title: Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain.
abstract: 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, Pdgfb(ret/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 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.
authors: From the Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institute, Huddinge, Stockholm 141 86, Sweden, the Department of Biochemistry, Faculty of Medicine, University of Khartoum, 11111 Khartoum, Sudan.
authors: Ahmed A
authors: AA
authors: Saeed
authors: the Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Guillem
authors: G
authors: Genové
authors: the Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Tian
authors: T
authors: Li
authors: the Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, D-53127 Bonn, Germany.
authors: Dieter
authors: D
authors: Lütjohann
authors: From the Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institute, Huddinge, Stockholm 141 86, Sweden.
authors: Maria
authors: M
authors: Olin
authors: the Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106, and.
authors: Natalia
authors: N
authors: Mast
authors: the Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106, and.
authors: Irina A
authors: IA
authors: Pikuleva
authors: the Institute of Mass Spectrometry, College of Medicine, Swansea University, Swansea SA2 8PP, United Kingdom.
authors: Peter
authors: P
authors: Crick
authors: the Institute of Mass Spectrometry, College of Medicine, Swansea University, Swansea SA2 8PP, United Kingdom.
authors: Yuqin
authors: Y
authors: Wang
authors: the Institute of Mass Spectrometry, College of Medicine, Swansea University, Swansea SA2 8PP, United Kingdom.
authors: William
authors: W
authors: Griffiths
authors: the Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
authors: Christer
authors: C
authors: Betsholtz
authors: From the Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institute, Huddinge, Stockholm 141 86, Sweden, ingemar.bjorkhem@karolinska.se.
authors: Ingemar
authors: I
authors: Björkhem
mesh_terms: D000818:Animals; D001483:Base Sequence; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D017931:DNA Primers; D020571:Genes, sis; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010944:Plants / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013261:Sterols / Q000378:metabolism
chemical_list: D017931:DNA Primers; D013261:Sterols; D002784:Cholesterol
keywords: Brain Metabolism; Cholesterol Regulation; Hydroxylase; Neurodegeneration; Sterol