Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation
Oxysterols, important regulators of cholesterol homeostasis in the brain, are affected by neurodegenerative diseases. Early-onset Alzheimer’s disease is associated with higher levels of circulating brain-derived 24S-hydroxycholesterol (24S-OHC). Conversion of cholesterol to 24S-OHC is mediated by ch...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/9/3309 |
| _version_ | 1797568648438611968 |
|---|---|
| author | Hiroshi Matsuoka Miyu Katayama Ami Ohishi Kaoruko Miya Riki Tokunaga Sou Kobayashi Yuya Nishimoto Kazutake Hirooka Akiho Shima Akihiro Michihara |
| author_facet | Hiroshi Matsuoka Miyu Katayama Ami Ohishi Kaoruko Miya Riki Tokunaga Sou Kobayashi Yuya Nishimoto Kazutake Hirooka Akiho Shima Akihiro Michihara |
| author_sort | Hiroshi Matsuoka |
| collection | DOAJ |
| description | Oxysterols, important regulators of cholesterol homeostasis in the brain, are affected by neurodegenerative diseases. Early-onset Alzheimer’s 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 α (RORα), a nuclear receptor that responds to oxysterol ligands. In humans, the promoter and first intronic regions of CYP39A1 contain two putative RORα response elements (ROREs). RORα binding and responses of these ROREs were assessed using electrophoretic mobility shift, chromatin immunoprecipitation, and luciferase reporter assays. CYP39A1 was upregulated by RORα overexpression in HEK293 cells, while RORα knockdown by siRNA significantly downregulated CYP39A1 expression in human hepatoma cells. Additionally, CYP39A1 was induced by RORα agonist treatment, suggesting that CYP39A1 expression is activated by RORα nuclear receptors. This may provide a way to increase CYP39A1 activity using RORα agonists, and help halt 24S-OHC accumulation in neurodegenerative illnesses. |
| first_indexed | 2024-03-10T19:59:57Z |
| format | Article |
| id | doaj.art-fdf4dc5e963b4689a123ac1607d00937 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:59:57Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-fdf4dc5e963b4689a123ac1607d009372023-11-19T23:42:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-05-01219330910.3390/ijms21093309Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element ActivationHiroshi Matsuoka0Miyu Katayama1Ami Ohishi2Kaoruko Miya3Riki Tokunaga4Sou Kobayashi5Yuya Nishimoto6Kazutake Hirooka7Akiho Shima8Akihiro Michihara9Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, JapanLaboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, JapanLaboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, JapanLaboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, JapanLaboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, JapanLaboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, JapanLaboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, JapanDepartment of Biotechnology, Faculty of Life Science and Biotechnology, Fukuyama University, Fukuyama, Hiroshima 729-0292, JapanLaboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, JapanLaboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, JapanOxysterols, important regulators of cholesterol homeostasis in the brain, are affected by neurodegenerative diseases. Early-onset Alzheimer’s 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 α (RORα), a nuclear receptor that responds to oxysterol ligands. In humans, the promoter and first intronic regions of CYP39A1 contain two putative RORα response elements (ROREs). RORα binding and responses of these ROREs were assessed using electrophoretic mobility shift, chromatin immunoprecipitation, and luciferase reporter assays. CYP39A1 was upregulated by RORα overexpression in HEK293 cells, while RORα knockdown by siRNA significantly downregulated CYP39A1 expression in human hepatoma cells. Additionally, CYP39A1 was induced by RORα agonist treatment, suggesting that CYP39A1 expression is activated by RORα nuclear receptors. This may provide a way to increase CYP39A1 activity using RORα agonists, and help halt 24S-OHC accumulation in neurodegenerative illnesses.https://www.mdpi.com/1422-0067/21/9/3309Alzheimer’s diseasecholesterol metabolismoxysterols24S-hydroxycholesterolCYP39A1retinoic acid receptor-related orphan receptor α |
| spellingShingle | Hiroshi Matsuoka Miyu Katayama Ami Ohishi Kaoruko Miya Riki Tokunaga Sou Kobayashi Yuya Nishimoto Kazutake Hirooka Akiho Shima Akihiro Michihara Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation International Journal of Molecular Sciences Alzheimer’s disease cholesterol metabolism oxysterols 24S-hydroxycholesterol CYP39A1 retinoic acid receptor-related orphan receptor α |
| title | Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation |
| title_full | Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation |
| title_fullStr | Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation |
| title_full_unstemmed | Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation |
| title_short | Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation |
| title_sort | orphan nuclear receptor rorα regulates enzymatic metabolism of cerebral 24s hydroxycholesterol through cyp39a1 intronic response element activation |
| topic | Alzheimer’s disease cholesterol metabolism oxysterols 24S-hydroxycholesterol CYP39A1 retinoic acid receptor-related orphan receptor α |
| url | https://www.mdpi.com/1422-0067/21/9/3309 |
| work_keys_str_mv | AT hiroshimatsuoka orphannuclearreceptorroraregulatesenzymaticmetabolismofcerebral24shydroxycholesterolthroughcyp39a1intronicresponseelementactivation AT miyukatayama orphannuclearreceptorroraregulatesenzymaticmetabolismofcerebral24shydroxycholesterolthroughcyp39a1intronicresponseelementactivation AT amiohishi orphannuclearreceptorroraregulatesenzymaticmetabolismofcerebral24shydroxycholesterolthroughcyp39a1intronicresponseelementactivation AT kaorukomiya orphannuclearreceptorroraregulatesenzymaticmetabolismofcerebral24shydroxycholesterolthroughcyp39a1intronicresponseelementactivation AT rikitokunaga orphannuclearreceptorroraregulatesenzymaticmetabolismofcerebral24shydroxycholesterolthroughcyp39a1intronicresponseelementactivation AT soukobayashi orphannuclearreceptorroraregulatesenzymaticmetabolismofcerebral24shydroxycholesterolthroughcyp39a1intronicresponseelementactivation AT yuyanishimoto orphannuclearreceptorroraregulatesenzymaticmetabolismofcerebral24shydroxycholesterolthroughcyp39a1intronicresponseelementactivation AT kazutakehirooka orphannuclearreceptorroraregulatesenzymaticmetabolismofcerebral24shydroxycholesterolthroughcyp39a1intronicresponseelementactivation AT akihoshima orphannuclearreceptorroraregulatesenzymaticmetabolismofcerebral24shydroxycholesterolthroughcyp39a1intronicresponseelementactivation AT akihiromichihara orphannuclearreceptorroraregulatesenzymaticmetabolismofcerebral24shydroxycholesterolthroughcyp39a1intronicresponseelementactivation |