title: X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes.
abstract: X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by mutations in the ABCD1 gene, encoding a member of the peroxisomal ABC transporter family. The ABCD1 protein transports CoA-activated very long-chain fatty acids (VLCFAs) into peroxisomes for degradation via β-oxidation. In the severest form, X-ALD patients suffer from inflammatory demyelination of the brain. As the extent of the metabolic defect in the main immune cells is unknown, we explored their phenotypes concerning mRNA expression pattern of the three peroxisomal ABC transporters, VLCFA accumulation and peroxisomal β-oxidation. In controls, ABCD1 expression was high in monocytes, intermediate in B cells and low in T cells; ABCD2 expression was extremely low in monocytes, intermediate in B cells and highest in T cells; ABCD3 mRNA was equally distributed. In X-ALD patients, the expression patterns remained unaltered; accordingly, monocytes, which lack compensatory VLCFA transport by ABCD2, displayed the severest biochemical phenotype with a 6-fold accumulation of C26:0 and a striking 70% reduction in peroxisomal β-oxidation activity. In contrast, VLCFA metabolism was close to control values in B cells and T cells, supporting the hypothesis that sufficient ABCD2 is present to compensate for ABCD1 deficiency. Thus, the vulnerability of the main immune cell types is highly variable in X-ALD. Based on these results, we propose that in X-ALD the halt of inflammation after allogeneic hematopoietic stem cell transplantation relies particularly on the replacement of the monocyte lineage. Additionally, these findings support the concept that ABCD2 is a target for pharmacological induction as an alternative therapeutic strategy.
authors.affiliation: Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna A-1090, Austria.
authors.forename: Franziska D
authors.initials: FD
authors.lastname: Weber
authors.forename: Christoph
authors.initials: C
authors.lastname: Wiesinger
authors.forename: Sonja
authors.initials: S
authors.lastname: Forss-Petter
authors.forename: Günther
authors.initials: G
authors.lastname: Regelsberger
authors.forename: Angelika
authors.initials: A
authors.lastname: Einwich
authors.forename: Willi H A
authors.initials: WH
authors.lastname: Weber
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Köhler
authors.forename: Hannes
authors.initials: H
authors.lastname: Stockinger
authors.forename: Johannes
authors.initials: J
authors.lastname: Berger
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000326:Adrenoleukodystrophy / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D050356:Lipid Metabolism; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000378:metabolism
chemical_list: C115572:ABCD1 protein, human; C431694:ABCD2 protein, human; C063305:ABCD3 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D005227:Fatty Acids