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1 UB - Université de Bourgogne 2 CSGA - Centre des Sciences du Goût et de l-Alimentation Dijon 3 Medical University of Vienna 4 UiO - University of Oslo

Abstract : X-linked adrenoleukodystrophy X-ALD is a rare neurodegenerative disorder characterized by the accumulation of very-long-chain fatty acids resulting from a β-oxidation defect. Oxidative stress and inflammation are also key components of the pathogenesis. X-ALD is caused by mutations in the ABCD1 gene, which encodes for a peroxisomal half ABC transporter predicted to participate in the entry of VLCFA-CoA into the peroxisome, the unique site of their β-oxidation. Two homologous peroxisomal ABC transporters, ABCD2 and ABCD3 have been proven to compensate for ABCD1 deficiency when overexpressed. Pharmacological induction of these target genes could therefore represent an alternative therapy for X-ALD patients. Since LXR activation was shown to repress ABCD2 expression, we investigated the effects of LXR antagonists in different cell lines. Cells were treated with GSK17 a LXR antagonist recently discovered from the GlaxoSmithKline compound collection, 22S-hydroxycholesterol 22S-HC, another LXR antagonist and 22R-HC an endogenous LXR agonist. We observed up-regulation of ABCD2, ABCD3 and CTNNB1 the gene encoding for β-catenin, which was recently demonstrated to induce ABCD2 expression in human HepG2 hepatoma cells and in X-ALD skin fibroblasts treated with LXR antagonists. Interestingly, induction in X-ALD fibroblasts was concomitant with a decrease in oxidative stress. Rats treated with 22S-HC showed hepatic induction of the 3 genes of interest. In human, we show by multiple tissue expression array that expression of ABCD2 appears to be inversely correlated with NR1H3 LXRα expression. Altogether, antagonists of LXR that are currently developed in the context of dyslipidemia may find another indication with X-ALD.

Keywords : x-ald very-long-chain fatty acid lxr hydroxycholesterol abcd2





Author: Catherine Gondcaille - Emmanuelle C. Genin - Tatiana E. Lopez - Alexandre M.M. Dias - Flore Geillon - Pierre Andreoletti - Mustap

Source: https://hal.archives-ouvertes.fr/



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