SCIENCE@home

Effects of a Disrupted Blood-Brain Barrier on Cholesterol Homeostasis in the Brain*

A. Saeed,G. Genové,Tian-hang Li,D. Lütjohann,M. Olin,Natalia Mast,I. Pikuleva,P. Crick,Yuqin Wang,W. Griffiths,C. Betsholtz,I. Björkhem

Published 2014 in Journal of Biological Chemistry

ABSTRACT

Background: The role of the blood-brain barrier for cholesterol homeostasis in the brain is not known. Results: Significant influx of cholesterol into the brain and increased efflux of 24(S)-hydroxycholesterol were observed in mice with a defect blood-brain barrier. Conclusion: A defect blood-brain barrier increases permeability for steroid flux in both directions. Significance: Elucidation of the role of the blood-brain barrier for brain cholesterol turnover. 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 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 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 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 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.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-41 of 41 references · Page 1 of 1

CITED BY

Showing 1-100 of 102 citing papers · Page 1 of 2

12
Next