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

Stéphane Fourcade, Montserrat Ruiz, Carme Camps, Agatha Schlüter, Sander M. Houten, Petra A.W. Mooyer, Teresa Pàmpols, Georges Dacremont, Ronald J.A. Wanders, Marisa Giròs, Aurora Pujol

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

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 ω9-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.

Original languageEnglish
Pages (from-to)E211-E221
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume296
Issue number1
DOIs
StatePublished - Jan 2009
Externally publishedYes

Keywords

  • Adenosine 5′-triphosphate-binding cassette transporters
  • Adrenoleukodystrophy
  • Docosahex-anoic acid
  • Peroxisome
  • Polyunsaturated fatty acid

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