A role for peroxisome proliferator-activated receptor alpha (PPARalpha ) in the control of cardiac malonyl-CoA levels: reduced fatty acid oxidation rates and increased glucose oxidation rates in the hearts of mice lacking PPARalpha are associated with higher concentrations of malonyl-CoA and reduced expression of malonyl-CoA decarboxylase.
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor transcription factor that has an important role in controlling cardiac metabolic gene expression. We determined whether mice lacking PPARalpha (PPARalpha (-/-) mice) have alterations in cardiac energy metabolism. Rates of palmitate oxidation were significantly decreased in isolated working hearts from PPARalpha (-/-) hearts compared with hearts from age-matched wild type mice (PPARalpha (+/+) mice), (62 +/- 12 versus 154 +/- 65 nmol/g dry weight/min, respectively, p < 0.05). This was compensated for by significant increases in the rates of glucose oxidation and glycolysis. The decreased fatty acid oxidation in PPARalpha (-/-) hearts was associated with increased levels of cardiac malonyl-CoA compared with PPARalpha (+/+) hearts (15.15 +/- 1.63 versus 7.37 +/- 1.31 nmol/g, dry weight, respectively, p < 0.05). Since malonyl-CoA is an important regulator of cardiac fatty acid oxidation, we also determined if the enzymes that control malonyl-CoA levels in the heart are under transcriptional control of PPARalpha. Expression of both mRNA and protein as well as the activity of malonyl-CoA decarboxylase, which degrades malonyl-CoA, were significantly decreased in the PPARalpha (-/-) hearts. In contrast, the expression and activity of acetyl-CoA carboxylase, which synthesizes malonyl-CoA and 5'-AMP-activated protein kinase, which regulates acetyl-CoA carboxylase, were not altered. Glucose transporter expression (GLUT1 and GLUT4) was not different between PPARalpha (-/-) and PPARalpha (+/+) hearts, suggesting that the increase in glycolysis and glucose oxidation in the PPARalpha null mice was not due to direct effects on glucose uptake but rather was occurring secondary to the decrease in fatty acid oxidation. This study demonstrates that PPARalpha is an important regulator of fatty acid oxidation in the heart and that this regulation of fatty acid oxidation may in part occur due to the transcriptional control of malonyl-CoA decarboxylase.
Campbell
Fiona M
FM
Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Kozak
Ray
R
Wagner
Alese
A
Altarejos
Judith Y
JY
Dyck
Jason R B
JR
Belke
Darrell D
DD
Severson
David L
DL
Kelly
Daniel P
DP
Lopaschuk
Gary D
GD
D000818:Animals; D001483:Base Sequence; D002262:Carboxy-Lyases / Q000378:metabolism*; D017931:DNA Primers; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006321:Heart / Q000502:physiology; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D008316:Malonyl Coenzyme A; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D005947:Glucose