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Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma
Cytochrome P450 (CYP) 27A1 is a key enzyme in both the acidic and neutral pathways of bile acid biosynthesis accepting cholesterol and ring-hydroxylated sterols as substrates introducing a (25R)26-hydroxy and ultimately a (25R)26-acid group to the sterol side-chain. In human, mutations in the CYP27A...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327153/ https://www.ncbi.nlm.nih.gov/pubmed/30471425 http://dx.doi.org/10.1016/j.bbalip.2018.11.006 |
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author | Griffiths, William J. Crick, Peter J. Meljon, Anna Theofilopoulos, Spyridon Abdel-Khalik, Jonas Yutuc, Eylan Parker, Josie E. Kelly, Diane E. Kelly, Steven L. Arenas, Ernest Wang, Yuqin |
author_facet | Griffiths, William J. Crick, Peter J. Meljon, Anna Theofilopoulos, Spyridon Abdel-Khalik, Jonas Yutuc, Eylan Parker, Josie E. Kelly, Diane E. Kelly, Steven L. Arenas, Ernest Wang, Yuqin |
author_sort | Griffiths, William J. |
collection | PubMed |
description | Cytochrome P450 (CYP) 27A1 is a key enzyme in both the acidic and neutral pathways of bile acid biosynthesis accepting cholesterol and ring-hydroxylated sterols as substrates introducing a (25R)26-hydroxy and ultimately a (25R)26-acid group to the sterol side-chain. In human, mutations in the CYP27A1 gene are the cause of the autosomal recessive disease cerebrotendinous xanthomatosis (CTX). Surprisingly, Cyp27a1 knockout mice (Cyp27a1−/−) do not present a CTX phenotype despite generating a similar global pattern of sterols. Using liquid chromatography – mass spectrometry and exploiting a charge-tagging approach for oxysterol analysis we identified over 50 cholesterol metabolites and precursors in the brain and circulation of Cyp27a1−/− mice. Notably, we identified (25R)26,7α- and (25S)26,7α-dihydroxy epimers of oxysterols and cholestenoic acids, indicating the presence of an additional sterol 26-hydroxylase in mouse. Importantly, our analysis also revealed elevated levels of 7α-hydroxycholest-4-en-3-one, which we found increased the number of oculomotor neurons in primary mouse brain cultures. 7α-Hydroxycholest-4-en-3-one is a ligand for the pregnane X receptor (PXR), activation of which is known to up-regulate the expression of CYP3A11, which we confirm has sterol 26-hydroxylase activity. This can explain the formation of (25R)26,7α- and (25S)26,7α-dihydroxy epimers of oxysterols and cholestenoic acids; the acid with the former stereochemistry is a liver X receptor (LXR) ligand that increases the number of oculomotor neurons in primary brain cultures. We hereby suggest that a lack of a motor neuron phenotype in some CTX patients and Cyp27a1−/− mice may involve increased levels of 7α-hydroxycholest-4-en-3-one and activation PXR, as well as increased levels of sterol 26-hydroxylase and the production of neuroprotective sterols capable of activating LXR. |
format | Online Article Text |
id | pubmed-6327153 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-63271532019-02-01 Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma Griffiths, William J. Crick, Peter J. Meljon, Anna Theofilopoulos, Spyridon Abdel-Khalik, Jonas Yutuc, Eylan Parker, Josie E. Kelly, Diane E. Kelly, Steven L. Arenas, Ernest Wang, Yuqin Biochim Biophys Acta Mol Cell Biol Lipids Article Cytochrome P450 (CYP) 27A1 is a key enzyme in both the acidic and neutral pathways of bile acid biosynthesis accepting cholesterol and ring-hydroxylated sterols as substrates introducing a (25R)26-hydroxy and ultimately a (25R)26-acid group to the sterol side-chain. In human, mutations in the CYP27A1 gene are the cause of the autosomal recessive disease cerebrotendinous xanthomatosis (CTX). Surprisingly, Cyp27a1 knockout mice (Cyp27a1−/−) do not present a CTX phenotype despite generating a similar global pattern of sterols. Using liquid chromatography – mass spectrometry and exploiting a charge-tagging approach for oxysterol analysis we identified over 50 cholesterol metabolites and precursors in the brain and circulation of Cyp27a1−/− mice. Notably, we identified (25R)26,7α- and (25S)26,7α-dihydroxy epimers of oxysterols and cholestenoic acids, indicating the presence of an additional sterol 26-hydroxylase in mouse. Importantly, our analysis also revealed elevated levels of 7α-hydroxycholest-4-en-3-one, which we found increased the number of oculomotor neurons in primary mouse brain cultures. 7α-Hydroxycholest-4-en-3-one is a ligand for the pregnane X receptor (PXR), activation of which is known to up-regulate the expression of CYP3A11, which we confirm has sterol 26-hydroxylase activity. This can explain the formation of (25R)26,7α- and (25S)26,7α-dihydroxy epimers of oxysterols and cholestenoic acids; the acid with the former stereochemistry is a liver X receptor (LXR) ligand that increases the number of oculomotor neurons in primary brain cultures. We hereby suggest that a lack of a motor neuron phenotype in some CTX patients and Cyp27a1−/− mice may involve increased levels of 7α-hydroxycholest-4-en-3-one and activation PXR, as well as increased levels of sterol 26-hydroxylase and the production of neuroprotective sterols capable of activating LXR. Elsevier 2019-02 /pmc/articles/PMC6327153/ /pubmed/30471425 http://dx.doi.org/10.1016/j.bbalip.2018.11.006 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Griffiths, William J. Crick, Peter J. Meljon, Anna Theofilopoulos, Spyridon Abdel-Khalik, Jonas Yutuc, Eylan Parker, Josie E. Kelly, Diane E. Kelly, Steven L. Arenas, Ernest Wang, Yuqin Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma |
title | Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma |
title_full | Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma |
title_fullStr | Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma |
title_full_unstemmed | Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma |
title_short | Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma |
title_sort | additional pathways of sterol metabolism: evidence from analysis of cyp27a1−/− mouse brain and plasma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327153/ https://www.ncbi.nlm.nih.gov/pubmed/30471425 http://dx.doi.org/10.1016/j.bbalip.2018.11.006 |
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