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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; Yuqin Wang
Journal of Biological Chemistry
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DOI (Published version): 10.1074/jbc.M114.556159
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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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.
Swansea University Medical School