PPARα mediates transcriptional upregulation of novel organic cation transporters-2 and -3 and enzymes involved in hepatic carnitine synthesis

We tested the hypothesis that transcription of novel organic cation transporters (OCTNs) is directly regulated by peroxisome proliferator-activated receptor (PPAR)-alpha. Therefore, wild-type mice and mice deficient in PPAR alpha (PPAR alpha(-/-)) were treated with the PPARa agonist WY 14,643. Wild-type mice treated with WY 14,643 had a greater abundance of OCTN2 mRNA in their liver, muscle, kidney, and small intestine and a greater abundance of OCTN3 mRNA in kidney and small intestine than did untreated wild-type mice (P < 0.05). Moreover, wild-type mice treated with WY 14,643 had greater mRNA abundances of enzymes involved in hepatic carnitine synthesis (4-N-trimethylaminobutyraldehyde dehydrogenase, gamma-butyrobetaine dioxygenase) and increased carnitine concentrations in liver and muscle than did untreated wild-type mice (P < 0.05). Untreated PPAR alpha(-/-) mice had a lower abundance of OCTN2 mRNA in liver, kidney, and small intestine and lower carnitine concentrations in plasma, liver, and kidney than did untreated wild-type mice (P < 0.05). In PPAR alpha(-/-) mice, treatment with WY 14,643 did not influence mRNA abundance of OCTN2 and OCTN3 and carnitine concentrations in all tissues analyzed. The abundance of OCTN1 mRNA in all the tissues analyzed was not changed by treatment with WY 14,643 in wildtype or PPAR alpha(-/-) mice. In conclusion, this study shows that transcriptional upregulation of OCTN2 and OCTN3 in tissues and of enzymes involved in hepatic carnitine biosynthesis are mediated by PPAR alpha. It also shows that PPAR alpha mediates changes of whole-body carnitine homeostasis in mice by upregulation of carnitine transporters and enzymes involved in carnitine synthesis.