Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant

Yutuc, Eylan; Ghosh, Arunabha; Abdel-Khalik, Jonas; Goenka, Anu; Asgari, Mohsen Ali; Lopez-Castejon, Gloria; Beaman, Glenda M; Wynn, Robert F; Newman, William G; Jones, Simon A; Griffiths, William; Wang, Yuqin

doi:10.1101/2025.07.29.25330953

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Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoieti...

Eylan Yutuc

, Arunabha Ghosh

, Jonas Abdel-Khalik, Anu Goenka

, Mohsen Ali Asgari, Gloria Lopez-Castejon

, Glenda M Beaman

, Robert F Wynn

, William G Newman

, Simon A Jones

, William Griffiths

, Yuqin Wang

medRxiv

Swansea University Authors: Eylan Yutuc , Jonas Abdel-Khalik, Mohsen Ali Asgari, William Griffiths , Yuqin Wang

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DOI (Published version): 10.1101/2025.07.29.25330953

Abstract

The CH25H (cholesterol 25-hyroxylase) and LIPA (lipase A, lysosomal acid type) genes are contiguousgenes on chromosome 10. CH25H is translated to cholesterol 25-hydroxylase which generates 25-hydroxycholesterol (25-HC) from cholesterol, while LIPA codes for lysosomal acid lipase (LAL) whichhydrolyse...

Full description

Published in:	medRxiv
Published:	Cold Spring Harbor Laboratory
URI:	https://cronfa.swan.ac.uk/Record/cronfa70079

first_indexed	2025-07-31T12:37:31Z
last_indexed	2025-12-13T05:28:42Z
id	cronfa70079
recordtype	SURis
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CH25H is translated to cholesterol 25-hydroxylase which generates 25-hydroxycholesterol (25-HC) from cholesterol, while LIPA codes for lysosomal acid lipase (LAL) whichhydrolyses cholesteryl esters in the endosome – lysosome compartment. Here we report the effecton the oxysterol pattern in plasma of the homozygous deletion of these two genes and theirrestoration by allogeneic hematopoietic stem cell transplant (HSCT). In the absence of CH25H, 25-HCis not detected in plasma, but surprisingly, 7α,25-dihydroxysterols are present, indicating theirformation by a second sterol 25-hydroxylase. As with the isolated deletion of LIPA seen in Wolmandisease, patients with the homozygous contiguous deletion show high levels of cholesterolautoxidation products in plasma. HSCT of patients with the contiguous deletion restores both 25-HCand autoxidation products to normal levels following an initial burst in autoxidation soon aftertransplant.</abstract><type>Journal Article</type><journal>medRxiv</journal><volume/><journalNumber/><paginationStart/><paginationEnd/><publisher>Cold Spring Harbor Laboratory</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic/><keywords/><publishedDay>0</publishedDay><publishedMonth>0</publishedMonth><publishedYear>0</publishedYear><publishedDate>0001-01-01</publishedDate><doi>10.1101/2025.07.29.25330953</doi><url/><notes>Preprint article before certification by peer review.</notes><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Not Required</apcterm><funders>BB/I001735/1, BB/N015932/1, BB/S019588/1, MR/X012387/1, MR/Y008057/1 and BB/L001942/1</funders><projectreference/><lastEdited>2025-12-12T14:17:24.3176848</lastEdited><Created>2025-07-31T13:27:19.5662836</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Eylan</firstname><surname>Yutuc</surname><orcid>0000-0001-9971-1950</orcid><order>1</order></author><author><firstname>Arunabha</firstname><surname>Ghosh</surname><orcid>0000-0002-8202-8693</orcid><order>2</order></author><author><firstname>Jonas</firstname><surname>Abdel-Khalik</surname><order>3</order></author><author><firstname>Anu</firstname><surname>Goenka</surname><orcid>0000-0002-8152-2155</orcid><order>4</order></author><author><firstname>Mohsen</firstname><surname>Ali Asgari</surname><order>5</order></author><author><firstname>Gloria</firstname><surname>Lopez-Castejon</surname><orcid>0000-0002-8585-3381</orcid><order>6</order></author><author><firstname>Glenda M</firstname><surname>Beaman</surname><orcid>0000-0002-6098-9995</orcid><order>7</order></author><author><firstname>Robert F</firstname><surname>Wynn</surname><orcid>0000-0002-6046-8428</orcid><order>8</order></author><author><firstname>William G</firstname><surname>Newman</surname><orcid>0000-0002-6382-4678</orcid><order>9</order></author><author><firstname>Simon A</firstname><surname>Jones</surname><orcid>0000-0002-5117-0566</orcid><order>10</order></author><author><firstname>William</firstname><surname>Griffiths</surname><orcid>0000-0002-4129-6616</orcid><order>11</order></author><author><firstname>Yuqin</firstname><surname>Wang</surname><orcid>0000-0002-3063-3066</orcid><order>12</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling	2025-12-12T14:17:24.3176848 v2 70079 2025-07-31 Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant 99332f073ce913a9b7d8b6441b17516d 0000-0001-9971-1950 Eylan Yutuc Eylan Yutuc true false 1ad85bb2d1b5ef373f12a2d3c1889823 Jonas Abdel-Khalik Jonas Abdel-Khalik true false 58bf75dabf1a8c8d58eda61b305d3cfd Mohsen Ali Asgari Mohsen Ali Asgari true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 2025-07-31 MEDS The CH25H (cholesterol 25-hyroxylase) and LIPA (lipase A, lysosomal acid type) genes are contiguousgenes on chromosome 10. CH25H is translated to cholesterol 25-hydroxylase which generates 25-hydroxycholesterol (25-HC) from cholesterol, while LIPA codes for lysosomal acid lipase (LAL) whichhydrolyses cholesteryl esters in the endosome – lysosome compartment. Here we report the effecton the oxysterol pattern in plasma of the homozygous deletion of these two genes and theirrestoration by allogeneic hematopoietic stem cell transplant (HSCT). In the absence of CH25H, 25-HCis not detected in plasma, but surprisingly, 7α,25-dihydroxysterols are present, indicating theirformation by a second sterol 25-hydroxylase. As with the isolated deletion of LIPA seen in Wolmandisease, patients with the homozygous contiguous deletion show high levels of cholesterolautoxidation products in plasma. HSCT of patients with the contiguous deletion restores both 25-HCand autoxidation products to normal levels following an initial burst in autoxidation soon aftertransplant. Journal Article medRxiv Cold Spring Harbor Laboratory 0 0 0 0001-01-01 10.1101/2025.07.29.25330953 Preprint article before certification by peer review. COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Not Required BB/I001735/1, BB/N015932/1, BB/S019588/1, MR/X012387/1, MR/Y008057/1 and BB/L001942/1 2025-12-12T14:17:24.3176848 2025-07-31T13:27:19.5662836 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Eylan Yutuc 0000-0001-9971-1950 1 Arunabha Ghosh 0000-0002-8202-8693 2 Jonas Abdel-Khalik 3 Anu Goenka 0000-0002-8152-2155 4 Mohsen Ali Asgari 5 Gloria Lopez-Castejon 0000-0002-8585-3381 6 Glenda M Beaman 0000-0002-6098-9995 7 Robert F Wynn 0000-0002-6046-8428 8 William G Newman 0000-0002-6382-4678 9 Simon A Jones 0000-0002-5117-0566 10 William Griffiths 0000-0002-4129-6616 11 Yuqin Wang 0000-0002-3063-3066 12
title	Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant
spellingShingle	Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant Eylan Yutuc Jonas Abdel-Khalik Mohsen Ali Asgari William Griffiths Yuqin Wang
title_short	Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant
title_full	Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant
title_fullStr	Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant
title_full_unstemmed	Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant
title_sort	Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant
author_id_str_mv	99332f073ce913a9b7d8b6441b17516d 1ad85bb2d1b5ef373f12a2d3c1889823 58bf75dabf1a8c8d58eda61b305d3cfd 3316b1d1b524be1831790933eed1c26e c92729b58622f9fdf6a0e7d8f4ce5081
author_id_fullname_str_mv	99332f073ce913a9b7d8b6441b17516d_*_Eylan Yutuc 1ad85bb2d1b5ef373f12a2d3c1889823__Jonas Abdel-Khalik 58bf75dabf1a8c8d58eda61b305d3cfd__Mohsen Ali Asgari 3316b1d1b524be1831790933eed1c26e__William Griffiths c92729b58622f9fdf6a0e7d8f4ce5081_**_Yuqin Wang
author	Eylan Yutuc Jonas Abdel-Khalik Mohsen Ali Asgari William Griffiths Yuqin Wang
author2	Eylan Yutuc Arunabha Ghosh Jonas Abdel-Khalik Anu Goenka Mohsen Ali Asgari Gloria Lopez-Castejon Glenda M Beaman Robert F Wynn William G Newman Simon A Jones William Griffiths Yuqin Wang
format	Journal article
container_title	medRxiv
institution	Swansea University
doi_str_mv	10.1101/2025.07.29.25330953
publisher	Cold Spring Harbor Laboratory
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 - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str	0
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description	The CH25H (cholesterol 25-hyroxylase) and LIPA (lipase A, lysosomal acid type) genes are contiguousgenes on chromosome 10. CH25H is translated to cholesterol 25-hydroxylase which generates 25-hydroxycholesterol (25-HC) from cholesterol, while LIPA codes for lysosomal acid lipase (LAL) whichhydrolyses cholesteryl esters in the endosome – lysosome compartment. Here we report the effecton the oxysterol pattern in plasma of the homozygous deletion of these two genes and theirrestoration by allogeneic hematopoietic stem cell transplant (HSCT). In the absence of CH25H, 25-HCis not detected in plasma, but surprisingly, 7α,25-dihydroxysterols are present, indicating theirformation by a second sterol 25-hydroxylase. As with the isolated deletion of LIPA seen in Wolmandisease, patients with the homozygous contiguous deletion show high levels of cholesterolautoxidation products in plasma. HSCT of patients with the contiguous deletion restores both 25-HCand autoxidation products to normal levels following an initial burst in autoxidation soon aftertransplant.
published_date	0001-01-01T05:24:03Z
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score	11.08976

Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoieti...

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