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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Neurociencias > Neurofarmacología y conducta > DA - CIMA - Neurociencias - Neurofarmacología y conducta - Artículos de Revista >

Side chain-oxidized oxysterols regulate the brain renin-angiotensin system through a liver X receptor-dependent mechanism
Authors: Mateos, L. (Laura)
Ismail, M.A. (M. A.)
Gil-Bea, F.J. (Francisco J.)
Schüle, R. (Rebecca)
Schöls, L. (Ludger)
Heverin, M. (M.)
Folkesson, R. (R.)
Björkhem, I. (Ingermar)
Cedazo-Minguez, A. (Ángel)
Keywords: Brain/drug effects
Hydroxycholesterols/pharmacology
Orphan Nuclear Receptors/metabolism
Renin-Angiotensin System/drug effects
Brain/metabolism
Issue Date: 2011
Publisher: American Society for Biochemistry and Molecular Biology
Publisher version: http://dx.doi.org/10.1074/jbc.M111.236877
ISSN: 0021-9258
Citation: Mateos L, Ismail MA, Gil-Bea FJ, Schüle R, Schöls L, Heverin M, et al. Side chain-oxidized oxysterols regulate the brain rennin-angiotensin system through a liver X receptor-dependent mechanism. J Biol Chem 2011 Jul 22;286(29):25574-25585.
Abstract
Disturbances in cholesterol metabolism have been associated with hypertension and neurodegenerative disorders. Because cholesterol metabolism in the brain is efficiently separated from plasma cholesterol by the blood-brain barrier (BBB), it is an unsolved paradox how high blood cholesterol can cause an effect in the brain. Here, we discuss the possibility that cholesterol metabolites permeable to the BBB might account for these effects. We show that 27-hydroxycholesterol (27-OH) and 24S-hydroxycholesterol (24S-OH) up-regulate the renin-angiotensin system (RAS) in the brain. Brains of mice on a cholesterol-enriched diet showed up-regulated angiotensin converting enzyme (ACE), angiotensinogen (AGT), and increased JAK/STAT activity. These effects were confirmed in in vitro studies with primary neurons and astrocytes exposed to 27-OH or 24S-OH, and were partially mediated by liver X receptors. In contrast, brain RAS activity was decreased in Cyp27a1-deficient mice, a model exhibiting reduced 27-OH production from cholesterol. Moreover, in humans, normocholesterolemic patients with elevated 27-OH levels, due to a CYP7B1 mutation, had markers of activated RAS in their cerebrospinal fluid. Our results demonstrate that side chain-oxidized oxysterols are modulators of brain RAS. Considering that levels of cholesterol and 27-OH correlate in the circulation and 27-OH can pass the BBB into the brain, we suggest that this cholesterol metabolite could be a link between high plasma cholesterol levels, hypertension, and neurodegeneration.
Permanent link: http://hdl.handle.net/10171/19667
Appears in Collections:DA - CIMA - Neurociencias - Neurofarmacología y conducta - Artículos de Revista

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