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Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain

A. A. Saeed, G. Genove, T. Li, D. Luetjohann, M. Olin, N. Mast, I. A. Pikuleva, P. Crick, Y. Wang, W. Griffiths, C. Betsholtz, I. Bjorkhem, William Griffiths Orcid Logo, Yuqin Wang Orcid Logo

Journal of Biological Chemistry

Swansea University Authors: William Griffiths Orcid Logo, Yuqin Wang Orcid Logo

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DOI (Published version): 10.1074/jbc.M114.556159

Abstract

Presence of the blood-brain barrier (BBB) is critical for cholesterol metabolism in the brain, preventing uptake of lipoprotein-bound cholesterol from the circulation. The metabolic consequences of a leaking BBB for cholesterol metabolism has not been studied previously. Here we used a pericyte-defi...

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Published in: Journal of Biological Chemistry
Published: 2014
URI: https://cronfa.swan.ac.uk/Record/cronfa18147
first_indexed 2014-07-18T01:30:21Z
last_indexed 2018-02-09T04:52:27Z
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recordtype SURis
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spelling 2015-11-23T15:36:55.1020851 v2 18147 2014-07-17 Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 2014-07-17 MEDS Presence of the blood-brain barrier (BBB) is critical for cholesterol metabolism in the brain, preventing uptake of lipoprotein-bound cholesterol from the circulation. The metabolic consequences of a leaking BBB for cholesterol metabolism has not been studied previously. Here we used a pericyte-deficient mouse model, pdgfbret/ret, shown to have increased permeability of the BBB to a range of low-molecular mass and high-molecular mass tracers. There was a significant accumulation of plant sterols in the brain of the pdgfbret/ret mice. By dietary treatment with 0.3% deuterium labeled cholesterol we could demonstrate a significant flux of cholesterol from the circulation into the brain of the mutant mice roughly corresponding to about half of the measured turnover of cholesterol in the brain. We expected the cholesterol flux into the brain to cause a downregulation of cholesterol synthesis. Instead cholesterol synthesis was increased by about 60%. The levels of 24S-hydroxycholesterol (24S-OHC) were significantly reduced in the brain of the pericyte deficient mice but increased in the circulation. After treatment with 1% cholesterol in diet the difference in cholesterol synthesis between mutants and controls disappeared. The findings are consistent with increased leakage of 24S-OHC from the brain into the circulation in the pericyte-deficient mice. This oxysterol is an efficient suppressor of cholesterol synthesis and the results are consistent with a regulatory role of 24S-OHC in the brain. To our knowledge this is the first demonstration that a defect BBB may lead to increased flux of a lipophilic compound out from the brain. The relevance of the findings for the human situation is discussed. Journal Article Journal of Biological Chemistry 31 12 2014 2014-12-31 10.1074/jbc.M114.556159 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2015-11-23T15:36:55.1020851 2014-07-17T08:53:41.3345985 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine A. A. Saeed 1 G. Genove 2 T. Li 3 D. Luetjohann 4 M. Olin 5 N. Mast 6 I. A. Pikuleva 7 P. Crick 8 Y. Wang 9 W. Griffiths 10 C. Betsholtz 11 I. Bjorkhem 12 William Griffiths 0000-0002-4129-6616 13 Yuqin Wang 0000-0002-3063-3066 14
title Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain
spellingShingle Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain
William Griffiths
Yuqin Wang
title_short Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain
title_full Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain
title_fullStr Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain
title_full_unstemmed Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain
title_sort Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain
author_id_str_mv 3316b1d1b524be1831790933eed1c26e
c92729b58622f9fdf6a0e7d8f4ce5081
author_id_fullname_str_mv 3316b1d1b524be1831790933eed1c26e_***_William Griffiths
c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
author William Griffiths
Yuqin Wang
author2 A. A. Saeed
G. Genove
T. Li
D. Luetjohann
M. Olin
N. Mast
I. A. Pikuleva
P. Crick
Y. Wang
W. Griffiths
C. Betsholtz
I. Bjorkhem
William Griffiths
Yuqin Wang
format Journal article
container_title Journal of Biological Chemistry
publishDate 2014
institution Swansea University
doi_str_mv 10.1074/jbc.M114.556159
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 0
active_str 0
description Presence of the blood-brain barrier (BBB) is critical for cholesterol metabolism in the brain, preventing uptake of lipoprotein-bound cholesterol from the circulation. The metabolic consequences of a leaking BBB for cholesterol metabolism has not been studied previously. Here we used a pericyte-deficient mouse model, pdgfbret/ret, shown to have increased permeability of the BBB to a range of low-molecular mass and high-molecular mass tracers. There was a significant accumulation of plant sterols in the brain of the pdgfbret/ret mice. By dietary treatment with 0.3% deuterium labeled cholesterol we could demonstrate a significant flux of cholesterol from the circulation into the brain of the mutant mice roughly corresponding to about half of the measured turnover of cholesterol in the brain. We expected the cholesterol flux into the brain to cause a downregulation of cholesterol synthesis. Instead cholesterol synthesis was increased by about 60%. The levels of 24S-hydroxycholesterol (24S-OHC) were significantly reduced in the brain of the pericyte deficient mice but increased in the circulation. After treatment with 1% cholesterol in diet the difference in cholesterol synthesis between mutants and controls disappeared. The findings are consistent with increased leakage of 24S-OHC from the brain into the circulation in the pericyte-deficient mice. This oxysterol is an efficient suppressor of cholesterol synthesis and the results are consistent with a regulatory role of 24S-OHC in the brain. To our knowledge this is the first demonstration that a defect BBB may lead to increased flux of a lipophilic compound out from the brain. The relevance of the findings for the human situation is discussed.
published_date 2014-12-31T18:37:44Z
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