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Defective cholesterol metabolism in amyotrophic lateral sclerosis

Jonas Abdel-Khalik, Eylan Yutuc Orcid Logo, Peter J. Crick, Jan-Åke Gustafsson, Margaret Warner, Gustavo Roman, Kevin Talbot, Elizabeth Gray, William Griffiths Orcid Logo, Martin R. Turner, Yuqin Wang Orcid Logo

Journal of Lipid Research, Start page: jlr.P071639

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

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DOI (Published version): 10.1194/jlr.P071639

Abstract

As neurons die cholesterol is released in the central nervous system (CNS), hence this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS) in which altered cholesterol levels have been linked to prognosis. More than 40 different...

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Published in: Journal of Lipid Research
ISSN: 0022-2275 1539-7262
Published: 2017
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URI: https://cronfa.swan.ac.uk/Record/cronfa30987
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More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalised to cholesterol, the cholesterol metabolite 3beta,7alpha-dihydroxycholest-5-en-26-oic acid, along with its precursor 3beta-hydroxycholest-5-en-26-oic acid and product 7alpha-hydroxy-3-oxocholest-4-en-26-oic acid were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3beta-hydroxycholest-5-en-26-oic acid was reduced in concentration in ALS patients compared to controls. We conclude that the acidic branch of bile acid biosynthesis, known to operative in-part in brain, is defective in ALS leading to a failure of the CNS to remove excess cholesterol which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3beta,7alpha-dihydroxycholest-5-en-26-oic acid.</abstract><type>Journal Article</type><journal>Journal of Lipid Research</journal><paginationStart>jlr.P071639</paginationStart><publisher/><issnPrint>0022-2275</issnPrint><issnElectronic>1539-7262</issnElectronic><keywords/><publishedDay>31</publishedDay><publishedMonth>1</publishedMonth><publishedYear>2017</publishedYear><publishedDate>2017-01-31</publishedDate><doi>10.1194/jlr.P071639</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><degreesponsorsfunders>RCUK, BB/I001735/1</degreesponsorsfunders><apcterm/><lastEdited>2019-09-24T16:02:20.6944781</lastEdited><Created>2016-11-08T08:49:06.4062009</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>Jonas</firstname><surname>Abdel-Khalik</surname><order>1</order></author><author><firstname>Eylan</firstname><surname>Yutuc</surname><orcid>0000-0001-9971-1950</orcid><order>2</order></author><author><firstname>Peter J.</firstname><surname>Crick</surname><order>3</order></author><author><firstname>Jan-&#xC5;ke</firstname><surname>Gustafsson</surname><order>4</order></author><author><firstname>Margaret</firstname><surname>Warner</surname><order>5</order></author><author><firstname>Gustavo</firstname><surname>Roman</surname><order>6</order></author><author><firstname>Kevin</firstname><surname>Talbot</surname><order>7</order></author><author><firstname>Elizabeth</firstname><surname>Gray</surname><order>8</order></author><author><firstname>William</firstname><surname>Griffiths</surname><orcid>0000-0002-4129-6616</orcid><order>9</order></author><author><firstname>Martin R.</firstname><surname>Turner</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>0030987-09012017085302.pdf</filename><originalFilename>AbdelKhalik.pdf</originalFilename><uploaded>2017-01-09T08:53:02.7170000</uploaded><type>Output</type><contentLength>1594485</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><embargoDate>2016-01-09T00:00:00.0000000</embargoDate><documentNotes>Distributed under the terms of a Creative Commons CC-BY license.</documentNotes><copyrightCorrect>true</copyrightCorrect></document><document><filename>0030987-20122016110528.pdf</filename><originalFilename>Defective_cholesterol_metabolism_in_amyotrophic_lateral_sclerosisv2.pdf</originalFilename><uploaded>2016-12-20T11:05:28.2700000</uploaded><type>Output</type><contentLength>764727</contentLength><contentType>application/pdf</contentType><version>Accepted Manuscript</version><cronfaStatus>true</cronfaStatus><embargoDate>2016-11-03T00:00:00.0000000</embargoDate><copyrightCorrect>true</copyrightCorrect></document></documents><OutputDurs/></rfc1807>
spelling 2019-09-24T16:02:20.6944781 v2 30987 2016-11-08 Defective cholesterol metabolism in amyotrophic lateral sclerosis 99332f073ce913a9b7d8b6441b17516d 0000-0001-9971-1950 Eylan Yutuc Eylan Yutuc true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 2016-11-08 BMS As neurons die cholesterol is released in the central nervous system (CNS), hence this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS) in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalised to cholesterol, the cholesterol metabolite 3beta,7alpha-dihydroxycholest-5-en-26-oic acid, along with its precursor 3beta-hydroxycholest-5-en-26-oic acid and product 7alpha-hydroxy-3-oxocholest-4-en-26-oic acid were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3beta-hydroxycholest-5-en-26-oic acid was reduced in concentration in ALS patients compared to controls. We conclude that the acidic branch of bile acid biosynthesis, known to operative in-part in brain, is defective in ALS leading to a failure of the CNS to remove excess cholesterol which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3beta,7alpha-dihydroxycholest-5-en-26-oic acid. Journal Article Journal of Lipid Research jlr.P071639 0022-2275 1539-7262 31 1 2017 2017-01-31 10.1194/jlr.P071639 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University RCUK, BB/I001735/1 2019-09-24T16:02:20.6944781 2016-11-08T08:49:06.4062009 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Jonas Abdel-Khalik 1 Eylan Yutuc 0000-0001-9971-1950 2 Peter J. Crick 3 Jan-Åke Gustafsson 4 Margaret Warner 5 Gustavo Roman 6 Kevin Talbot 7 Elizabeth Gray 8 William Griffiths 0000-0002-4129-6616 9 Martin R. Turner 10 Yuqin Wang 0000-0002-3063-3066 11 0030987-09012017085302.pdf AbdelKhalik.pdf 2017-01-09T08:53:02.7170000 Output 1594485 application/pdf Version of Record true 2016-01-09T00:00:00.0000000 Distributed under the terms of a Creative Commons CC-BY license. true 0030987-20122016110528.pdf Defective_cholesterol_metabolism_in_amyotrophic_lateral_sclerosisv2.pdf 2016-12-20T11:05:28.2700000 Output 764727 application/pdf Accepted Manuscript true 2016-11-03T00:00:00.0000000 true
title Defective cholesterol metabolism in amyotrophic lateral sclerosis
spellingShingle Defective cholesterol metabolism in amyotrophic lateral sclerosis
Eylan Yutuc
William Griffiths
Yuqin Wang
title_short Defective cholesterol metabolism in amyotrophic lateral sclerosis
title_full Defective cholesterol metabolism in amyotrophic lateral sclerosis
title_fullStr Defective cholesterol metabolism in amyotrophic lateral sclerosis
title_full_unstemmed Defective cholesterol metabolism in amyotrophic lateral sclerosis
title_sort Defective cholesterol metabolism in amyotrophic lateral sclerosis
author_id_str_mv 99332f073ce913a9b7d8b6441b17516d
3316b1d1b524be1831790933eed1c26e
c92729b58622f9fdf6a0e7d8f4ce5081
author_id_fullname_str_mv 99332f073ce913a9b7d8b6441b17516d_***_Eylan Yutuc
3316b1d1b524be1831790933eed1c26e_***_William Griffiths
c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
author Eylan Yutuc
William Griffiths
Yuqin Wang
author2 Jonas Abdel-Khalik
Eylan Yutuc
Peter J. Crick
Jan-Åke Gustafsson
Margaret Warner
Gustavo Roman
Kevin Talbot
Elizabeth Gray
William Griffiths
Martin R. Turner
Yuqin Wang
format Journal article
container_title Journal of Lipid Research
container_start_page jlr.P071639
publishDate 2017
institution Swansea University
issn 0022-2275
1539-7262
doi_str_mv 10.1194/jlr.P071639
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 As neurons die cholesterol is released in the central nervous system (CNS), hence this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS) in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalised to cholesterol, the cholesterol metabolite 3beta,7alpha-dihydroxycholest-5-en-26-oic acid, along with its precursor 3beta-hydroxycholest-5-en-26-oic acid and product 7alpha-hydroxy-3-oxocholest-4-en-26-oic acid were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3beta-hydroxycholest-5-en-26-oic acid was reduced in concentration in ALS patients compared to controls. We conclude that the acidic branch of bile acid biosynthesis, known to operative in-part in brain, is defective in ALS leading to a failure of the CNS to remove excess cholesterol which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3beta,7alpha-dihydroxycholest-5-en-26-oic acid.
published_date 2017-01-31T03:37:47Z
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