Abstract
Oxysterols are cholesterol metabolites that serve multiple functions in lipid metabolism, including as liver X receptor (LXR) ligands. 27-hydroxycholesterol (27HC) is an abundant oxysterol metabolized by CYP7B1. How 27HC impacts vascular health is unknown. We show that elevations in 27HC via cyp7b1 deletion promote atherosclerosis in apoe(-/-) mice without altering lipid status; furthermore, estrogen-related atheroprotection is attenuated. In wild-type mice, leukocyte-endothelial cell adhesion is increased by 27HC via estrogen receptor (ER)-dependent processes. In monocytes/macrophages, 27HC upregulates proinflammatory genes and increases adhesion via ERα. In endothelial cells, 27HC is also proadhesive via ERα, and in contrast to estrogen, which blunts NF-κB activation, 27HC stimulates NF-κB activation via Erk1,2 and JNK-dependent IκBα degradation. Whereas 27HC administration to apoe(-/-) mice increases atherosclerosis, apoe(-/-);erα(-/-) are unaffected. Thus, 27HC promotes atherosclerosis via proinflammatory processes mediated by ERα, and it attenuates estrogen-related atheroprotection. Strategies to lower 27HC may complement approaches targeting cholesterol to prevent vascular disease.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Apolipoproteins E / metabolism
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Atherosclerosis / metabolism
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Atherosclerosis / pathology
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Cell Adhesion / drug effects
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Cell Line
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Cholesterol / metabolism*
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Cytochrome P450 Family 7
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Cytokines / genetics
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Cytokines / metabolism
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism*
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Female
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Hydroxycholesterols / metabolism
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Hydroxycholesterols / pharmacology*
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I-kappa B Proteins / metabolism
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Inflammation
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JNK Mitogen-Activated Protein Kinases / metabolism
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Male
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism
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RNA Interference
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RNA, Small Interfering / metabolism
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Steroid Hydroxylases / deficiency
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Steroid Hydroxylases / genetics
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Steroid Hydroxylases / metabolism
Substances
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Apolipoproteins E
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Cytokines
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Estrogen Receptor alpha
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Hydroxycholesterols
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I-kappa B Proteins
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NF-kappa B
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Nfkbia protein, mouse
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RNA, Small Interfering
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NF-KappaB Inhibitor alpha
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27-hydroxycholesterol
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Cholesterol
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Steroid Hydroxylases
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Cytochrome P450 Family 7
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Cyp7b1 protein, mouse
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3