title: Metabolism of saturated and polyunsaturated very-long-chain fatty acids in fibroblasts from patients with defects in peroxisomal beta-oxidation.
abstract: The metabolism of [1-14C]lignoceric acid (C24:0) and [1-14C]tetracosatetraenoic acid (C24:4, n-6) was studied in normal skin fibroblast cultures and in cultures from patients with defects in peroxisomal beta-oxidation (but normal peroxisomal numbers). Cells from X-linked adrenoleukodystrophy (ALD) patients with a presumed defect in a peroxisomal acyl-CoA synthetase, specific for fatty acids of carbon chain lengths greater than 22 (very-long-chain fatty acids; VLCFA), showed a relatively normal production of radiolabelled CO2 and water-soluble metabolites from [1-14C]C24:0. However, the products of synthesis from acetate de novo (released by beta-oxidation), i.e. C16 and C18 fatty acids, were decreased, and carbon chain elongation of the fatty acid was increased. In contrast, cell lines from two patients with an unidentified lesion in peroxisomal beta-oxidation (peroxisomal disease, PD) showed a marked deficiency in CO2 and water-soluble metabolite production, a decreased synthesis of C16 and C18 fatty acids and an increase in carbon chain elongation. The relatively normal beta-oxidation activity of ALD cells appears to be related to low uptake of substrate, as a defect in beta-oxidation is apparent when measurements are performed on cell suspensions under high uptake conditions. Oxidation of [1-14C]C24:4 was relatively normal in ALD cells and in the cells from one PD patient but abnormal in those from the other. Our data suggest that, despite the deficiency in VLCFA CoA synthetase, ALD cells retain a near normal ability to oxidize both saturated and polyunsaturated VLCFA under some culture conditions. However, acetate released by beta-oxidation of the saturated VLCFA and, to a much lesser degree, the polyunsaturated VLCFA, appears to be used preferentially for the production of CO2 and water-soluble products, and acetate availability for fatty acid synthesis in other subcellular compartments is markedly decreased. It is likely that the increased carbon chain elongation of the saturated VLCFA which is also observed reflects the increased availability of substrate (C24:0) and/or an increase in microsomal elongation activity in ALD cells.
authors.affiliation: Department of Chemical Pathology, Adelaide Children's Hospital, South Australia.
authors.forename: J M
authors.initials: JM
authors.lastname: Street
authors.forename: H
authors.initials: H
authors.lastname: Singh
authors.forename: A
authors.initials: A
authors.lastname: Poulos
mesh_terms: D000326:Adrenoleukodystrophy / Q000097:blood / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism* / Q000493:pharmacokinetics; D005347:Fibroblasts / Q000378:metabolism* / Q000648:ultrastructure; D005971:Glutamates / Q000096:biosynthesis; D006801:Humans; D050356:Lipid Metabolism; D008830:Microbodies / Q000378:metabolism*; D010084:Oxidation-Reduction; D012867:Skin / Q000166:cytology
chemical_list: D002250:Carbon Radioisotopes; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D005971:Glutamates; D002245:Carbon Dioxide; C065411:tetracosatetraenoic acid; C010210:lignoceric acid