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Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients

Peter J. Crick, William Griffiths Orcid Logo, Juan Zhang, Martin Beibel, Jonas Abdel-Khalik, Jens Kuhle, Andreas W. Sailer, Yuqin Wang Orcid Logo

Molecular Neurobiology

Swansea University Authors: William Griffiths Orcid Logo, Yuqin Wang Orcid Logo

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DOI (Published version): 10.1007/s12035-016-0281-9

Abstract

Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control p...

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Published in: Molecular Neurobiology
ISSN: 0893-7648 1559-1182
Published: 2016
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URI: https://cronfa.swan.ac.uk/Record/cronfa31214
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We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control patients. Analysis was performed following enzyme-assisted derivatisation by liquid chromatography-mass spectrometry (LC-MS) exploiting multistage fragmentation (MS n ). We found increased concentrations of bile acid precursors in CSF from each of the disease states and that patients with inflammatory CNS disease classified as suspected autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P &amp;#60; 0.05) in CSF. Cholesterol concentrations in CSF were not changed except for patients diagnosed with amyotrophic lateral sclerosis (P &amp;#60; 0.01) or pathogen-based infections of the CNS (P &amp;#60; 0.05) where they were elevated. In plasma, we found that 25-HC (P &amp;#60; 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P &amp;#60; 0.05) and 7&#x3B1;-hydroxy-3-oxocholest-4-enoic acid (7&#x3B1;H,3O-CA, P &amp;#60; 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7&#x3B1;H,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on IL-1 family cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of up-regulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophages</abstract><type>Journal Article</type><journal>Molecular Neurobiology</journal><publisher/><issnPrint>0893-7648</issnPrint><issnElectronic>1559-1182</issnElectronic><keywords/><publishedDay>31</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2016</publishedYear><publishedDate>2016-12-31</publishedDate><doi>10.1007/s12035-016-0281-9</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><degreesponsorsfunders>RCUK, BBSRC, BB/I001735/1</degreesponsorsfunders><apcterm/><lastEdited>2019-09-24T16:03:58.6758751</lastEdited><Created>2016-11-24T13:12:17.5674488</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Peter J.</firstname><surname>Crick</surname><order>1</order></author><author><firstname>William</firstname><surname>Griffiths</surname><orcid>0000-0002-4129-6616</orcid><order>2</order></author><author><firstname>Juan</firstname><surname>Zhang</surname><order>3</order></author><author><firstname>Martin</firstname><surname>Beibel</surname><order>4</order></author><author><firstname>Jonas</firstname><surname>Abdel-Khalik</surname><order>5</order></author><author><firstname>Jens</firstname><surname>Kuhle</surname><order>6</order></author><author><firstname>Andreas W.</firstname><surname>Sailer</surname><order>7</order></author><author><firstname>Yuqin</firstname><surname>Wang</surname><orcid>0000-0002-3063-3066</orcid><order>8</order></author></authors><documents><document><filename>0031214-09012017142312.pdf</filename><originalFilename>griffiths.art_10.1007_s12035-016-0281-9.pdf</originalFilename><uploaded>2017-01-09T14:23:12.4470000</uploaded><type>Output</type><contentLength>918102</contentLength><contentType>application/pdf</contentType><version>Enhanced Version of Record</version><cronfaStatus>true</cronfaStatus><embargoDate>2017-01-09T00:00:00.0000000</embargoDate><documentNotes>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.</documentNotes><copyrightCorrect>true</copyrightCorrect></document></documents><OutputDurs/></rfc1807>
spelling 2019-09-24T16:03:58.6758751 v2 31214 2016-11-24 Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 2016-11-24 BMS Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control patients. Analysis was performed following enzyme-assisted derivatisation by liquid chromatography-mass spectrometry (LC-MS) exploiting multistage fragmentation (MS n ). We found increased concentrations of bile acid precursors in CSF from each of the disease states and that patients with inflammatory CNS disease classified as suspected autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P &#60; 0.05) in CSF. Cholesterol concentrations in CSF were not changed except for patients diagnosed with amyotrophic lateral sclerosis (P &#60; 0.01) or pathogen-based infections of the CNS (P &#60; 0.05) where they were elevated. In plasma, we found that 25-HC (P &#60; 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P &#60; 0.05) and 7α-hydroxy-3-oxocholest-4-enoic acid (7αH,3O-CA, P &#60; 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on IL-1 family cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of up-regulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophages Journal Article Molecular Neurobiology 0893-7648 1559-1182 31 12 2016 2016-12-31 10.1007/s12035-016-0281-9 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University RCUK, BBSRC, BB/I001735/1 2019-09-24T16:03:58.6758751 2016-11-24T13:12:17.5674488 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Peter J. Crick 1 William Griffiths 0000-0002-4129-6616 2 Juan Zhang 3 Martin Beibel 4 Jonas Abdel-Khalik 5 Jens Kuhle 6 Andreas W. Sailer 7 Yuqin Wang 0000-0002-3063-3066 8 0031214-09012017142312.pdf griffiths.art_10.1007_s12035-016-0281-9.pdf 2017-01-09T14:23:12.4470000 Output 918102 application/pdf Enhanced Version of Record true 2017-01-09T00:00:00.0000000 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. true
title Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients
spellingShingle Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients
William Griffiths
Yuqin Wang
title_short Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients
title_full Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients
title_fullStr Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients
title_full_unstemmed Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients
title_sort Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients
author_id_str_mv 3316b1d1b524be1831790933eed1c26e
c92729b58622f9fdf6a0e7d8f4ce5081
author_id_fullname_str_mv 3316b1d1b524be1831790933eed1c26e_***_William Griffiths
c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
author William Griffiths
Yuqin Wang
author2 Peter J. Crick
William Griffiths
Juan Zhang
Martin Beibel
Jonas Abdel-Khalik
Jens Kuhle
Andreas W. Sailer
Yuqin Wang
format Journal article
container_title Molecular Neurobiology
publishDate 2016
institution Swansea University
issn 0893-7648
1559-1182
doi_str_mv 10.1007/s12035-016-0281-9
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control patients. Analysis was performed following enzyme-assisted derivatisation by liquid chromatography-mass spectrometry (LC-MS) exploiting multistage fragmentation (MS n ). We found increased concentrations of bile acid precursors in CSF from each of the disease states and that patients with inflammatory CNS disease classified as suspected autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P &#60; 0.05) in CSF. Cholesterol concentrations in CSF were not changed except for patients diagnosed with amyotrophic lateral sclerosis (P &#60; 0.01) or pathogen-based infections of the CNS (P &#60; 0.05) where they were elevated. In plasma, we found that 25-HC (P &#60; 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P &#60; 0.05) and 7α-hydroxy-3-oxocholest-4-enoic acid (7αH,3O-CA, P &#60; 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on IL-1 family cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of up-regulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophages
published_date 2016-12-31T03:38:07Z
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