A role for the human peroxisomal half-transporter ABCD3 in the oxidation of dicarboxylic acids

Peroxisomes play a major role in human cellular lipid metabolism, including fatty acid β-oxidation. Free fatty acids (FFAs) can enter peroxisomes through passive diffusion or by means of ATP binding cassette (ABC) transporters, including HsABCD1 (ALDP, adrenoleukodystrophy protein), HsABCD2 (ALDRP) and HsABCD3 (PMP70). The physiological functions of the different peroxisomal half-ABCD transporters have not been fully determined yet, but there are clear indications that both HsABCD1 and HsABCD2 are required for the breakdown of fatty acids in peroxisomes. Here we report that the phenotype of the pxa1/pxa2Δ yeast mutant, i.e. impaired oxidation of oleic acid, cannot only be partially rescued by HsABCD1, HsABCD2, but also by HsABCD3, which indicates that each peroxisomal half-transporter can function as homodimer. Fatty acid oxidation measurements using various fatty acids revealed that although the substrate specificities of HsABCD1, HsABCD2 and HsABCD3 are overlapping, they have distinctive preferences. Indeed, most hydrophobic C24:0 and C26:0 fatty acids are preferentially transported by HsABCD1, C22:0 and C22:6 by HsABCD2 and most hydrophilic substrates like long-chain unsaturated-, long branched-chain- and long-chain dicarboxylic fatty acids by HsABCD3. All these fatty acids are most likely transported as CoA esters. We postulate a role for human ABCD3 in the oxidation of dicarboxylic acids and a role in buffering fatty acids that are overflowing from the mitochondrial β-oxidation system