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Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma / William, Griffiths; Spyridon, Theofilopoulos; Eylan, Yutuc; Josie, Parker; Diane, Kelly; Steven, Kelly; Yuqin, Wang

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Volume: 1864, Issue: 2, Pages: 191 - 211

Swansea University Authors: William, Griffiths, Spyridon, Theofilopoulos, Eylan, Yutuc, Josie, Parker, Diane, Kelly, Steven, Kelly, Yuqin, Wang

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Abstract

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...

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Published in: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ISSN: 1388-1981
Published: Elsevier BV 2019
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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 &#x2013; 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)26,7&#x3B1;- and (25S)26,7&#x3B1;-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 7&#x3B1;-hydroxycholest-4-en-3-one, which we found increased the number of oculomotor neurons in primary mouse brain cultures. 7&#x3B1;-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)26,7&#x3B1;- and (25S)26,7&#x3B1;-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 7&#x3B1;-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.</abstract><type>Journal Article</type><journal>Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids</journal><volume>1864</volume><journalNumber>2</journalNumber><paginationStart>191</paginationStart><paginationEnd>211</paginationEnd><publisher>Elsevier BV</publisher><issnPrint>1388-1981</issnPrint><keywords>CYP27A1, cerebrotendinous xanthomatosis, oxysterol, cholestenoic acid, brain, mass spectrometry</keywords><publishedDay>28</publishedDay><publishedMonth>2</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-02-28</publishedDate><doi>10.1016/j.bbalip.2018.11.006</doi><url>http://dx.doi.org/10.1016/j.bbalip.2018.11.006</url><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><sponsorsfunders>RCUK, BB/N015932/1</sponsorsfunders><lastEdited>2020-07-21T12:19:51.9346097</lastEdited><Created>2018-11-23T09:13:51.0381715</Created><authors><author><firstname>William</firstname><surname>Griffiths</surname><orcid>0000-0002-4129-6616</orcid><order>1</order></author><author><firstname>Peter J.</firstname><surname>Crick</surname><order>2</order></author><author><firstname>Anna</firstname><surname>Meljon</surname><order>3</order></author><author><firstname>Spyridon</firstname><surname>Theofilopoulos</surname><orcid>0000-0003-1986-0943</orcid><order>4</order></author><author><firstname>Jonas</firstname><surname>Abdel-Khalik</surname><order>5</order></author><author><firstname>Eylan</firstname><surname>Yutuc</surname><orcid>0000-0001-9971-1950</orcid><order>6</order></author><author><firstname>Josie</firstname><surname>Parker</surname><orcid>0000-0002-3855-4194</orcid><order>7</order></author><author><firstname>Diane</firstname><surname>Kelly</surname><orcid>0000-0003-2231-0192</orcid><order>8</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><orcid>0000-0001-7991-5040</orcid><order>9</order></author><author><firstname>Ernest</firstname><surname>Arenas</surname><order>10</order></author><author><firstname>Yuqin</firstname><surname>Wang</surname><orcid>0000-0002-3063-3066</orcid><order>11</order></author></authors><documents><document><filename>46057__12271__20415c5c756b4859964f64d6008e7fbe.pdf</filename><originalFilename>46057.pdf</originalFilename><uploaded>2018-12-27T10:47:10.5630000</uploaded><type>Output</type><contentLength>4472063</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><action/><embargoDate>2018-12-26T00:00:00.0000000</embargoDate><documentNotes>Released under the terms of a Creative Commons Attribution License (CC-BY).</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2020-07-21T12:19:51.9346097 v2 46057 2018-11-23 Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false bcd1bdbdf59d0724d2f9e9a48e671107 0000-0003-1986-0943 Spyridon Theofilopoulos Spyridon Theofilopoulos true false 99332f073ce913a9b7d8b6441b17516d 0000-0001-9971-1950 Eylan Yutuc Eylan Yutuc true false e563ed4e1c7db8d1e131fb78a5f8d0d5 0000-0002-3855-4194 Josie Parker Josie Parker true false 5ccf81e5d5beedf32ef8d7c3d7ac6c8c 0000-0003-2231-0192 Diane Kelly Diane Kelly true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 2018-11-23 BMS 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. Journal Article Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1864 2 191 211 Elsevier BV 1388-1981 CYP27A1, cerebrotendinous xanthomatosis, oxysterol, cholestenoic acid, brain, mass spectrometry 28 2 2019 2019-02-28 10.1016/j.bbalip.2018.11.006 http://dx.doi.org/10.1016/j.bbalip.2018.11.006 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University RCUK, BB/N015932/1 2020-07-21T12:19:51.9346097 2018-11-23T09:13:51.0381715 William Griffiths 0000-0002-4129-6616 1 Peter J. Crick 2 Anna Meljon 3 Spyridon Theofilopoulos 0000-0003-1986-0943 4 Jonas Abdel-Khalik 5 Eylan Yutuc 0000-0001-9971-1950 6 Josie Parker 0000-0002-3855-4194 7 Diane Kelly 0000-0003-2231-0192 8 Steven Kelly 0000-0001-7991-5040 9 Ernest Arenas 10 Yuqin Wang 0000-0002-3063-3066 11 46057__12271__20415c5c756b4859964f64d6008e7fbe.pdf 46057.pdf 2018-12-27T10:47:10.5630000 Output 4472063 application/pdf Version of Record true 2018-12-26T00:00:00.0000000 Released under the terms of a Creative Commons Attribution License (CC-BY). true eng
title Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma
spellingShingle Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma
William, Griffiths
Spyridon, Theofilopoulos
Eylan, Yutuc
Josie, Parker
Diane, Kelly
Steven, Kelly
Yuqin, Wang
title_short 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_sort Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma
author_id_str_mv 3316b1d1b524be1831790933eed1c26e
bcd1bdbdf59d0724d2f9e9a48e671107
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author_id_fullname_str_mv 3316b1d1b524be1831790933eed1c26e_***_William, Griffiths
bcd1bdbdf59d0724d2f9e9a48e671107_***_Spyridon, Theofilopoulos
99332f073ce913a9b7d8b6441b17516d_***_Eylan, Yutuc
e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie, Parker
5ccf81e5d5beedf32ef8d7c3d7ac6c8c_***_Diane, Kelly
b17cebaf09b4d737b9378a3581e3de93_***_Steven, Kelly
c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin, Wang
author William, Griffiths
Spyridon, Theofilopoulos
Eylan, Yutuc
Josie, Parker
Diane, Kelly
Steven, Kelly
Yuqin, Wang
format Journal article
container_title Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
container_volume 1864
container_issue 2
container_start_page 191
publishDate 2019
institution Swansea University
issn 1388-1981
doi_str_mv 10.1016/j.bbalip.2018.11.006
publisher Elsevier BV
url http://dx.doi.org/10.1016/j.bbalip.2018.11.006
document_store_str 1
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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.
published_date 2019-02-28T04:13:13Z
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