Influence of pharmacological PPARα activators on carnitine homeostasis in proliferating and non-proliferating species

Former studies in rats demonstrated that starvation or treatment with the hypolipidemic drug clofibrate causes a marked increase in the concentration of carnitine in the liver. The molecular mechanisms underlying these phenomena in rats, however, have been largely unknown. Since both, fasting and clofibrate treatment lead to an activation of peroxisome proliferator-activated receptor alpha (PPAR alpha), a ligand-activated transcription factor that acts as an important regulator of lipid metabolism and energy homeostasis, the hypothesis has been raised that activation of this nuclear receptor is responsible for the alterations in carnitine homeostasis observed in rodents by either stimulating carnitine uptake or carnitine biosynthesis or both of them. The present review summarizes recent evidence from studies with rodents and pigs supporting the hypothesis that activation of PPAR alpha is responsible for the alterations in carnitine homeostasis previously observed. According to these novel results an essential role for PPAR alpha in the regulation of carnitine uptake and carnitine biosynthesis in rodents and pigs has been clearly established. Due to the strong similarities in the gene response to PPAR alpha agonists and the similar metabolic features and anatomic conditions between pigs and humans, it is likely that pharmacological PPAR alpha agonists exert similar effects in humans. (C) 2009 Elsevier Ltd. All rights reserved.