Cholesterol-deprivation increases mono-unsaturated very long-chain fatty acids in skin fibroblasts from patients with X-linked adrenoleukodystrophy.
X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is characterized by a striking and unpredictable variation in phenotypic expression. It ranges from a rapidly progressive and fatal cerebral demyelinating disease in childhood (CCALD), to the milder slowly progressive form in adulthood (AMN). X-ALD is caused by mutations in the ABCD1 gene that encodes a peroxisomal membrane located ABC half-transporter named ALDP. Mutations in ALDP result in reduced beta-oxidation of very long-chain fatty acids (VLCFA, >22 carbon atoms) in peroxisomes and elevated levels of VLCFA in plasma and tissues. Previously, it has been shown that culturing skin fibroblasts from X-ALD patients in lipoprotein-deficient medium results in reduced VLCFA levels and increased expression of the functionally redundant ALD-related protein (ALDRP). The aim of this study was to further resolve the interaction between cholesterol and VLCFA metabolism in X-ALD. Our data show that the reduction in 26:0 in X-ALD fibroblasts grown in lipoprotein-deficient culture medium (free of cholesterol) is offset by a significant increase in both the level and synthesis of 26:1. We also demonstrate that cholesterol-deprivation results in increased expression of stearoyl-CoA-desaturase (SCD) and increased desaturation of 18:0 to 18:1. Finally, there was no increase in [1-(14)C]-26:0 beta-oxidation. Taken together, we conclude that cholesterol-deprivation reduces saturated VLCFA, but increases mono-unsaturated VLCFA. These data may have implications for treatment of X-ALD patients with lovastatin.
Engelen
M
M
Academic Medical Center, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Ofman
R
R
Mooijer
P A W
PA
Poll-The
B T
BT
Wanders
R J A
RJ
Kemp
S
S
D000326:Adrenoleukodystrophy / Q000378:metabolism*; D002784:Cholesterol / Q000172:deficiency*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D010084:Oxidation-Reduction; D012867:Skin / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism
D005229:Fatty Acids, Monounsaturated; D002784:Cholesterol; D013230:Stearoyl-CoA Desaturase