Role of Peroxisome Proliferator-Activated Receptor-α in the Mechanism Underlying Changes in Renal Pyruvate Dehydrogenase Kinase Isoform 4 Protein Expression in Starvation and after Refeeding

• Published in: Archives of biochemistry and biophysics 2001-11, Vol.395 (2), p.246-252
• Main Authors: Sugden, Mary C., Bulmer, Karen, Gibbons, Geoffrey F., Holness, Mark J.
• Format: Article
• Language: English
• Subjects: Animals; Female; Food Deprivation; Immunoblotting; kidney; Kidney - enzymology; Lipid Metabolism; Mice; Mice, Transgenic; peroxisome proliferator-activated receptor-α; Protein Binding; Protein Isoforms; Protein Kinases - chemistry; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases; pyruvate dehydrogenase complex; pyruvate dehydrogenase kinase; rat; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Cytoplasmic and Nuclear - physiology; starvation; Time Factors; Transcription Factors - metabolism; Transcription Factors - physiology; Tricarboxylic Acids - metabolism; Up-Regulation
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1006/abbi.2001.2586

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-α (PPARα), plays a pivotal role in the cellular metabolic response to fatty acids and is abundant in kidney. In the present study we used PPARα null mice to examine the potential role of PPARα 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 PPARα null mice. The present results define a critical role for PPARα in renal adaptation to fasting, and identify PDK4 as a downstream target of PPARα 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 β-oxidation into the TCA cycle, allowing adequate ATP production for brisk rates of gluconeogenesis.