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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain
Journal of Biological Chemistry, Volume 289, No. 34, Year 2014
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Description
The 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 have 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 brains of the Pdgfb ret/ret mice. By dietary treatment with 0.3% deuterium-labeled cholesterol, we could demonstrate a significant flux of cholesterol from the circulation into the brains 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 down-regulation of cholesterol synthesis. Instead, cholesterol synthesis was increased by about 60%. The levels of 24(S)-hydroxycholesterol (24S-OHC) were significantly reduced in the brains 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 pericytedeficient 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 defective 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. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Authors & Co-Authors
Saeed, Ahmed A.
Sweden, Stockholm
Karolinska Universitetssjukhuset
Sudan, Khartoum
University of Khartoum Faculty of Medicine
Genové, Guillem
Sweden, Stockholm
Karolinska Institutet
Li, Tian
Sweden, Stockholm
Karolinska Institutet
Lütjohann, Dieter
Germany, Bonn
Universität Bonn
Olin, Maria
Sweden, Stockholm
Karolinska Universitetssjukhuset
Mast, Natalia V.
United States, Cleveland
Case Western Reserve University
Pikuleva, Irina A.
United States, Cleveland
Case Western Reserve University
Crick, Peter J.
United Kingdom, Swansea
Swansea University
Wang, Yuqin
United Kingdom, Swansea
Swansea University
Griffiths, William J.
United Kingdom, Swansea
Swansea University
Betsholtz, Christer A.
Sweden, Stockholm
Karolinska Institutet
Björkhem, Ingemar
Sweden, Stockholm
Karolinska Universitetssjukhuset
Statistics
Citations: 84
Authors: 12
Affiliations: 6
Identifiers
Doi:
10.1074/jbc.M114.556159
ISSN:
00219258
e-ISSN:
1083351X
Research Areas
Noncommunicable Diseases