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Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation

1
Laboratory of Genome Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
2
Department of Biotechnology, Faculty of Life Science and Biotechnology, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(9), 3309; https://doi.org/10.3390/ijms21093309
Received: 2 April 2020 / Revised: 28 April 2020 / Accepted: 6 May 2020 / Published: 7 May 2020
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. View Full-Text
Keywords: Alzheimer’s disease; cholesterol metabolism; oxysterols; 24S-hydroxycholesterol; CYP39A1; retinoic acid receptor-related orphan receptor α; intronic response element Alzheimer’s disease; cholesterol metabolism; oxysterols; 24S-hydroxycholesterol; CYP39A1; retinoic acid receptor-related orphan receptor α; intronic response element
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MDPI and ACS Style

Matsuoka, H.; Katayama, M.; Ohishi, A.; Miya, K.; Tokunaga, R.; Kobayashi, S.; Nishimoto, Y.; Hirooka, K.; Shima, A.; Michihara, A. Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation. Int. J. Mol. Sci. 2020, 21, 3309. https://doi.org/10.3390/ijms21093309

AMA Style

Matsuoka H, Katayama M, Ohishi A, Miya K, Tokunaga R, Kobayashi S, Nishimoto Y, Hirooka K, Shima A, Michihara A. Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation. International Journal of Molecular Sciences. 2020; 21(9):3309. https://doi.org/10.3390/ijms21093309

Chicago/Turabian Style

Matsuoka, Hiroshi, Miyu Katayama, Ami Ohishi, Kaoruko Miya, Riki Tokunaga, Sou Kobayashi, Yuya Nishimoto, Kazutake Hirooka, Akiho Shima, and Akihiro Michihara. 2020. "Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation" International Journal of Molecular Sciences 21, no. 9: 3309. https://doi.org/10.3390/ijms21093309

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