title: Side chain-oxidized oxysterols regulate the brain renin-angiotensin system through a liver X receptor-dependent mechanism.
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.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, NOVUM, SE-14186 Stockholm, Sweden. Laura.Mateos-Montejo@ki.se
authors.forename: Laura
authors.initials: L
authors.lastname: Mateos
authors.forename: Muhammad-Al-Mustafa
authors.initials: MA
authors.lastname: Ismail
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gil-Bea
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Maura
authors.initials: M
authors.lastname: Heverin
authors.forename: Ronnie
authors.initials: R
authors.lastname: Folkesson
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Angel
authors.initials: A
authors.lastname: Cedazo-Mínguez
mesh_terms: D000808:Angiotensinogen / Q000096:biosynthesis; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015419:Spastic Paraplegia, Hereditary / Q000134:cerebrospinal fluid / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002791:Cholesterol, Dietary; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D000808:Angiotensinogen; C044563:24-hydroxycholesterol; C076996:27-hydroxycholesterol