression of FAO occurs in Ppara −/− mice following exposure to hypoxia (8). Moreover, although hypoxic exposure results in an impaired cardiac energetic reserve in both humans (10) and rodents (8), increasing PPARα activity and FAO in hypoxic mice through a high-fat diet did not improve energetics and in fact worsened contractile function (8), thus it appears that down-regulation of FAO in the hypoxic heart is protective. Recent work, however, has suggested that both FAO and energetics might be preserved in hypoxic tissues by dietary supplementation with inorganic nitrate (NO 3 − ).…”

The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high-energy phosphate metabolism

“…In our study, the increase in glycolytic flux was greater than that of pyruvate dehydrogenase (PDH) flux, meaning that the decrease in palmitate oxidation did not reach significance. However, following hypoxia, mouse hearts have been shown to have increased glycolytic flux, increased lactate production, and significantly decreased fatty acid oxidation (11). …”