ABC half-transporter relative gene expression and metabolism of conjugated linoleic acid in X- linked Adrenoleukodystrophy

X−linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by altered VLCFA peroxisomal beta-oxidation. The mutated gene ABCD1 codes for the peroxisomal ABC half-transporter ALDP. Because overexpression of ABCD1’s closest homologue, ABCD2, has been shown to partially compensate for ALDP deficiency, there is particular interest in developing approaches that increase ABCD2 expression . One of the possible candidates is conjugated linoleic acid (CLA), which is a naturally ocurring fatty acid (FA) and a good ligand for PPAR-alpha , a regulator of peroxisomal beta-oxidation key enzymes. Moreover CLA is partially metabolized by the peroxisomes. Skin-fibroblasts obtained from controls and X-ALD patients, were grown in standard conditions. CLA isomers and fenofibrate were supplemented separately to the cells for different times. Gene expression was evaluated by real-time PCR . CLA metabolites were measured by HPLC-DAD-MS. In untreated conditions ABCD2 was upregulated in X-ALD fibroblasts towards the controls. Fenofibrate, used as positive control, increased both PPAR-alpha and ABCD2 mRNA levels after 18 h. CLA isomers differently induced PPAR-alpha and ABCD2 mRNA, the latter was particularly enhanced after 24 and 48h in X-ALD fibroblasts. The higher induction of PPAR-alpha and ABCD2 mRNA by CLA was associated to its metabolism to Conjugated 16:2 , derived by its peroxisomal beta-oxidation . The basal ABCD2 upregulation in X-ALD fibroblasts towards the controls clearly indicated a partial physiological compensation for ALDP deficiency. CLA isomers were able to modulate PPARalpha and ABCD2 relative gene expression.