Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart

J Clin Invest. 2007 Dec;117(12):3930-9. doi: 10.1172/JCI32578.

Abstract

In the diabetic heart, chronic activation of the PPARalpha pathway drives excessive fatty acid (FA) oxidation, lipid accumulation, reduced glucose utilization, and cardiomyopathy. The related nuclear receptor, PPARbeta/delta, is also highly expressed in the heart, yet its function has not been fully delineated. To address its role in myocardial metabolism, we generated transgenic mice with cardiac-specific expression of PPARbeta/delta, driven by the myosin heavy chain (MHC-PPARbeta/delta mice). In striking contrast to MHC-PPARalpha mice, MHC-PPARbeta/delta mice had increased myocardial glucose utilization, did not accumulate myocardial lipid, and had normal cardiac function. Consistent with these observed metabolic phenotypes, we found that expression of genes involved in cellular FA transport were activated by PPARalpha but not by PPARbeta/delta. Conversely, cardiac glucose transport and glycolytic genes were activated in MHC-PPARbeta/delta mice, but repressed in MHC-PPARalpha mice. In reporter assays, we showed that PPARbeta/delta and PPARalpha exerted differential transcriptional control of the GLUT4 promoter, which may explain the observed isotype-specific effects on glucose uptake. Furthermore, myocardial injury due to ischemia/reperfusion injury was significantly reduced in the MHC-PPARbeta/delta mice compared with control or MHC-PPARalpha mice, consistent with an increased capacity for myocardial glucose utilization. These results demonstrate that PPARalpha and PPARbeta/delta drive distinct cardiac metabolic regulatory programs and identify PPARbeta/delta as a potential target for metabolic modulation therapy aimed at cardiac dysfunction caused by diabetes and ischemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / genetics
  • Cardiomyopathies / genetics
  • Cardiomyopathies / metabolism*
  • Cardiomyopathies / pathology
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus / pathology
  • Fatty Acids / genetics
  • Fatty Acids / metabolism
  • Glucose / metabolism
  • Glucose Transporter Type 4 / biosynthesis
  • Glucose Transporter Type 4 / genetics
  • Mice
  • Mice, Transgenic
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / pathology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Oxidation-Reduction
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • PPAR delta / genetics
  • PPAR delta / metabolism*
  • PPAR-beta / genetics
  • PPAR-beta / metabolism*
  • Promoter Regions, Genetic / genetics

Substances

  • Fatty Acids
  • Glucose Transporter Type 4
  • PPAR alpha
  • PPAR delta
  • PPAR-beta
  • Slc2a4 protein, mouse
  • Glucose