1. Abcd2 is a strong modifier of the metabolic impairments in peritoneal macrophages of ABCD1-deficient mice
- Author
-
Muneer, Z., Wiesinger, C., Voigtländer, T., Werner, H., Berger, J., and Forss-Petter, S.
- Subjects
Male ,endocrine system diseases ,lcsh:Medicine ,Gene Expression ,ATP Binding Cassette Transporter, Subfamily D, Member 1 ,Biochemistry ,Mice ,White Blood Cells ,Animal Cells ,Gene Order ,Medicine and Health Sciences ,lcsh:Science ,Mice, Knockout ,Brain Diseases ,Fatty Acids ,Neurodegenerative Diseases ,Animal Models ,Lipids ,Neurology ,Gene Targeting ,Cellular Structures and Organelles ,Cellular Types ,Oxidation-Reduction ,Research Article ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Fatty Acid Elongases ,Immune Cells ,Genetic Vectors ,Immunology ,Mouse Models ,ATP Binding Cassette Transporter, Subfamily D ,Research and Analysis Methods ,Molecular Genetics ,Model Organisms ,Acetyltransferases ,Coenzyme A Ligases ,Peroxisomes ,Genetics ,Animals ,Gene Silencing ,RNA, Messenger ,Molecular Biology ,Blood Cells ,Macrophages ,Inborn Errors of Metabolism ,lcsh:R ,nutritional and metabolic diseases ,Biology and Life Sciences ,Cell Biology ,Lipid Metabolism ,Demyelinating Disorders ,Gene Expression Regulation ,Metabolic Disorders ,Macrophages, Peritoneal ,lcsh:Q ,ATP-Binding Cassette Transporters - 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.
- Published
- 2014