LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity

Tomonori Ishikawa, Ivan S. Yuhanna, Junko Umetani, Wan Ru Lee, Kenneth S. Korach, Philip W. Shaul, Michihisa Umetani

Research output: Contribution to journalArticle

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Abstract

Liver X receptors (LXR) are stimulated by cholesterol-derived oxysterols and serve as transcription factors to regulate gene expression in response to alterations in cholesterol. In the present study, we investigated the role of LXRs in vascular endothelial cells (ECs) and discovered that LXRβ has nonnuclear function and stimulates EC migration by activating endothelial NOS (eNOS). This process is mediated by estrogen receptor-α (ERα). LXR activation promoted the direct binding of LXRβ to the ligand-binding domain of ERα and initiated an extranuclear signaling cascade that requires ERα Ser118 phosphorylation by PI3K/AKT. Further studies revealed that LXRβ and ERα are colocalized and functionally coupled in EC plasma membrane caveolae/lipid rafts. In isolated aortic rings, LXR activation of NOS caused relaxation, while in mice, LXR activation stimulated carotid artery reendothelialization via LXRβ- and ERα-dependent processes. These studies demonstrate that LXRβ has nonnuclear function in EC caveolae/lipid rafts that entails crosstalk with ERα, which promotes NO production and maintains endothelial monolayer integrity in vivo.

Original languageEnglish (US)
Pages (from-to)3488-3497
Number of pages10
JournalJournal of Clinical Investigation
Volume123
Issue number8
DOIs
StatePublished - Aug 1 2013

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Estrogen Receptors
Lipids
Endothelial Cells
Caveolae
Cholesterol
Cell Membrane
Liver X Receptors
Membrane Lipids
Phosphatidylinositol 3-Kinases
Carotid Arteries
Cell Movement
Transcription Factors
Phosphorylation
Ligands
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ishikawa, T., Yuhanna, I. S., Umetani, J., Lee, W. R., Korach, K. S., Shaul, P. W., & Umetani, M. (2013). LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity. Journal of Clinical Investigation, 123(8), 3488-3497. https://doi.org/10.1172/JCI66533

LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity. / Ishikawa, Tomonori; Yuhanna, Ivan S.; Umetani, Junko; Lee, Wan Ru; Korach, Kenneth S.; Shaul, Philip W.; Umetani, Michihisa.

In: Journal of Clinical Investigation, Vol. 123, No. 8, 01.08.2013, p. 3488-3497.

Research output: Contribution to journalArticle

Ishikawa, T, Yuhanna, IS, Umetani, J, Lee, WR, Korach, KS, Shaul, PW & Umetani, M 2013, 'LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity', Journal of Clinical Investigation, vol. 123, no. 8, pp. 3488-3497. https://doi.org/10.1172/JCI66533
Ishikawa, Tomonori ; Yuhanna, Ivan S. ; Umetani, Junko ; Lee, Wan Ru ; Korach, Kenneth S. ; Shaul, Philip W. ; Umetani, Michihisa. / LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 8. pp. 3488-3497.
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