Abstract
BackgroundThe novel organic cation transporter 2 (OCTN2) is the physiologically most important carnitine transporter in tissues and is responsible for carnitine absorption in the intestine, carnitine reabsorption in the kidney and distribution of carnitine between tissues. Genetic studies clearly demonstrated that the mouse OCTN2 gene is directly regulated by peroxisome proliferator-activated receptor α (PPARα). Despite its well conserved role as an important regulator of lipid catabolism in general, the specific genes under control of PPARα within each lipid metabolic pathway were shown to differ between species and it is currently unknown whether the OCTN2 gene is also a PPARα target gene in pig, cattle, and human. In the present study we examined the hypothesis that the porcine, bovine, and human OCTN2 gene are also PPARα target genes.ResultsUsing positional cloning and reporter gene assays we identified a functional PPRE, each in the intron 1 of the porcine, bovine, and human OCTN2 gene. Gel shift assay confirmed binding of PPARα to this PPRE in the porcine, bovine, and the human OCTN2 gene.ConclusionsThe results of the present study show that the porcine, bovine, and human OCTN2 gene, like the mouse OCTN2 gene, is directly regulated by PPARα. This suggests that regulation of genes involved in carnitine uptake by PPARα is highly conserved across species.
Highlights
The novel organic cation transporter 2 (OCTN2) is the physiologically most important carnitine transporter in tissues and is responsible for carnitine absorption in the intestine, carnitine reabsorption in the kidney and distribution of carnitine between tissues
Like in porcine and human cells, we have recently shown that mRNA and protein levels of OCTN2 are increased by the peroxisome proliferator-activated receptor α (PPARα) agonist WY-14,643 about 2.2- and 1.4-fold, respectively, in bovine MDBK cells and co-treatment of MDBK cells with a PPARα antagonist abolished the effect of WY-14,643 [22] suggesting that bovine OCTN2 is probably regulated directly by PPARα
The present results show that the intron 1 of porcine, bovine, and human OCTN2 gene contains a functional peroxisome proliferator response elements (PPRE) which is critical for PPARα-dependent regulation of the OCTN2 gene
Summary
The novel organic cation transporter 2 (OCTN2) is the physiologically most important carnitine transporter in tissues and is responsible for carnitine absorption in the intestine, carnitine reabsorption in the kidney and distribution of carnitine between tissues. Genetic studies clearly demonstrated that the mouse OCTN2 gene is directly regulated by peroxisome proliferator-activated receptor α (PPARα). Carnitine plays an important role in lipid and energy metabolism by acting as a shuttling molecule for the translocation of long-chain fatty acids from the cytosol into the mitochondrial matrix, where β-oxidation occurs. The mechanism underlying this phenomenon remained obscure until it was demonstrated many years later that activation of hepatic PPARα, which is induced by both energy deprivation and fibrate treatment, causes an up-regulation of the novel organic cation transporter 2 (OCTN2) in liver cells [14]. It could be shown recently that the mouse gene encoding OCTN2 contains a functional PPRE in intron 1 and is directly activated by PPARα [8]
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