| First Author | Sugden MC | Year | 2001 |
| Journal | Arch Biochem Biophys | Volume | 395 |
| Issue | 2 | Pages | 246-52 |
| PubMed ID | 11697863 | Mgi Jnum | J:72837 |
| Mgi Id | MGI:2153671 | Doi | 10.1006/abbi.2001.2586 |
| Citation | Sugden MC, et al. (2001) Role of Peroxisome Proliferator-Activated Receptor-alpha in the Mechanism Underlying Changes in Renal Pyruvate Dehydrogenase Kinase Isoform 4 Protein Expression in Starvation and after Refeeding. Arch Biochem Biophys 395(2):246-52 |
| abstractText | The pyruvate dehydrogenase complex (PDC) occupies a strategic role in renal intermediary metabolism, via partitioning of pyruvate flux between oxidation and entry into the gluconeogenic pathway. Inactivation of PDC via activation of pyruvate dehydrogenase kinases (PDKs), which catalyze PDC phosphorylation, occurs secondary to increased fatty acid oxidation (FAO). In kidney, inactivation of PDC after prolonged starvation is mediated by up-regulation of the protein expression of two PDK isoforms, PDK2 and PDK4. The lipid-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPARalpha), plays a pivotal role in the cellular metabolic response to fatty acids and is abundant in kidney. In the present study we used PPARalpha null mice to examine the potential role of PPARalpha in regulating renal PDK protein expression. In wild-type mice, fasting (24 h) induced marked up-regulation of the protein expression of PDK4, together with modest up-regulation of PDK2 protein expression. In striking contrast, renal protein expression of PDK4 was only marginally induced by fasting in PPARalpha null mice. The present results define a critical role for PPARalpha in renal adaptation to fasting, and identify PDK4 as a downstream target of PPARalpha activation in the kidney. We propose that specific up-regulation of renal PDK4 protein expression in starvation, by maintaining PDC activity relatively low, facilitates pyruvate carboxylation to oxaloacetate and therefore entry of acetyl-CoA derived from FA beta-oxidation into the TCA cycle, allowing adequate ATP production for brisk rates of gluconeogenesis. Copyright 2001 Academic Press. |
