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Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis

Philip Höflinger, Stefan Hauser, Eylan Yutuc Orcid Logo, Holger Hengel, Lauren Griffiths Orcid Logo, Florentine Radelfahr, Owain Howell Orcid Logo, Yuqin Wang Orcid Logo, Sonja L. Connor, P. Barton Duell, Andrea E. DeBarber, Peter Martus, Dieter Lütjohann, William Griffiths Orcid Logo, Ludger Schöls

Journal of Lipid Research, Volume: 62, Start page: 100078

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

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DOI (Published version): 10.1016/j.jlr.2021.100078

Abstract

Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss of function mutations in CYP27A1 resulting in altered bile acid and lipid metabolism. We aimed to identify metabolic aberrations that drive neurodegeneration in CTX despite chenodeoxycholic acid (CDCA) treatment. Therefore, w...

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Published in: Journal of Lipid Research
ISSN: 0022-2275
Published: Elsevier BV 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa56747
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We aimed to identify metabolic aberrations that drive neurodegeneration in CTX despite chenodeoxycholic acid (CDCA) treatment. Therefore, we analyzed 26 sterol metabolites in serum and CSF of patients with CTX and in one CTX brain using chromatographic separation techniques coupled to mass spectrometry. Samples of drug naive patients were compared to patients treated with CDCA and healthy controls. We identified 7&#x3B1;,12&#x3B1;-dihydroxycholest-4-en-3-one as the most prominently elevated metabolite in serum and CSF of drug naive patients compared to controls. Standard diagnostic markers like 5&#x3B1;-cholestanol and 7&#x3B1;-hydroxycholesterol were less consistently elevated in CTX. CDCA treatment substantially reduced or even normalized levels of all metabolites increased in untreated patients with CTX. Independent of CDCA treatment, metabolites of the 27-hydroxylation pathway were almost completely absent in all patients with CTX. 27-hydroxylated metabolites accounted for ~45% of total free sterol content in CSF of healthy controls but &lt;2% in patients with CTX. Metabolic changes in brain tissue corresponded well with findings in CSF. Interestingly, 7&#x3B1;,12&#x3B1;-dihydroxycholest-4-en-3-one and 5&#x3B1;-cholestanol did not exert toxicity in neuronal cell culture. In conclusion, we propose that increased 7&#x3B1;,12&#x3B1;-dihydroxycholest-4-en-3-one and lack of 27-hydroxycholesterol may be the most sensitive metabolic biomarkers of CTX. As CDCA cannot reliably prevent disease progression despite reduction of most accumulated metabolites, supplementation of 27-hydroxylated bile acid intermediates or replacement of CYP27A1 might be required to counter neurodegeneration in patients with progressive disease despite CDCA treatment.</abstract><type>Journal Article</type><journal>Journal of Lipid Research</journal><volume>62</volume><journalNumber/><paginationStart>100078</paginationStart><paginationEnd/><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0022-2275</issnPrint><issnElectronic/><keywords/><publishedDay>20</publishedDay><publishedMonth>4</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-04-20</publishedDate><doi>10.1016/j.jlr.2021.100078</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>UK Biotechnology and Biological Sciences Research Council, grant numbers BB/I001735/1, BB/N015932/1 and BB/L001942/1.</funders><projectreference/><lastEdited>2022-07-25T14:55:06.1836149</lastEdited><Created>2021-04-27T13:55:40.3053887</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>Philip</firstname><surname>H&#xF6;flinger</surname><order>1</order></author><author><firstname>Stefan</firstname><surname>Hauser</surname><order>2</order></author><author><firstname>Eylan</firstname><surname>Yutuc</surname><orcid>0000-0001-9971-1950</orcid><order>3</order></author><author><firstname>Holger</firstname><surname>Hengel</surname><order>4</order></author><author><firstname>Lauren</firstname><surname>Griffiths</surname><orcid>0000-0002-8713-3687</orcid><order>5</order></author><author><firstname>Florentine</firstname><surname>Radelfahr</surname><order>6</order></author><author><firstname>Owain</firstname><surname>Howell</surname><orcid>0000-0003-2157-9157</orcid><order>7</order></author><author><firstname>Yuqin</firstname><surname>Wang</surname><orcid>0000-0002-3063-3066</orcid><order>8</order></author><author><firstname>Sonja L.</firstname><surname>Connor</surname><order>9</order></author><author><firstname>P. 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spelling 2022-07-25T14:55:06.1836149 v2 56747 2021-04-27 Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis 99332f073ce913a9b7d8b6441b17516d 0000-0001-9971-1950 Eylan Yutuc Eylan Yutuc true false 8811c280da03bf66352d97f756e91ae1 0000-0002-8713-3687 Lauren Griffiths Lauren Griffiths true false 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false 2021-04-27 BMS Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss of function mutations in CYP27A1 resulting in altered bile acid and lipid metabolism. We aimed to identify metabolic aberrations that drive neurodegeneration in CTX despite chenodeoxycholic acid (CDCA) treatment. Therefore, we analyzed 26 sterol metabolites in serum and CSF of patients with CTX and in one CTX brain using chromatographic separation techniques coupled to mass spectrometry. Samples of drug naive patients were compared to patients treated with CDCA and healthy controls. We identified 7α,12α-dihydroxycholest-4-en-3-one as the most prominently elevated metabolite in serum and CSF of drug naive patients compared to controls. Standard diagnostic markers like 5α-cholestanol and 7α-hydroxycholesterol were less consistently elevated in CTX. CDCA treatment substantially reduced or even normalized levels of all metabolites increased in untreated patients with CTX. Independent of CDCA treatment, metabolites of the 27-hydroxylation pathway were almost completely absent in all patients with CTX. 27-hydroxylated metabolites accounted for ~45% of total free sterol content in CSF of healthy controls but <2% in patients with CTX. Metabolic changes in brain tissue corresponded well with findings in CSF. Interestingly, 7α,12α-dihydroxycholest-4-en-3-one and 5α-cholestanol did not exert toxicity in neuronal cell culture. In conclusion, we propose that increased 7α,12α-dihydroxycholest-4-en-3-one and lack of 27-hydroxycholesterol may be the most sensitive metabolic biomarkers of CTX. As CDCA cannot reliably prevent disease progression despite reduction of most accumulated metabolites, supplementation of 27-hydroxylated bile acid intermediates or replacement of CYP27A1 might be required to counter neurodegeneration in patients with progressive disease despite CDCA treatment. Journal Article Journal of Lipid Research 62 100078 Elsevier BV 0022-2275 20 4 2021 2021-04-20 10.1016/j.jlr.2021.100078 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee UK Biotechnology and Biological Sciences Research Council, grant numbers BB/I001735/1, BB/N015932/1 and BB/L001942/1. 2022-07-25T14:55:06.1836149 2021-04-27T13:55:40.3053887 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Philip Höflinger 1 Stefan Hauser 2 Eylan Yutuc 0000-0001-9971-1950 3 Holger Hengel 4 Lauren Griffiths 0000-0002-8713-3687 5 Florentine Radelfahr 6 Owain Howell 0000-0003-2157-9157 7 Yuqin Wang 0000-0002-3063-3066 8 Sonja L. Connor 9 P. Barton Duell 10 Andrea E. DeBarber 11 Peter Martus 12 Dieter Lütjohann 13 William Griffiths 0000-0002-4129-6616 14 Ludger Schöls 15 56747__19905__9c23e69f77b64ad2a41dcfde5433e11d.pdf 56747.pdf 2021-05-14T16:43:52.3851892 Output 2283988 application/pdf Version of Record true © 2021 The authors. This is an open access article under the CC BY-NC-ND license true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
spellingShingle Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
Eylan Yutuc
Lauren Griffiths
Owain Howell
Yuqin Wang
William Griffiths
title_short Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
title_full Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
title_fullStr Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
title_full_unstemmed Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
title_sort Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
author_id_str_mv 99332f073ce913a9b7d8b6441b17516d
8811c280da03bf66352d97f756e91ae1
58c995486fc93a242b987640b692db8c
c92729b58622f9fdf6a0e7d8f4ce5081
3316b1d1b524be1831790933eed1c26e
author_id_fullname_str_mv 99332f073ce913a9b7d8b6441b17516d_***_Eylan Yutuc
8811c280da03bf66352d97f756e91ae1_***_Lauren Griffiths
58c995486fc93a242b987640b692db8c_***_Owain Howell
c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
3316b1d1b524be1831790933eed1c26e_***_William Griffiths
author Eylan Yutuc
Lauren Griffiths
Owain Howell
Yuqin Wang
William Griffiths
author2 Philip Höflinger
Stefan Hauser
Eylan Yutuc
Holger Hengel
Lauren Griffiths
Florentine Radelfahr
Owain Howell
Yuqin Wang
Sonja L. Connor
P. Barton Duell
Andrea E. DeBarber
Peter Martus
Dieter Lütjohann
William Griffiths
Ludger Schöls
format Journal article
container_title Journal of Lipid Research
container_volume 62
container_start_page 100078
publishDate 2021
institution Swansea University
issn 0022-2275
doi_str_mv 10.1016/j.jlr.2021.100078
publisher Elsevier BV
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 Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss of function mutations in CYP27A1 resulting in altered bile acid and lipid metabolism. We aimed to identify metabolic aberrations that drive neurodegeneration in CTX despite chenodeoxycholic acid (CDCA) treatment. Therefore, we analyzed 26 sterol metabolites in serum and CSF of patients with CTX and in one CTX brain using chromatographic separation techniques coupled to mass spectrometry. Samples of drug naive patients were compared to patients treated with CDCA and healthy controls. We identified 7α,12α-dihydroxycholest-4-en-3-one as the most prominently elevated metabolite in serum and CSF of drug naive patients compared to controls. Standard diagnostic markers like 5α-cholestanol and 7α-hydroxycholesterol were less consistently elevated in CTX. CDCA treatment substantially reduced or even normalized levels of all metabolites increased in untreated patients with CTX. Independent of CDCA treatment, metabolites of the 27-hydroxylation pathway were almost completely absent in all patients with CTX. 27-hydroxylated metabolites accounted for ~45% of total free sterol content in CSF of healthy controls but <2% in patients with CTX. Metabolic changes in brain tissue corresponded well with findings in CSF. Interestingly, 7α,12α-dihydroxycholest-4-en-3-one and 5α-cholestanol did not exert toxicity in neuronal cell culture. In conclusion, we propose that increased 7α,12α-dihydroxycholest-4-en-3-one and lack of 27-hydroxycholesterol may be the most sensitive metabolic biomarkers of CTX. As CDCA cannot reliably prevent disease progression despite reduction of most accumulated metabolites, supplementation of 27-hydroxylated bile acid intermediates or replacement of CYP27A1 might be required to counter neurodegeneration in patients with progressive disease despite CDCA treatment.
published_date 2021-04-20T04:11:56Z
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