{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T10:02:08Z","timestamp":1792404128646,"version":"4.4.0"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T00:00:00Z","timestamp":1588809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013454","name":"Fukuyama University","doi-asserted-by":"publisher","award":["GARP 2019-103"],"award-info":[{"award-number":["GARP 2019-103"]}],"id":[{"id":"10.13039\/501100013454","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oxysterols, important regulators of cholesterol homeostasis in the brain, are affected by neurodegenerative diseases. Early-onset Alzheimer\u2019s disease is associated with higher levels of circulating brain-derived 24S-hydroxycholesterol (24S-OHC). Conversion of cholesterol to 24S-OHC is mediated by cholesterol 24S-hydroxylase in the brain, which is the major pathway for oxysterol elimination, followed by oxidation through hepatic first-pass metabolism by CYP39A1. Abnormal CYP39A1 expression results in accumulation of 24S-OHC, influencing neurodegenerative disease-related deterioration; thus, it is important to understand the normal elimination of 24S-OHC and the system regulating CYP39A1, a selective hepatic metabolic enzyme of 24S-OHC. We examined the role of transcriptional regulation by retinoic acid receptor-related orphan receptor \u03b1 (ROR\u03b1), a nuclear receptor that responds to oxysterol ligands. In humans, the promoter and first intronic regions of CYP39A1 contain two putative ROR\u03b1 response elements (ROREs). ROR\u03b1 binding and responses of these ROREs were assessed using electrophoretic mobility shift, chromatin immunoprecipitation, and luciferase reporter assays. CYP39A1 was upregulated by ROR\u03b1 overexpression in HEK293 cells, while ROR\u03b1 knockdown by siRNA significantly downregulated CYP39A1 expression in human hepatoma cells. Additionally, CYP39A1 was induced by ROR\u03b1 agonist treatment, suggesting that CYP39A1 expression is activated by ROR\u03b1 nuclear receptors. This may provide a way to increase CYP39A1 activity using ROR\u03b1 agonists, and help halt 24S-OHC accumulation in neurodegenerative illnesses.<\/jats:p>","DOI":"10.3390\/ijms21093309","type":"journal-article","created":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T03:45:20Z","timestamp":1588909520000},"page":"3309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Orphan Nuclear Receptor ROR\u03b1 Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9423-5473","authenticated-orcid":false,"given":"Hiroshi","family":"Matsuoka","sequence":"first","affiliation":[{"name":"Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyu","family":"Katayama","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ami","family":"Ohishi","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoruko","family":"Miya","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riki","family":"Tokunaga","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sou","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Nishimoto","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5879-936X","authenticated-orcid":false,"given":"Kazutake","family":"Hirooka","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Faculty of Life Science and Biotechnology, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiho","family":"Shima","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Michihara","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1194\/jlr.R400004-JLR200","article-title":"Cholesterol metabolism in the central nervous system during early development and in the mature animal","volume":"45","author":"Dietschy","year":"2004","journal-title":"J. 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