Mouse OCTN2 is directly regulated by peroxisome proliferator-activated receptor α (PPARα) via a PPRE located in the first intron

Gaiping Wen , Robert Ringseis , Klaus Eder

Recent studies provided strong evidence to suggest that OCTN2 is a direct target gene of PPARα. However, subsequent studies failed to demonstrate a functional peroxisome proliferator response element (PPRE) in the promoter region of the OCTN2 gene. In the present study we hypothesized that the OCTN2 gene is transcriptionally induced by PPARα via a functional PPRE located in the first intron. -analysis of the first intron of mouse OCTN2 revealed eleven putative PPRE with high similarity to the consensus PPRE. In addition, reporter gene assays using a mouse OCTN2 intron reporter construct containing a cluster of three partially overlapping PPRE (PPREint-1-8-10) revealed a marked response to exogenous mouse PPARα/RXRα and subsequent stimulation with PPARα agonist WY- 14,643. Introduction of a selective mutation in either PPRE8 or PPRE10 in the PPREint-1-8- 10 reporter constructs caused a substantial loss of the responsiveness to PPARα activation, but a selective mutation in PPRE1 resulted in a complete loss of responsiveness to PPARα activation. Moreover, gel shift assays revealed binding of PPARα/RXRα heterodimer to the PPRE1 of mouse OCTN2 first intron. In conclusion, the present study shows that mouse OCTN2 is a direct target gene of PPARα and that transcriptional up-regulation of OCTN2 by PPARα is likely mediated via PPRE1 in its first intron.

Mots clés: Peroxisome proliferator-activated receptor α (PPARα); Carnitine; Novel organic cation transporter 2 (OCTN2)

Gaiping Wen, Robert Ringseis, Klaus Eder. Mouse OCTN2 is directly regulated by peroxisome proliferator-activated receptor α (PPARα) via a PPRE located in the first intron. Biochemical Pharmacology, 2009, 79 (5), pp.768. ⟨10.1016/j.bcp.2009.10.002⟩. ⟨hal-00547634⟩