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Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5 / Anna Meljon; Peter J. Crick; Eylan Yutuc; Joyce L. Yau; Jonathan R. Seckl; Spyridon Theofilopoulos; Ernest Arenas; Yuqin Wang; William J. Griffiths

Biomolecules, Volume: 9, Issue: 4, Start page: 149

Swansea University Author: Griffiths, William

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DOI (Published version): 10.3390/biom9040149

Abstract

Deficiency in cytochrome P450 (CYP) 7B1, also known as oxysterol 7α-hydroxylase, in humans leads to hereditary spastic paraplegia type 5 (SPG5) and in some cases in infants to liver disease. SPG5 is medically characterized by loss of motor neurons in the corticospinal tract. In an effort to gain a b...

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Published in: Biomolecules
ISSN: 2218-273X
Published: 2019
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URI: https://cronfa.swan.ac.uk/Record/cronfa50195
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spelling 2019-09-24T15:55:52Z v2 50195 2019-05-02 Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5 William Griffiths William Griffiths true 0000-0002-4129-6616 false 3316b1d1b524be1831790933eed1c26e 3e4851c27dfd9cf65adbd476d1f7a3bf zaxgD1SlXhR1pE5DoDi9bR8j7kl4zZwebz0wEHEQAUk= 2019-05-02 BMS Deficiency in cytochrome P450 (CYP) 7B1, also known as oxysterol 7α-hydroxylase, in humans leads to hereditary spastic paraplegia type 5 (SPG5) and in some cases in infants to liver disease. SPG5 is medically characterized by loss of motor neurons in the corticospinal tract. In an effort to gain a better understanding of the fundamental biochemistry of this disorder, we have extended our previous profiling of the oxysterol content of brain and plasma of Cyp7b1 knockout (-/-) mice to include, amongst other sterols, 25-hydroxylated cholesterol metabolites. Although brain cholesterol levels do not differ between wild-type (wt) and knockout mice, we find, using a charge-tagging methodology in combination with liquid chromatography-mass spectrometry (LC-MS) and multistage fragmentation (MSn), that there is a build-up of the CYP7B1 substrate 25-hydroxycholesterol (25-HC) in Cyp7b1-/- mouse brain and plasma. As reported earlier, levels of (25R)26-hydroxycholesterol (26-HC), 3β-hydroxycholest-5-en-(25R)26-oic acid and 24S,25-epoxycholesterol (24S,25-EC) are similarly elevated in brain and plasma. Side-chain oxysterols including 25-HC, 26-HC and 24S,25-EC are known to bind to INSIG (insulin-induced gene) and inhibit the processing of SREBP-2 (sterol regulatory element-binding protein-2) to its active form as a master regulator of cholesterol biosynthesis. We suggest the concentration of cholesterol in brain of the Cyp7b1-/- mouse is maintained by balancing reduced metabolism, as a consequence of a loss in CYP7B1, with reduced biosynthesis. The Cyp7b1-/- mouse does not show a motor defect; whether the defect in humans is a consequence of less efficient homeostasis of cholesterol in brain has yet to be uncovered. Journal article Biomolecules 9 4 149 2218-273X 0 0 2019 2019-01-01 10.3390/biom9040149 Swansea University Medical School CMED BMS Biomarkers and genes None 2019-09-24T15:55:52Z 2019-05-02T08:29:39Z Swansea University Medical School Medicine Anna Meljon 1 Peter J. Crick 2 Eylan Yutuc 3 Joyce L. Yau 4 Jonathan R. Seckl 5 Spyridon Theofilopoulos 6 Ernest Arenas 7 Yuqin Wang 8 William J. Griffiths 9 0050195-02052019083155.pdf biomolecules-09-00149.pdf 2019-05-02T08:31:55Z Output 3543684 application/pdf VoR true Published to Cronfa 24/05/2019 2019-05-02T00:00:00 Released under the terms of a Creative Commons Attribution License (CC-BY). true eng
title Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5
spellingShingle Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5
Griffiths, William
title_short Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5
title_full Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5
title_fullStr Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5
title_full_unstemmed Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5
title_sort Mining for Oxysterols in Cyp7b1−/− Mouse Brain and Plasma: Relevance to Spastic Paraplegia Type 5
author_id_str_mv 3316b1d1b524be1831790933eed1c26e
author_id_fullname_str_mv 3316b1d1b524be1831790933eed1c26e_***_Griffiths, William
author Griffiths, William
author2 Anna Meljon
Peter J. Crick
Eylan Yutuc
Joyce L. Yau
Jonathan R. Seckl
Spyridon Theofilopoulos
Ernest Arenas
Yuqin Wang
William J. Griffiths
format Journal article
container_title Biomolecules
container_volume 9
container_issue 4
container_start_page 149
publishDate 2019
institution Swansea University
issn 2218-273X
doi_str_mv 10.3390/biom9040149
college_str Swansea University Medical School
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hierarchy_top_title Swansea University Medical School
hierarchy_parent_id swanseauniversitymedicalschool
hierarchy_parent_title Swansea University Medical School
department_str Medicine{{{_:::_}}}Swansea University Medical School{{{_:::_}}}Medicine
document_store_str 1
active_str 1
researchgroup_str Biomarkers and genes
description Deficiency in cytochrome P450 (CYP) 7B1, also known as oxysterol 7α-hydroxylase, in humans leads to hereditary spastic paraplegia type 5 (SPG5) and in some cases in infants to liver disease. SPG5 is medically characterized by loss of motor neurons in the corticospinal tract. In an effort to gain a better understanding of the fundamental biochemistry of this disorder, we have extended our previous profiling of the oxysterol content of brain and plasma of Cyp7b1 knockout (-/-) mice to include, amongst other sterols, 25-hydroxylated cholesterol metabolites. Although brain cholesterol levels do not differ between wild-type (wt) and knockout mice, we find, using a charge-tagging methodology in combination with liquid chromatography-mass spectrometry (LC-MS) and multistage fragmentation (MSn), that there is a build-up of the CYP7B1 substrate 25-hydroxycholesterol (25-HC) in Cyp7b1-/- mouse brain and plasma. As reported earlier, levels of (25R)26-hydroxycholesterol (26-HC), 3β-hydroxycholest-5-en-(25R)26-oic acid and 24S,25-epoxycholesterol (24S,25-EC) are similarly elevated in brain and plasma. Side-chain oxysterols including 25-HC, 26-HC and 24S,25-EC are known to bind to INSIG (insulin-induced gene) and inhibit the processing of SREBP-2 (sterol regulatory element-binding protein-2) to its active form as a master regulator of cholesterol biosynthesis. We suggest the concentration of cholesterol in brain of the Cyp7b1-/- mouse is maintained by balancing reduced metabolism, as a consequence of a loss in CYP7B1, with reduced biosynthesis. The Cyp7b1-/- mouse does not show a motor defect; whether the defect in humans is a consequence of less efficient homeostasis of cholesterol in brain has yet to be uncovered.
published_date 2019-01-01T05:18:31Z
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score 10.86316