Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism.
Long-chain fatty acids (FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the significance of PPARalpha in FA-mediated expression has been demonstrated, the role of the PPARbeta/delta and PPARgamma isoforms in cardiac lipid metabolism is unknown. To explore the involvement of each of the PPAR isoforms, neonatal rat cardiomyocytes were exposed to FA or to ligands specific for either PPARalpha (Wy-14,643), PPARbeta/delta (L-165041, GW501516), or PPARgamma (ciglitazone and rosiglitazone). Their effect on FA oxidation rate, expression of metabolic genes, and muscle-type carnitine palmitoyltransferase-1 (MCPT-1) promoter activity was determined. Consistent with the PPAR isoform expression pattern, the FA oxidation rate increased in cardiomyocytes exposed to PPARalpha and PPARbeta/delta ligands, but not to PPARgamma ligands. Likewise, the FA-mediated expression of FA-handling proteins was mimicked by PPARalpha and PPARbeta/delta, but not by PPARgamma ligands. As expected, in embryonic rat heart-derived H9c2 cells, which only express PPARbeta/delta, the FA-induced expression of genes was mimicked by the PPARbeta/delta ligand only, indicating that FA also act as ligands for the PPARbeta/delta isoform. In cardiomyocytes, MCPT-1 promoter activity was unresponsive to PPARgamma ligands. However, addition of PPARalpha and PPARbeta/delta ligands dose-dependently induced promoter activity. Collectively, the present findings demonstrate that, next to PPARalpha, PPARbeta/delta, but not PPARgamma, plays a prominent role in the regulation of cardiac lipid metabolism, thereby warranting further research into the role of PPARbeta/delta in cardiac disease.
Gilde
Andries J
AJ
Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
van der Lee
Karin A J M
KA
Willemsen
Peter H M
PH
Chinetti
Giulia
G
van der Leij
Feike R
FR
van der Vusse
Ger J
GJ
Staels
Bart
B
van Bilsen
Marc
M
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology; D050356:Lipid Metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation
D005227:Fatty Acids; D020033:Protein Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors