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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...

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Autores principales: Matsuoka, Hiroshi, Katayama, Miyu, Ohishi, Ami, Miya, Kaoruko, Tokunaga, Riki, Kobayashi, Sou, Nishimoto, Yuya, Hirooka, Kazutake, Shima, Akiho, Michihara, Akihiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246805/
https://www.ncbi.nlm.nih.gov/pubmed/32392803
http://dx.doi.org/10.3390/ijms21093309
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author Matsuoka, Hiroshi
Katayama, Miyu
Ohishi, Ami
Miya, Kaoruko
Tokunaga, Riki
Kobayashi, Sou
Nishimoto, Yuya
Hirooka, Kazutake
Shima, Akiho
Michihara, Akihiro
author_facet Matsuoka, Hiroshi
Katayama, Miyu
Ohishi, Ami
Miya, Kaoruko
Tokunaga, Riki
Kobayashi, Sou
Nishimoto, Yuya
Hirooka, Kazutake
Shima, Akiho
Michihara, Akihiro
author_sort Matsuoka, Hiroshi
collection PubMed
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.
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spelling pubmed-72468052020-06-10 Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation Matsuoka, Hiroshi Katayama, Miyu Ohishi, Ami Miya, Kaoruko Tokunaga, Riki Kobayashi, Sou Nishimoto, Yuya Hirooka, Kazutake Shima, Akiho Michihara, Akihiro Int J Mol Sci Article 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. MDPI 2020-05-07 /pmc/articles/PMC7246805/ /pubmed/32392803 http://dx.doi.org/10.3390/ijms21093309 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Matsuoka, Hiroshi
Katayama, Miyu
Ohishi, Ami
Miya, Kaoruko
Tokunaga, Riki
Kobayashi, Sou
Nishimoto, Yuya
Hirooka, Kazutake
Shima, Akiho
Michihara, Akihiro
Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246805/
https://www.ncbi.nlm.nih.gov/pubmed/32392803
http://dx.doi.org/10.3390/ijms21093309
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