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Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis

Tina Raselli, Tom Hearn, Annika Wyss, Kirstin Atrott, Alain Peter, Isabelle Frey-Wagner, Marianne R. Spalinger, Ewerton M. Maggio, Andreas W. Sailer, Johannes Schmitt, Philipp Schreiner, Anja Moncsek, Joachim Mertens, Michael Scharl, William Griffiths Orcid Logo, Marco Bueter, Andreas Geier, Gerhard Rogler, Yuqin Wang, Benjamin Misselwitz

Journal of Lipid Research, Volume: 60, Issue: 7, Pages: 1270 - 1283

Swansea University Author: William Griffiths Orcid Logo

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DOI (Published version): 10.1194/jlr.M093229

Abstract

Non-alcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein Barr virus induced G protein coupled receptor 2 (EBI2) and its oxysterol ligand 7α,25-dihydro...

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Published in: Journal of Lipid Research
ISSN: 0022-2275 1539-7262
Published: 2019
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URI: https://cronfa.swan.ac.uk/Record/cronfa50635
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2020-06-16T15:25:46.4276920</datestamp><bib-version>v2</bib-version><id>50635</id><entry>2019-06-04</entry><title>Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis</title><swanseaauthors><author><sid>3316b1d1b524be1831790933eed1c26e</sid><ORCID>0000-0002-4129-6616</ORCID><firstname>William</firstname><surname>Griffiths</surname><name>William Griffiths</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2019-06-04</date><deptcode>BMS</deptcode><abstract>Non-alcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein Barr virus induced G protein coupled receptor 2 (EBI2) and its oxysterol ligand 7&#x3B1;,25-dihydroxycholesterol (7&#x3B1;,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in livers of NASH patients by liquid chromatography-mass spectrometry and tested the role of the EBI2-7&#x3B1;,25-diHC-system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared to controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype related differences were observed in Ebi2-/- animals and animals with defects in the 7&#x3B1;,25-diHC synthesizing enzymes CH25H and CYP7B1 compared to wildtype littermate controls,arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by enhanced level of 7&#x3B1;- hydroxycholest-4-en-3-one, and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.</abstract><type>Journal Article</type><journal>Journal of Lipid Research</journal><volume>60</volume><journalNumber>7</journalNumber><paginationStart>1270</paginationStart><paginationEnd>1283</paginationEnd><publisher/><issnPrint>0022-2275</issnPrint><issnElectronic>1539-7262</issnElectronic><keywords>nonalcoholic fatty liver disease, Epstein- Barr virus-induced gene 2, cholesterol 25 hydroxylase, 25-hydroxycholesterol 7 hydroxylase, mouse feeding model</keywords><publishedDay>31</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-12-31</publishedDate><doi>10.1194/jlr.M093229</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><degreesponsorsfunders>UKRI, BB/L001942/1</degreesponsorsfunders><apcterm/><lastEdited>2020-06-16T15:25:46.4276920</lastEdited><Created>2019-06-04T14:10:00.9850127</Created><authors><author><firstname>Tina</firstname><surname>Raselli</surname><order>1</order></author><author><firstname>Tom</firstname><surname>Hearn</surname><order>2</order></author><author><firstname>Annika</firstname><surname>Wyss</surname><order>3</order></author><author><firstname>Kirstin</firstname><surname>Atrott</surname><order>4</order></author><author><firstname>Alain</firstname><surname>Peter</surname><order>5</order></author><author><firstname>Isabelle</firstname><surname>Frey-Wagner</surname><order>6</order></author><author><firstname>Marianne R.</firstname><surname>Spalinger</surname><order>7</order></author><author><firstname>Ewerton M.</firstname><surname>Maggio</surname><order>8</order></author><author><firstname>Andreas W.</firstname><surname>Sailer</surname><order>9</order></author><author><firstname>Johannes</firstname><surname>Schmitt</surname><order>10</order></author><author><firstname>Philipp</firstname><surname>Schreiner</surname><order>11</order></author><author><firstname>Anja</firstname><surname>Moncsek</surname><order>12</order></author><author><firstname>Joachim</firstname><surname>Mertens</surname><order>13</order></author><author><firstname>Michael</firstname><surname>Scharl</surname><order>14</order></author><author><firstname>William</firstname><surname>Griffiths</surname><orcid>0000-0002-4129-6616</orcid><order>15</order></author><author><firstname>Marco</firstname><surname>Bueter</surname><order>16</order></author><author><firstname>Andreas</firstname><surname>Geier</surname><order>17</order></author><author><firstname>Gerhard</firstname><surname>Rogler</surname><order>18</order></author><author><firstname>Yuqin</firstname><surname>Wang</surname><order>19</order></author><author><firstname>Benjamin</firstname><surname>Misselwitz</surname><order>20</order></author></authors><documents><document><filename>0050635-24072019100649.pdf</filename><originalFilename>50635v2.pdf</originalFilename><uploaded>2019-07-24T10:06:49.0500000</uploaded><type>Output</type><contentLength>2219099</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><embargoDate>2019-07-04T00:00:00.0000000</embargoDate><documentNotes>Distributed under the terms of a Creative Commons Attribution International 4.0 (CC-BY) Licence</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2020-06-16T15:25:46.4276920 v2 50635 2019-06-04 Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false 2019-06-04 BMS Non-alcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein Barr virus induced G protein coupled receptor 2 (EBI2) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in livers of NASH patients by liquid chromatography-mass spectrometry and tested the role of the EBI2-7α,25-diHC-system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared to controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype related differences were observed in Ebi2-/- animals and animals with defects in the 7α,25-diHC synthesizing enzymes CH25H and CYP7B1 compared to wildtype littermate controls,arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by enhanced level of 7α- hydroxycholest-4-en-3-one, and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH. Journal Article Journal of Lipid Research 60 7 1270 1283 0022-2275 1539-7262 nonalcoholic fatty liver disease, Epstein- Barr virus-induced gene 2, cholesterol 25 hydroxylase, 25-hydroxycholesterol 7 hydroxylase, mouse feeding model 31 12 2019 2019-12-31 10.1194/jlr.M093229 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University UKRI, BB/L001942/1 2020-06-16T15:25:46.4276920 2019-06-04T14:10:00.9850127 Tina Raselli 1 Tom Hearn 2 Annika Wyss 3 Kirstin Atrott 4 Alain Peter 5 Isabelle Frey-Wagner 6 Marianne R. Spalinger 7 Ewerton M. Maggio 8 Andreas W. Sailer 9 Johannes Schmitt 10 Philipp Schreiner 11 Anja Moncsek 12 Joachim Mertens 13 Michael Scharl 14 William Griffiths 0000-0002-4129-6616 15 Marco Bueter 16 Andreas Geier 17 Gerhard Rogler 18 Yuqin Wang 19 Benjamin Misselwitz 20 0050635-24072019100649.pdf 50635v2.pdf 2019-07-24T10:06:49.0500000 Output 2219099 application/pdf Version of Record true 2019-07-04T00:00:00.0000000 Distributed under the terms of a Creative Commons Attribution International 4.0 (CC-BY) Licence true eng
title Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
spellingShingle Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
William Griffiths
title_short Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
title_full Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
title_fullStr Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
title_full_unstemmed Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
title_sort Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
author_id_str_mv 3316b1d1b524be1831790933eed1c26e
author_id_fullname_str_mv 3316b1d1b524be1831790933eed1c26e_***_William Griffiths
author William Griffiths
author2 Tina Raselli
Tom Hearn
Annika Wyss
Kirstin Atrott
Alain Peter
Isabelle Frey-Wagner
Marianne R. Spalinger
Ewerton M. Maggio
Andreas W. Sailer
Johannes Schmitt
Philipp Schreiner
Anja Moncsek
Joachim Mertens
Michael Scharl
William Griffiths
Marco Bueter
Andreas Geier
Gerhard Rogler
Yuqin Wang
Benjamin Misselwitz
format Journal article
container_title Journal of Lipid Research
container_volume 60
container_issue 7
container_start_page 1270
publishDate 2019
institution Swansea University
issn 0022-2275
1539-7262
doi_str_mv 10.1194/jlr.M093229
document_store_str 1
active_str 0
description Non-alcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein Barr virus induced G protein coupled receptor 2 (EBI2) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in livers of NASH patients by liquid chromatography-mass spectrometry and tested the role of the EBI2-7α,25-diHC-system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared to controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype related differences were observed in Ebi2-/- animals and animals with defects in the 7α,25-diHC synthesizing enzymes CH25H and CYP7B1 compared to wildtype littermate controls,arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by enhanced level of 7α- hydroxycholest-4-en-3-one, and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.
published_date 2019-12-31T04:02:10Z
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score 10.999207

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