{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:06:08Z","timestamp":1792073168034,"version":"4.4.0"},"reference-count":77,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund FWF","doi-asserted-by":"publisher","award":["DOC 33-B27"],"award-info":[{"award-number":["DOC 33-B27"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation of very long-chain fatty acids (VLCFA). Strongly affected cell types, such as oligodendrocytes, adrenocortical cells and macrophages, exhibit high cholesterol turnover. Here, we investigated how ABCD1 deficiency affects cholesterol metabolism in human X-ALD patient-derived fibroblasts and CNS tissues of Abcd1-deficient mice. Lipidome analyses revealed increased levels of cholesterol esters (CE), containing both saturated VLCFA and mono\/polyunsaturated (V)LCFA. The elevated CE(26:0) and CE(26:1) levels remained unchanged in LXR agonist-treated Abcd1 KO mice despite reduced total C26:0. Under high-cholesterol loading, gene expression of SOAT1, converting cholesterol to CE and lipid droplet formation were increased in human X-ALD fibroblasts versus healthy control fibroblasts. However, the expression of NCEH1, catalysing CE hydrolysis and the cholesterol transporter ABCA1 and cholesterol efflux were also upregulated. Elevated Soat1 and Abca1 expression and lipid droplet content were confirmed in the spinal cord of X-ALD mice, where expression of the CNS cholesterol transporter Apoe was also elevated. The extent of peroxisome-lipid droplet co-localisation appeared low and was not impaired by ABCD1-deficiency in cholesterol-loaded primary fibroblasts. Finally, addressing steroidogenesis, progesterone-induced cortisol release was amplified in X-ALD fibroblasts. These results link VLCFA to cholesterol homeostasis and justify further consideration of therapeutic approaches towards reducing VLCFA and cholesterol levels in X-ALD.<\/jats:p>","DOI":"10.3390\/biom13091333","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T11:31:18Z","timestamp":1693481478000},"page":"1333","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["ABCD1 Transporter Deficiency Results in Altered Cholesterol Homeostasis"],"prefix":"10.3390","volume":"13","author":[{"given":"Agnieszka","family":"Buda","sequence":"first","affiliation":[{"name":"Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Forss-Petter","sequence":"additional","affiliation":[{"name":"Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Hua","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada"},{"name":"Department of Biochemistry, University of Toronto, Toronto, ON M5G 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9153-5734","authenticated-orcid":false,"given":"Yorrick","family":"Jaspers","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Lassnig","sequence":"additional","affiliation":[{"name":"Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Waidhofer-S\u00f6llner","sequence":"additional","affiliation":[{"name":"Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2023-064X","authenticated-orcid":false,"given":"Stephan","family":"Kemp","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kim","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada"},{"name":"Department of Biochemistry, University of Toronto, Toronto, ON M5G 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Weinhofer","sequence":"additional","affiliation":[{"name":"Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0182-2658","authenticated-orcid":false,"given":"Johannes","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/ana.101","article-title":"Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening","volume":"49","author":"Bezman","year":"2001","journal-title":"Ann. 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