[HTML][HTML] The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor alpha

M Umetani, P Ghosh, T Ishikawa, J Umetani, M Ahmed… - Cell metabolism, 2014 - cell.com
M Umetani, P Ghosh, T Ishikawa, J Umetani, M Ahmed, C Mineo, PW Shaul
Cell metabolism, 2014cell.com
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 …
Summary
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.
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