A key role for the peroxisomal ABCD2 transporter in fatty acid homeostasis.
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 omega9-monounsaturated fatty acids and in the synthesis of docosahexanoic acid (DHA). Also, we demonstrated a defective VLCFA beta-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.
Fourcade
Stéphane
S
Centre de Genètica Mèdica i Molecular, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
Ruiz
Montserrat
M
Camps
Carme
C
Schlüter
Agatha
A
Houten
Sander M
SM
Mooyer
Petra A W
PA
Pàmpols
Teresa
T
Dacremont
Georges
G
Wanders
Ronald J A
RJ
Giròs
Marisa
M
Pujol
Aurora
A
D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000378:metabolism*; D005227:Fatty Acids / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism*; D010802:Phylogeny; D012584:Sciatic Nerve / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism
C508354:ABCD2 protein, mouse; D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; D004041:Dietary Fats; D005227:Fatty Acids