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This Article Full Text Full Text (PDF) Supplemental Figures and Tables All Versions of this Article: 296/1/E211    most recent 90736.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Fourcade, S. Articles by Pujol, A. Search for Related Content PubMed PubMed Citation Articles by Fourcade, S. Articles by Pujol, A.

A key role for the peroxisomal ABCD2 transporter in fatty acid homeostasis

¹Centre de Genètica Mèdica i Molecular, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat; ²Institut de Neuropatologia de Bellvitge, Institut d'Investigació Biomèdica de Bellvitge-Universitat de Barcelona; ³Center for Biomedical Research on Rare Diseases; ⁴Institut de Bioquimica Clinica, Hospital Clínic de Barcelona, Barcelona, Spain; ⁵Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and ⁶University of Ghent, Ghent, Belgium; and ⁷Catalan Institution of Research and Advanced Studies, Barcelona, Spain

Submitted 1 September 2008 ; accepted in final form 6 October 2008

Peroxisomes are essential organelles exerting key functions in fatty acid metabolism such as the degradation of very long-chain fatty acids (VLCFAs). VLCFAs accumulate in X-adrenoleukodystrophy (X-ALD), a disease caused by deficiency of the Abcd1 peroxisomal transporter. Its closest homologue, Abcd2, exhibits a high degree of functional redundancy on the catabolism of VLCFA, being able to prevent X-ALD-related neurodegeneration in the mouse. In the search for specific roles of Abcd2, we screened fatty acid profiles in organs and primary neurons of mutant knockout mice lacking Abcd2 in basal conditions and under dietary challenges. Our results indicate that ABCD2 plays a role in the degradation of long-chain saturated and 9-monounsaturated fatty acids and in the synthesis of docosahexanoic acid (DHA). Also, we demonstrated a defective VLCFA β-oxidation ex vivo in brain slices of Abcd1 and Abcd2 knockouts, using radiolabeled hexacosanoic acid and the precursor of DHA as substrates. As DHA levels are inversely correlated with the incidence of Alzheimer's and several degenerative conditions, we suggest that ABCD2 may act as modulator/modifier gene and therapeutic target in rare and common human disorders.

adrenoleukodystrophy; adenosine 5'-triphosphate-binding cassette transporters; peroxisome; polyunsaturated fatty acid; docosahexanoic acid

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