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

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

doi:10.1172/jci66533

Cited by 47 publications

(35 citation statements)

References 55 publications

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“…Therefore, lipid rafts are a necessary component of the immune synapse: cells receive antigen stimulation, the signal is enriched to stimulate parts of the molecular aggregates, and lipid rafts undergo dynamic changes. For example, the inner layer of plasma membrane contains acytelated tyrosine protein kinase family (Ishikawa et al, 2013). Lipid rafts are dispersed in the plasma membrane and can drift sideways.…”

Section: Discussionmentioning

confidence: 99%

Effects of acrylonitrile on lymphocyte lipid rafts and RAS/RAF/MAPK/ERK signaling pathways

Li¹,

Li²,

Huang³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. Acrylonitrile (ACN) is a widely used chemical in the production of plastics, resins, nitriles, acrylic fibers, and synthetic rubber. Previous epidemiological investigations and animal studies have confirmed that ACN affects the lymphocytes and spleen. However, the immune toxicity mechanism is unknown. Lipid rafts are cell membrane structures that are rich in cholesterol and involved in cell signal transduction. The B cell lymophoma-10 (Bcl10) protein is a joint protein that is important in lymphocyte development and signal pathways. This study was conducted to examine the in vitro effects of ACN. We separated lipid rafts, and analyzed Bcl10 protein and caveolin. Western blotting was used to detect mitogen-activated protein kinase (MAPK) and phosphorylated MAPK levels. The results indicated that with increasing ACN concentration, the total amount of Bcl10 remained stable, but was concentrated mainly in part 4 to part 11 in electrophoretic band district which is high density in gradient centrifugation. Caveolin-1 was evaluated as a lipid raft marker protein; caveolin-1 content and position were relatively unchanged. Western blotting showed that in a certain range, MAPK protein was secreted at a higher level. At some ACN exposure levels, MAPK protein secretion was significantly decreased compared to the control group (P < 0.05). These results indicate that ACN can cause immune toxicity by damaging lipid raft structures, causing Bcl10 protein and lipid raft separation and restraining Ras-Raf-MAPK-extracellular signal-regulated kinase signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Effects of acrylonitrile on lymphocyte lipid rafts and RAS/RAF/MAPK/ERK signaling pathways

Li¹,

Li²,

Huang³

et al. 2014

Genet. Mol. Res.

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“…Mice used for macrophage isolation were wild-type, era −/− or lxrα −/− ;lxrβ −/− (Ishikawa et al, 2013). Processes in endothelial cells were interrogated in primary bovine aortic endothelial cells (BAEC)(Chambliss et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2014

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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 monocyte/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, via Erk1,2- and JNK-dependent IκBα degradation 27HC stimulates NF-κB activation. Whereas 27HC administration to apoe−/− mice increases atherosclerosis, apoe−/−;erα−/− are unaffected. Thus, 27HC promotes atherosclerosis via novel 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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“…Notably, this extranuclear signalling by LXR required Ser118 phosphorylation of ERα, which facilitated the association of these two receptors, presumably occurring directly at the plasma membrane. Furthermore, this Ser118 phosphorylation of the membrane pool of ER was demonstrated to depend on LXR activation and to be necessary for stimulating the activity of endothelial nitric oxide synthase in response to both ER and LXR ligands 108 . This suggests that, as in the case of the nuclear ERα, in which Ser118 phosphorylation promotes transcriptional activity, this specific phosphorylation also regulates membrane steroid receptor function.…”

Section: Physiological Implicationsmentioning

confidence: 97%

“…Recent studies have shown that in the context of blood vessel repair membrane ERα does not operate alone but colocalizes with liver X receptor-β (LXRβ; also known as NR1H2) 108 (FIG. 4c).…”

Section: Physiological Implicationsmentioning

confidence: 99%

Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors

Levin

Hammes

2016

Nat Rev Mol Cell Biol

244

198

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Steroid hormone receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most steroid receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of steroid hormone signalling and its roles in health and disease.

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

Cited by 47 publications

References 55 publications

Effects of acrylonitrile on lymphocyte lipid rafts and RAS/RAF/MAPK/ERK signaling pathways

Effects of acrylonitrile on lymphocyte lipid rafts and RAS/RAF/MAPK/ERK signaling pathways

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

Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors

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