Cell Metabolism
Volume 20, Issue 1, 1 July 2014, Pages 172-182
Journal home page for Cell Metabolism

Article
The Cholesterol Metabolite 27-Hydroxycholesterol Promotes Atherosclerosis via Proinflammatory Processes Mediated by Estrogen Receptor Alpha

https://doi.org/10.1016/j.cmet.2014.05.013Get rights and content
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Highlights

  • 27HC promotes atherosclerosis and prevents estrogen-related atheroprotection

  • 27HC actions via ER increase leukocyte-endothelial cell adhesion in vivo in mice

  • The 27HC-ERα tandem has proinflammatory actions in macrophages

  • The 27HC-ERα tandem also has proinflammatory actions in endothelial cells

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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