Role of peroxisome proliferator-activated receptor-alpha in the mechanism underlying changes in renal pyruvate dehydrogenase kinase isoform 4 proteinexpression in starvation and after refeeding

The pyruvate dehydrogenase complex (PDC) occupies a strategic role in renal intermediary metabolism, via partitioning of pyruvate flux between oxidati on and entry into the gluconeogenic pathway. Inactivation of PDC via activa tion of pyruvate dehydrogenase kinases (PDKs), which catalyze PDC phosphory lation, occurs secondary to increased fatty acid oxidation (FAO). In kidney , inactivation of PDC after prolonged starvation is mediated by up-regulati on of the protein expression of two PDK isoforms, PDK2 and PDK4. The lipid- activated transcription factor, peroxisome proliferator-activated receptor- alpha (PPAR alpha), plays a pivotal role in the cellular metabolic response to fatty acids and is abundant in kidney. In the present study we used PPA R alpha null mice to examine the potential role of PPAR alpha in regulating renal PDK protein expression. In wild-type mice, fasting (24 h) induced ma rked up-regulation of the protein expression of PDK4, together with modest up-regulation of PDK2 protein expression. In striking contrast, renal prote in expression of PDK4 was only marginally induced by fasting in PPAR alpha null mice. The present results define a critical role for PPAR alpha in ren al adaptation to fasting, and identify PDK4 as a downstream target of PPAR alpha activation in the kidney. We propose that specific up-regulation of r enal PDK4 protein expression in starvation, by maintaining PDC activity rel atively low, facilitates pyruvate carboxylation to oxaloacetate and therefo re entry of acetyl-CoA derived from FA beta -oxidation into the TCA cycle, allowing adequate ATP production for brisk rates of gluconeogenesis. (C) 20 01 Academic Press.