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J. Biol. Chem., Vol. 277, Issue 6, 4098-4103, February 8, 2002
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From the Peroxisome
proliferator-activated receptor
A Role for Peroxisome Proliferator-activated Receptor
(PPAR) in the Control of Cardiac Malonyl-CoA Levels
REDUCED FATTY ACID OXIDATION RATES AND INCREASED GLUCOSE
OXIDATION RATES IN THE HEARTS OF MICE LACKING PPAR
ARE ASSOCIATED
WITH HIGHER CONCENTRATIONS OF MALONYL-CoA AND REDUCED EXPRESSION OF
MALONYL-CoA DECARBOXYLASE*
§,,,,,
, and**
Departments of Pharmacology and Pediatrics,
University of Alberta, Edmonton, Alberta T6G 2S2, Canada, the
¶ Department of Pharmacology and Therapeutics, University of
Calgary, Calgary, Alberta T2N 4N1, Canada and the Center
for Cardiovascular Research, Cardiovascular Division, Washington
University School of Medicine, St. Louis, Missouri 63110
(PPAR) is a nuclear receptor
transcription factor that has an important role in controlling cardiac
metabolic gene expression. We determined whether mice lacking PPAR
(PPAR (
/) mice) have alterations in cardiac energy metabolism.
Rates of palmitate oxidation were significantly decreased in isolated
working hearts from PPAR (/) hearts compared with hearts from
age-matched wild type mice (PPAR (+/+) 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 PPAR (/) hearts was associated with increased levels of cardiac malonyl-CoA compared with PPAR (+/+) 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 PPAR. Expression of
both mRNA and protein as well as the activity of malonyl-CoA
decarboxylase, which degrades malonyl-CoA, were significantly decreased
in the PPAR (/) 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 PPAR (/) and PPAR (+/+)
hearts, suggesting that the increase in glycolysis and glucose
oxidation in the PPAR 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 PPAR 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.
*
This work was funded by grants from the Canadian Diabetes
Association and the Canadian Institutes for Health Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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