title: The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy.
abstract: X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). X-ALD is characterized by the accumulation of very long-chain fatty acids (VLCFA; > or =C24) in plasma and tissues. In this manuscript we provide insight into the pathway underlying the elevated levels of C26:0 in X-ALD. ALDP transports VLCFacyl-CoA across the peroxisomal membrane. A deficiency in ALDP impairs peroxisomal beta-oxidation of VLCFA but also raises cytosolic levels of VLCFacyl-CoA which are substrate for further elongation. We identify ELOVL1 (elongation of very-long-chain-fatty acids) as the single elongase catalysing the synthesis of both saturated VLCFA (C26:0) and mono-unsaturated VLCFA (C26:1). ELOVL1 expression is not increased in X-ALD fibroblasts suggesting that increased levels of C26:0 result from increased substrate availability due to the primary deficiency in ALDP. Importantly, ELOVL1 knockdown reduces elongation of C22:0 to C26:0 and lowers C26:0 levels in X-ALD fibroblasts. Given the likely pathogenic effects of high C26:0 levels, our findings highlight the potential of modulating ELOVL1 activity in the treatment of X-ALD.
authors.affiliation: Academic Medical Center, Departments of Pediatrics and Clinical Chemistry, University of Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Ofman
authors.forename: Inge M E
authors.initials: IM
authors.lastname: Dijkstra
authors.forename: Carlo W T
authors.initials: CW
authors.lastname: van Roermund
authors.forename: Nena
authors.initials: N
authors.lastname: Burger
authors.forename: Marjolein
authors.initials: M
authors.lastname: Turkenburg
authors.forename: Arno
authors.initials: A
authors.lastname: van Cruchten
authors.forename: Catherine E
authors.initials: CE
authors.lastname: van Engen
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000326:Adrenoleukodystrophy / Q000503:physiopathology*; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D006801:Humans; D020675:Peroxisomes / Q000378:metabolism
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C000630949:ELOVL1 protein, human; D005227:Fatty Acids; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases