Control of cardiac pyruvate dehydrogenase activity in peroxisome proliferator-activated receptor-alpha transgenic mice.
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. Because the transcriptional regulator peroxisome proliferator-activated receptor (PPAR)-alpha increases PDK expression in some tissues, we examined what role PPAR-alpha has in regulating glucose oxidation in hearts from mice overexpressing PPAR-alpha (MHC-PPAR-alpha mice). Glucose oxidation rates were decreased in isolated working hearts from MHC-PPAR-alpha mice compared with wild-type littermates (428 +/- 113 vs. 771 +/- 63 nmol x g dry weight-1x 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-alpha and wild-type animals, even though the expression of the PDK isoform PDK1 was increased in MHC-PPAR-alpha mice. Glucose oxidation rates in both MHC-PPAR-alpha and wild-type mouse hearts were decreased after 48-h fasting (which increases PPAR-alpha expression) or by treatment of mice with the PPAR-alpha agonist WY-14,643 for 1 wk. 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-alpha activation decreases glucose oxidation in hearts mainly by decreasing the 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.
Hopkins
Teresa A
TA
Departments of Pharmacology and Pediatrics, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Sugden
Mary C
MC
Holness
Mark J
MJ
Kozak
Ray
R
Dyck
Jason R B
JR
Lopaschuk
Gary D
GD
D000818:Animals; D002952:Citric Acid Cycle / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D015151:Immunoblotting; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D009206:Myocardium / Q000201:enzymology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D011494:Protein Kinases / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines / Q000494:pharmacology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D005227:Fatty Acids; D007527:Isoenzymes; C000631433:Pdk1 protein, mouse; D011743:Pyrimidines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019308:Palmitic Acid; C006253:pirinixic acid; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D018995:Myosin Heavy Chains; D005947:Glucose