Evaluation of the therapeutic potential of PPARα agonists for X-linked adrenoleukodystrophy

Abstract

Adrenoleukodystrophy protein (ABCD1), a peroxisomal membrane protein, is mutated in patients affected by X-linked adrenoleukodystrophy (X-ALD). Adrenoleukodystrophy-related protein (ABCD2) is the closest relative of ABCD1. Pharmacological induction of ABCD2 gene expression has been proposed as a novel therapy strategy for X-ALD. Fibrates induce peroxisome proliferation and Abcd2 expression in rodent liver. Here we evaluate the possibility of using peroxisome proliferator-activated receptor α (PPARα) agonists for pharmacological induction of ABCD2 expression. In the liver of PPARα-deficient mice, both the constitutive and the fenofibrate-inducible Abcd2 gene expression was found to be PPARα-dependent. In the brain, PPARα-deficiency has no effect on Abcd2 expression. In mice orally treated with the novel, highly selective, and potent PPARα agonists GW 7647, GW 6867, and tetradecylthioacetic acid, Abcd2 expression was induced in liver and adrenal glands, but not in brain and testis. None of four putative PPREs identified in the 5 ′-flanking DNA and in intron 1 of the Abcd2 gene conferred fibrate response in luciferase reporter assays. Thus, although fibrate-mediated Abcd2 induction is PPARα-dependent, it appears to be an indirect mechanism. Within the mouse Abcd2 promoter, a putative sterol regulatory element (SRE) similar in sequence and position to the characterized SRE sequence of the human ABCD2 promoter, was identified. A PPARα dependent induction of the sterol regulatory-binding protein 2 (SREBP2) and a down-regulation of SREBP1c mRNA levels could be demonstrated after fenofibrate treatment of mice. Our results suggest that the PPARα agonist-mediated induction of Abcd2 expression seems to be indirect and possibly mediated by SREBP2.