Effects of the testosterone metabolite dihydrotestosterone and 5 alpha-androstan-3 alpha,17 beta-diol on very long chain fatty acid metabolism in X-adrenoleukodystrophic fibroblasts.
X-Adrenoleukodystrophy (X-ALD) is a peroxisomal disorder associated with the abnormal accumulation of very long chain fatty acids (VLCFA) in plasma and tissues. We have demonstrated that the androgen dihydrotestosterone (DHT) and 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-diol) have favorable effect on VLCFA metabolism. We have investigated the effect of androgens on peroxisomal beta-oxidation, the incorporation of labelled lignoceric acid into cholesterol esters and VLCFA elongation, in cultured skin-fibroblasts from control and X-ALD patients. The androgens significantly increased peroxisomal beta-oxidation in X-ALD fibroblasts although VLCFA levels were not normalized. The major effect was on the incorporation of labelled lignoceric acid into cholesterol esters, since the enhanced lignoceric acid incorporation into cholesterol ester fraction, which occurred in X-ALD fibroblasts, was reduced towards normal values. In contrast, the androgens had no effect on the elongation pathway.
Petroni
A
A
Department of Pharmacological Sciences, University of Milan, Centre of Excellence of Neurodegenerative Diseases, via Balzaretti 9, 20133 Milan, Italy. Anna.Petroni@unimi.it
Blasevich
M
M
Uziel
G
G
D000326:Adrenoleukodystrophy / Q000378:metabolism* / Q000473:pathology; D015113:Androstane-3,17-diol / Q000494:pharmacology*; D002478:Cells, Cultured; D002648:Child; D002788:Cholesterol Esters / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects*
D002788:Cholesterol Esters; D005227:Fatty Acids; D013196:Dihydrotestosterone; D015113:Androstane-3,17-diol; C010210:lignoceric acid