title: Abcd2 is a strong modifier of the metabolic impairments in peritoneal macrophages of ABCD1-deficient mice.
abstract: The inherited peroxisomal disorder X-linked adrenoleukodystrophy (X-ALD), associated with neurodegeneration and inflammatory cerebral demyelination, is caused by mutations in the ABCD1 gene encoding the peroxisomal ATP-binding cassette (ABC) transporter ABCD1 (ALDP). ABCD1 transports CoA-esters of very long-chain fatty acids (VLCFA) into peroxisomes for degradation by β-oxidation; thus, ABCD1 deficiency results in VLCFA accumulation. The closest homologue, ABCD2 (ALDRP), when overexpressed, compensates for ABCD1 deficiency in X-ALD fibroblasts and in Abcd1-deficient mice. Microglia/macrophages have emerged as important players in the progression of neuroinflammation. Human monocytes, lacking significant expression of ABCD2, display severely impaired VLCFA metabolism in X-ALD. Here, we used thioglycollate-elicited primary mouse peritoneal macrophages (MPMΦ) from Abcd1 and Abcd2 single- and double-deficient mice to establish how these mutations affect VLCFA metabolism. By quantitative RT-PCR, Abcd2 mRNA was about half as abundant as Abcd1 mRNA in wild-type and similarly abundant in Abcd1-deficient MPMΦ. VLCFA (C26∶0) accumulated about twofold in Abcd1-deficient MPMΦ compared with wild-type controls, as measured by gas chromatography-mass spectrometry. In Abcd2-deficient macrophages VLCFA levels were normal. However, upon Abcd1/Abcd2 double-deficiency, VLCFA accumulation was markedly increased (sixfold) compared with Abcd1-deficient MPMΦ. Elovl1 mRNA, encoding the rate-limiting enzyme for elongation of VLCFA, was equally abundant across all genotypes. Peroxisomal β-oxidation of C26∶0 amounted to 62% of wild-type activity in Abcd1-deficient MPMΦ and was significantly more impaired (29% residual activity) upon Abcd1/Abcd2 double-deficiency. Single Abcd2 deficiency did not significantly compromise β-oxidation of C26∶0. Thus, the striking accumulation of VLCFA in double-deficient MPMΦ compared with single Abcd1 deficiency was due to the loss of ABCD2-mediated, compensatory transport of VLCFA into peroxisomes. We propose that moderate endogenous expression of Abcd2 in Abcd1-deficient murine macrophages prevents the severe metabolic phenotype observed in human X-ALD monocytes, which lack appreciable expression of ABCD2. This supports upregulation of ABCD2 as a therapeutic concept in X-ALD.
authors.affiliation: Center for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Zahid
authors.initials: Z
authors.lastname: Muneer
authors.affiliation: Center for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wiesinger
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Till
authors.initials: T
authors.lastname: Voigtländer
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Hauke B
authors.initials: HB
authors.lastname: Werner
authors.affiliation: Center for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Berger
authors.affiliation: Center for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Sonja
authors.initials: S
authors.lastname: Forss-Petter
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism*; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003066:Coenzyme A Ligases / Q000378:metabolism; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D023061:Gene Order; D020868:Gene Silencing; D018390:Gene Targeting; D005822:Genetic Vectors / Q000235:genetics; D050356:Lipid Metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: C508354:ABCD2 protein, mouse; D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C552836:Abcd1 protein, mouse; C000630949:ELOVL1 protein, human; D005227:Fatty Acids; D012333:RNA, Messenger; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase