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

Michihisa Umetani, Pritam Ghosh, Tomonori Ishikawa, Junko Umetani, Mohamed Ahmed, Chieko Mineo, Philip W. Shaul

Research output: Contribution to journalArticle

91 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)172-182
Number of pages11
JournalCell Metabolism
Volume20
Issue number1
DOIs
StatePublished - Jul 1 2014

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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