LXR antagonists induce ABCD2 expression |
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Authors: | Catherine Gondcaille Emmanuelle C Genin Tatiana E Lopez Alexandre MM Dias Flore Geillon Pierre Andreoletti Mustapha Cherkaoui-Malki Thomas Nury Gérard Lizard Isabelle Weinhofer Johannes Berger Eili T Kase Doriane Trompier Stéphane Savary |
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Institution: | 1. Laboratoire Bio-PeroxIL, EA7270 University of Burgundy, 6 Bd Gabriel, Dijon F-21000, France;2. Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria;3. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway |
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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 GSK(17) (a LXR antagonist recently discovered from the GlaxoSmithKline compound collection), 22(S)-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. |
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Keywords: | ACOX Acyl-CoA oxidase ABC ATP binding cassette DHA docosahexaenoic acid (C22:6 n &minus 3) H2DCFDA 2&prime 7&prime -dichlorodihydrofluorescein diacetate HC hydroxycholesterol HFD high fat diet LXR Liver X receptor LXRE LXR response element MTE multiple tissue expression MUFA monounsaturated fatty acids PPAR peroxisome proliferator activated receptor PUFA Polyunsaturated Fatty acids ROS reactive oxygen species SREBP sterol regulatory element binding protein TcF T cell factor T3 triiodothyronine T4 thyroxine TR thyroid hormone receptor TRE thyroid hormone response element VLCFA very-long-chain fatty acids X-ALD X-linked adrenoleukodystrophy |
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