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

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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

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Estrogen Receptor alpha
Atherosclerosis
Cholesterol
Estrogen Receptors
Apolipoproteins E
Estrogens
Endothelial Cells
27-hydroxycholesterol
Vascular Diseases
Lipid Metabolism
Cell Adhesion
Blood Vessels
Monocytes
Leukocytes
Up-Regulation
Macrophages
Ligands
Lipids

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology
  • Medicine(all)

Cite this

The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor alpha. / Umetani, Michihisa; Ghosh, Pritam; Ishikawa, Tomonori; Umetani, Junko; Ahmed, Mohamed; Mineo, Chieko; Shaul, Philip W.

In: Cell Metabolism, Vol. 20, No. 1, 01.07.2014, p. 172-182.

Research output: Contribution to journalArticle

Umetani, Michihisa ; Ghosh, Pritam ; Ishikawa, Tomonori ; Umetani, Junko ; Ahmed, Mohamed ; Mineo, Chieko ; Shaul, Philip W. / The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor alpha. In: Cell Metabolism. 2014 ; Vol. 20, No. 1. pp. 172-182.
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