The role of peroxisome proliferator-activated receptor alpha in transcriptional regulation of novel organic cation transporters.
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 (PPARalpha), the hypothesis has been raised that activation of this nuclear receptor could lead to an up-regulation of novel organic cation transporters (OCTN) which facilitate transport of carnitine and several other organic cations through membranes. Studies in rodents and pigs have indeed shown that treatment with PPARalpha agonists causes an up-regulation of OCTN2 in liver and other tissues such as muscle and small intestine. Additional experiments with PPARalpha-null and corresponding wild-type mice, which were either fasted or treated with the high-affinity PPARalpha agonist WY-14,643, revealed that transcriptional up-regulation of OCTN2 and OCTN3 is dependent on PPARalpha. An up-regulation of OCTN by PPARalpha activation could be regarded as a means to supply cells with sufficient carnitine required for transport of excessive amounts of fatty acids into the mitochondrion during fasting, and therefore plays an important role in the adaptive response of the metabolism to fasting. Due to the strong similarities in the gene response to PPARalpha agonists and the similar metabolic features and anatomic conditions between pigs and humans, it is likely that pharmacological PPARalpha agonists exert similar effects in humans.
Eder
Klaus
K
Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-Universität Giessen, Heinrich-Buff-Ring 26-32, Giessen, Germany. klaus.eder@ernaehrung.uni-giessen.de
Ringseis
Robert
R
D000818:Animals; D002331:Carnitine / Q000378:metabolism; D006801:Humans; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D013045:Species Specificity; D013217:Starvation; D014158:Transcription, Genetic
D027701:Organic Cation Transport Proteins; D047493:PPAR alpha; D002331:Carnitine