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Sterols and oxysterols in brain and the immune system. / Anna Meljon

Swansea University Author: Anna Meljon

Abstract

This project investigates sterol and oxysterol content of murine brain and macrophages. Oxysterols are oxidised forms of cholesterol implicated in a wide array of biological functions. The compounds were analysed with LC-MS LTQ-Orbitrap high resolution system, which provides a highly sensitive and a...

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Published: 2014
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa42246
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first_indexed 2018-08-02T18:54:14Z
last_indexed 2019-10-21T16:47:28Z
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spelling 2018-08-29T14:59:26.3868043 v2 42246 2018-08-02 Sterols and oxysterols in brain and the immune system. 6af6621afb74242fd9ef718a275409c7 NULL Anna Meljon Anna Meljon true true 2018-08-02 This project investigates sterol and oxysterol content of murine brain and macrophages. Oxysterols are oxidised forms of cholesterol implicated in a wide array of biological functions. The compounds were analysed with LC-MS LTQ-Orbitrap high resolution system, which provides a highly sensitive and accurate tool for analysis of metabolites. We profiled a sterol content of newborn murine brain and identified a broad spectrum of oxysterols. Some of these compounds are implicated in neurogenesis, a number of other oxysterols derived from desmosterol were identified in brain tissue for the first time. We analysed murine model of human disease arising from reduced ability to produce cholesterol (SLOS). The sterol profile showed an altered level of cholesterol precursors and generally lowered concentration of oxysterols. Next, we moved to analysis of brain lipidome from animals with disrupted mechanisms of cholesterol metabolism. Cholesterol hydroxylase Cyp46al provides the mechanism of cholesterol removal from the brain. The study of the knock out mice did not reveal the existence of any compensatory mechanisms. The results showed mainly the reduction in cholesterol synthesis. We profiled a sterol content of Cyp27al-/- mouse brain. Cyp27al participates in bile acid synthesis. The steroid profile revealed changed pattern of mono- and polihydroxylated sterols suggesting an upregulation of an alternative pathway of bile acid synthesis. We also analysed the consequence of deficiency of another enzyme involved in bile acids synthesis Cyp7bl. In brain of Cyp7bl-/- mouse we found elevated levels of known Cyp7bl substrates, and increased concentration of other, putative substrates for this enzyme. The last experimental chapter concentrates on analysis of murine macrophages treated with interferon beta and gamma. The treatment induced an increased production of 25-hydroxycholesterol. This links sterol metabolism with mechanisms of immune defence. E-Thesis Neurosciences.;Biochemistry. 31 12 2014 2014-12-31 COLLEGE NANME Swansea University Medical School COLLEGE CODE Swansea University Doctoral Ph.D 2018-08-29T14:59:26.3868043 2018-08-02T16:24:28.5577850 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Anna Meljon NULL 1 0042246-02082018162439.pdf 10797954.pdf 2018-08-02T16:24:39.4930000 Output 24428230 application/pdf E-Thesis true 2018-08-02T16:24:39.4930000 false
title Sterols and oxysterols in brain and the immune system.
spellingShingle Sterols and oxysterols in brain and the immune system.
Anna Meljon
title_short Sterols and oxysterols in brain and the immune system.
title_full Sterols and oxysterols in brain and the immune system.
title_fullStr Sterols and oxysterols in brain and the immune system.
title_full_unstemmed Sterols and oxysterols in brain and the immune system.
title_sort Sterols and oxysterols in brain and the immune system.
author_id_str_mv 6af6621afb74242fd9ef718a275409c7
author_id_fullname_str_mv 6af6621afb74242fd9ef718a275409c7_***_Anna Meljon
author Anna Meljon
author2 Anna Meljon
format E-Thesis
publishDate 2014
institution Swansea University
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 This project investigates sterol and oxysterol content of murine brain and macrophages. Oxysterols are oxidised forms of cholesterol implicated in a wide array of biological functions. The compounds were analysed with LC-MS LTQ-Orbitrap high resolution system, which provides a highly sensitive and accurate tool for analysis of metabolites. We profiled a sterol content of newborn murine brain and identified a broad spectrum of oxysterols. Some of these compounds are implicated in neurogenesis, a number of other oxysterols derived from desmosterol were identified in brain tissue for the first time. We analysed murine model of human disease arising from reduced ability to produce cholesterol (SLOS). The sterol profile showed an altered level of cholesterol precursors and generally lowered concentration of oxysterols. Next, we moved to analysis of brain lipidome from animals with disrupted mechanisms of cholesterol metabolism. Cholesterol hydroxylase Cyp46al provides the mechanism of cholesterol removal from the brain. The study of the knock out mice did not reveal the existence of any compensatory mechanisms. The results showed mainly the reduction in cholesterol synthesis. We profiled a sterol content of Cyp27al-/- mouse brain. Cyp27al participates in bile acid synthesis. The steroid profile revealed changed pattern of mono- and polihydroxylated sterols suggesting an upregulation of an alternative pathway of bile acid synthesis. We also analysed the consequence of deficiency of another enzyme involved in bile acids synthesis Cyp7bl. In brain of Cyp7bl-/- mouse we found elevated levels of known Cyp7bl substrates, and increased concentration of other, putative substrates for this enzyme. The last experimental chapter concentrates on analysis of murine macrophages treated with interferon beta and gamma. The treatment induced an increased production of 25-hydroxycholesterol. This links sterol metabolism with mechanisms of immune defence.
published_date 2014-12-31T03:52:46Z
_version_ 1760947881229942784
score 10.937284

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