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Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates

Jonas Abdel-Khalik, Tom Hearn Orcid Logo, Alison Dickson, Peter Crick, Eylan Yutuc Orcid Logo, Karl Austin-Muttitt, Brian W. Bigger, Andrew A. Morris, Cedric H. Shackleton, Peter T. Clayton, Takashi Iida, Ria Sircar, Rajat Rohatgi, Hanns-Ulrich Marschall, Jan Sjövall, Ingemar Björkhem, Jonathan Mullins Orcid Logo, William Griffiths Orcid Logo, Yuqin Wang Orcid Logo

The Journal of Steroid Biochemistry and Molecular Biology, Volume: 206, Start page: 105794

Swansea University Authors: Jonas Abdel-Khalik, Tom Hearn Orcid Logo, Alison Dickson, Peter Crick, Eylan Yutuc Orcid Logo, Karl Austin-Muttitt, Jonathan Mullins Orcid Logo, William Griffiths Orcid Logo, Yuqin Wang Orcid Logo

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DOI (Published version): 10.1016/j.jsbmb.2020.105794

Abstract

Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz s...

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Published in: The Journal of Steroid Biochemistry and Molecular Biology
ISSN: 0960-0760
Published: Elsevier BV 2021
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They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual &#x394;5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography &#x2013; mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7&#x3B2;-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3&#x3B2;-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7&#x3B2;-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7&#x3B2;-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.</abstract><type>Journal Article</type><journal>The Journal of Steroid Biochemistry and Molecular Biology</journal><volume>206</volume><journalNumber/><paginationStart>105794</paginationStart><paginationEnd/><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0960-0760</issnPrint><issnElectronic/><keywords>sterol; oxysterol; bile acid7-dehydrocholesterol; Smith-Lemli-Opitz syndrome; high-performance liquid chromatography; mass spectrometry; Hedgehog signalling pathway</keywords><publishedDay>1</publishedDay><publishedMonth>2</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-02-01</publishedDate><doi>10.1016/j.jsbmb.2020.105794</doi><url/><notes/><college>COLLEGE NANME</college><department>Medicine</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>PMSC</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>UKRI, BB/N015932/1</funders><projectreference/><lastEdited>2022-11-02T11:17:27.4169953</lastEdited><Created>2020-11-18T13:47:10.4323808</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>Tom</firstname><surname>Hearn</surname><orcid>0000-0002-8670-6236</orcid><order>2</order></author><author><firstname>Alison</firstname><surname>Dickson</surname><order>3</order></author><author><firstname>Peter</firstname><surname>Crick</surname><orcid/><order>4</order></author><author><firstname>Eylan</firstname><surname>Yutuc</surname><orcid>0000-0001-9971-1950</orcid><order>5</order></author><author><firstname>Karl</firstname><surname>Austin-Muttitt</surname><order>6</order></author><author><firstname>Brian W.</firstname><surname>Bigger</surname><order>7</order></author><author><firstname>Andrew A.</firstname><surname>Morris</surname><order>8</order></author><author><firstname>Cedric H.</firstname><surname>Shackleton</surname><order>9</order></author><author><firstname>Peter T.</firstname><surname>Clayton</surname><order>10</order></author><author><firstname>Takashi</firstname><surname>Iida</surname><order>11</order></author><author><firstname>Ria</firstname><surname>Sircar</surname><order>12</order></author><author><firstname>Rajat</firstname><surname>Rohatgi</surname><order>13</order></author><author><firstname>Hanns-Ulrich</firstname><surname>Marschall</surname><order>14</order></author><author><firstname>Jan</firstname><surname>Sj&#xF6;vall</surname><order>15</order></author><author><firstname>Ingemar</firstname><surname>Bj&#xF6;rkhem</surname><order>16</order></author><author><firstname>Jonathan</firstname><surname>Mullins</surname><orcid>0000-0003-0144-2962</orcid><order>17</order></author><author><firstname>William</firstname><surname>Griffiths</surname><orcid>0000-0002-4129-6616</orcid><order>18</order></author><author><firstname>Yuqin</firstname><surname>Wang</surname><orcid>0000-0002-3063-3066</orcid><order>19</order></author></authors><documents><document><filename>55690__18919__e52f25e694c248b6a4176abcda9f7cb8.pdf</filename><originalFilename>55690.VOR.pdf</originalFilename><uploaded>2020-12-22T13:04:39.2221326</uploaded><type>Output</type><contentLength>8043624</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>&#xA9; 2020 Author(s). 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spelling 2022-11-02T11:17:27.4169953 v2 55690 2020-11-18 Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates 1ad85bb2d1b5ef373f12a2d3c1889823 Jonas Abdel-Khalik Jonas Abdel-Khalik true false 178364849acc94043710f4704d2e05bc 0000-0002-8670-6236 Tom Hearn Tom Hearn true false 82dc4360769527a5f3a0cd9d85cdff40 Alison Dickson Alison Dickson true false 9e8253a728dc2ad7303ee8928fc85560 Peter Crick Peter Crick true false 99332f073ce913a9b7d8b6441b17516d 0000-0001-9971-1950 Eylan Yutuc Eylan Yutuc true false fafc0917b48af4eaec154646854867f8 Karl Austin-Muttitt Karl Austin-Muttitt true false 4cf2dddedbe1dacb506ec925fdbd5b40 0000-0003-0144-2962 Jonathan Mullins Jonathan Mullins true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 2020-11-18 PMSC Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography – mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway. Journal Article The Journal of Steroid Biochemistry and Molecular Biology 206 105794 Elsevier BV 0960-0760 sterol; oxysterol; bile acid7-dehydrocholesterol; Smith-Lemli-Opitz syndrome; high-performance liquid chromatography; mass spectrometry; Hedgehog signalling pathway 1 2 2021 2021-02-01 10.1016/j.jsbmb.2020.105794 COLLEGE NANME Medicine COLLEGE CODE PMSC Swansea University UKRI, BB/N015932/1 2022-11-02T11:17:27.4169953 2020-11-18T13:47:10.4323808 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Jonas Abdel-Khalik 1 Tom Hearn 0000-0002-8670-6236 2 Alison Dickson 3 Peter Crick 4 Eylan Yutuc 0000-0001-9971-1950 5 Karl Austin-Muttitt 6 Brian W. Bigger 7 Andrew A. Morris 8 Cedric H. Shackleton 9 Peter T. Clayton 10 Takashi Iida 11 Ria Sircar 12 Rajat Rohatgi 13 Hanns-Ulrich Marschall 14 Jan Sjövall 15 Ingemar Björkhem 16 Jonathan Mullins 0000-0003-0144-2962 17 William Griffiths 0000-0002-4129-6616 18 Yuqin Wang 0000-0002-3063-3066 19 55690__18919__e52f25e694c248b6a4176abcda9f7cb8.pdf 55690.VOR.pdf 2020-12-22T13:04:39.2221326 Output 8043624 application/pdf Version of Record true © 2020 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 (CC BY) License. true eng https://creativecommons.org/licenses/by/4.0/
title Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates
spellingShingle Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates
Jonas Abdel-Khalik
Tom Hearn
Alison Dickson
Peter Crick
Eylan Yutuc
Karl Austin-Muttitt
Jonathan Mullins
William Griffiths
Yuqin Wang
title_short Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates
title_full Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates
title_fullStr Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates
title_full_unstemmed Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates
title_sort Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates
author_id_str_mv 1ad85bb2d1b5ef373f12a2d3c1889823
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author_id_fullname_str_mv 1ad85bb2d1b5ef373f12a2d3c1889823_***_Jonas Abdel-Khalik
178364849acc94043710f4704d2e05bc_***_Tom Hearn
82dc4360769527a5f3a0cd9d85cdff40_***_Alison Dickson
9e8253a728dc2ad7303ee8928fc85560_***_Peter Crick
99332f073ce913a9b7d8b6441b17516d_***_Eylan Yutuc
fafc0917b48af4eaec154646854867f8_***_Karl Austin-Muttitt
4cf2dddedbe1dacb506ec925fdbd5b40_***_Jonathan Mullins
3316b1d1b524be1831790933eed1c26e_***_William Griffiths
c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
author Jonas Abdel-Khalik
Tom Hearn
Alison Dickson
Peter Crick
Eylan Yutuc
Karl Austin-Muttitt
Jonathan Mullins
William Griffiths
Yuqin Wang
author2 Jonas Abdel-Khalik
Tom Hearn
Alison Dickson
Peter Crick
Eylan Yutuc
Karl Austin-Muttitt
Brian W. Bigger
Andrew A. Morris
Cedric H. Shackleton
Peter T. Clayton
Takashi Iida
Ria Sircar
Rajat Rohatgi
Hanns-Ulrich Marschall
Jan Sjövall
Ingemar Björkhem
Jonathan Mullins
William Griffiths
Yuqin Wang
format Journal article
container_title The Journal of Steroid Biochemistry and Molecular Biology
container_volume 206
container_start_page 105794
publishDate 2021
institution Swansea University
issn 0960-0760
doi_str_mv 10.1016/j.jsbmb.2020.105794
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 Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography – mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.
published_date 2021-02-01T04:10:06Z
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