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

Cell Metab. 2014 Jul 1;20(1):172-82. doi: 10.1016/j.cmet.2014.05.013. Epub 2014 Jun 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Cell Adhesion / drug effects
  • Cell Line
  • Cholesterol / metabolism*
  • Cytochrome P450 Family 7
  • Cytokines / genetics
  • Cytokines / metabolism
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Hydroxycholesterols / metabolism
  • Hydroxycholesterols / pharmacology*
  • I-kappa B Proteins / metabolism
  • Inflammation
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Steroid Hydroxylases / deficiency
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism

Substances

  • Apolipoproteins E
  • Cytokines
  • Estrogen Receptor alpha
  • Hydroxycholesterols
  • I-kappa B Proteins
  • NF-kappa B
  • Nfkbia protein, mouse
  • RNA, Small Interfering
  • NF-KappaB Inhibitor alpha
  • 27-hydroxycholesterol
  • Cholesterol
  • Steroid Hydroxylases
  • Cytochrome P450 Family 7
  • Cyp7b1 protein, mouse
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3