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1 Departments of Pharmacology/Pediatrics, University of Alberta, Edmonton, Alberta, Canada
2 Department of Diabetes and Metabolic Medicine, University of London, London, United Kingdom
* To whom correspondence should be addressed. E-mail: gary.lopaschuk{at}ualberta.ca.
The pyruvate dehydrogenase enzyme complex (PDC) is rate-limiting for glucose oxidation in the heart. Inhibition of PDC by end-product feedback and phosphorylation by pyruvate dehydrogenase kinase (PDK) operate in concert to
inhibit PDC activity. Since the transcriptional regulator peroxisome proliferator activated receptor alpha (PPAR
) increases PDK expression in some tissues, we
examined what role PPAR has in regulating glucose oxidation in hearts from mice over-expressing PPAR (MHC-PPAR). Glucose oxidation rates were decreased in isolated working hearts from MHC-PPARa mice compared to wildtype littermates (428±113 vs. 771±63 nmol.g dry weight-1 .min-1, respectively), which was accompanied by a parallel increase in fatty acid oxidation. However, there was no difference in PDC activity between MHC-PPAR and wild-type animals, even though the expression of the PDK isoform, PDK1, was increased in MHC-PPAR mice. Glucose oxidation rates in both MHC-PPAR and wild-type mouse hearts were decreased following 48 hour fasting (which increases PPAR expression), or by treatment of mice with the PPAR agonist WY 14,643 for one week. Despite this, PDC activity in both animal groups was not altered. Taken together, these data suggest that glucose oxidation rates in the heart can be dramatically altered independent of PDK phosphorylation and inhibition of PDC by PDK. It also suggests that PPAR activation decreases glucose oxidation in the hearts mainly by decreasing flux of pyruvate through PDC due to negative feedback of PDC by fatty acid oxidation reaction products, rather than by the phosphorylated state of the PDC complex.
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