S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization

Lee, Mi-Hye; Appleton, Kathryn M.; El‐Shewy, Hesham M.; Sorci‐Thomas, Mary G.; Thomas, Michael J.; Lopes‐Virella, Maria F.; Luttrell, Louis M.; Hammad, Samar M.; Klein, Richard L.

doi:10.1194/jlr.m070706

Cited by 37 publications

(32 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ca 2+ signaling in endothelial cells has a multitude of physiological and pathophysiological roles . S1P 1 receptor‐mediated Ca 2+ signaling was described in cardiomyocytes, aortic smooth muscle cells and human umbilical vein endothelial cells, suggesting that Ca 2+ signaling is a physiological response and a potentially important second messenger pathway. Selective S1P 1 receptor pathway activation, in addition to S1P receptor subtype selectivity, might thus lead to distinct pharmacological profiles of different selective S1P 1 receptor modulators.…”

Section: Discussionmentioning

confidence: 99%

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

Piali

Birker‐Robaczewska

Lescop

et al. 2017

Pharmacology Res & Perspec

View full text Add to dashboard Cite

Sphingosine‐1‐phosphate receptor 1 (S1P1) modulators sequester circulating lymphocytes within lymph nodes, thereby preventing potentially pathogenic autoimmune cells from exiting into the blood stream and reaching inflamed tissues. S1P1 receptor modulation may thus offer potential to treat various autoimmune diseases. The first nonselective S1P1‐5 receptor modulator FTY720/fingolimod/Gilenya® has successfully demonstrated clinical efficacy in relapsing forms of multiple sclerosis. However, cardiovascular, hepatic, and respiratory side‐effects were reported and there is a need for novel S1P1 receptor modulators with better safety profiles. Here, we describe the discovery of cenerimod, a novel, potent and selective S1P1 receptor modulator with unique S1P1 receptor signaling properties and absence of broncho‐ and vasoconstrictor effects ex vivo and in vivo. Cenerimod dose‐dependently lowered circulating lymphocyte counts in rats and mice after oral administration and effectively attenuated disease parameters in a mouse experimental autoimmune encephalitis (EAE) model. Cenerimod has potential as novel therapy with improved safety profile for autoimmune diseases with high unmet medical need.

show abstract

Section: Discussionmentioning

confidence: 99%

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

Piali

Birker‐Robaczewska

Lescop

et al. 2017

Pharmacology Res & Perspec

View full text Add to dashboard Cite

show abstract

“…Regarding Ca 2+ signalling evoked by HDL, Lee at al. demonstrated that a concomitant activation of Sphingosine-1-Phosphate Receptor (S1PR) was necessary to mobilize cytosolic calcium in primary rat aortic smooth muscle and HEK293 cells [16]. Interestingly, the association between SR-BI and S1PR induced by sphingosine-1-phosphate provoked a remarkable Ca 2+ increase that developed rapidly and transiently.…”

Section: Discussionmentioning

confidence: 99%

Biological Redox Impact of Tocopherol Isomers Is Mediated by Fast Cytosolic Calcium Increases in Living Caco-2 Cells

et al. 2020

View full text Add to dashboard Cite

Most of the biological impacts of Vitamin E, including the redox effects, have been raised from studies with α-tocopherol only, despite the fact that tocopherol-containing foods carry mixed tocopherol isomers. Here, we investigated the cellular mechanisms involved in the immediate antioxidant responses evoked by α-, γand δ-tocopherol in Caco-2 cells. In order to track the cytosolic redox impact, we performed imaging on cells expressing HyPer, a fluorescent redox biosensor, while cytosolic calcium fluctuations were monitored by means of Fura-2 dye and imaging. With this approach, we could observe fast cellular responses evoked by the addition of α-, γand δ-tocopherol at concentrations as low as 2.5 µM. Each isomer induced rapid and consistent increases in cytosolic calcium with fast kinetics, which were affected by chelation of extracellular Ca 2+ , suggesting that tocopherols promoted a calcium entry upon the contact with the plasma membrane. In terms of redox effects, δ-tocopherol was the only isomer that evoked a significant change in the HyPer signal at 5 µM. By mimicking Ca 2+ entry with ionomycin and monensin, a decline in the HyPer signal was induced as well. Finally, by silencing calcium with 1,2-bis(o-aminophenoxy)ethane-N,N,N ,N -tetraacetic acid (BAPTA), an intracellular Ca 2+ chelator, none of the isomers were able to induce redox changes. Altogether, our data indicate that an elevation in cytoplasmic Ca 2+ is necessary for the development of a tocopherol-induced antioxidant impact on the cytoplasm of Caco-2 cells reported by HyPer biosensor.

show abstract

“…Another possibility invokes the preferential binding to HDL to certain cell types. SR-BI is a cell-surface receptor that binds HDL, and it has been shown to interact with S1PRs and allow activation by HDL-bound S1P 40 .…”

Section: Discussionmentioning

confidence: 99%

Hepatic FoxOs induce apolipoprotein M and are required for sphingosine-1-phosphate to bind high density lipoproteins

Izquierdo

Shanmugarajah

Lee

et al. 2019

Preprint

View full text Add to dashboard Cite

The authors declare no conflicts of interest.Abbreviations: AAV=adeno-associated virus, ApoM=apolipoprotein M, DIO=diet induced obese, FPLC=fast protein liquid chromatography, HDL=high density lipoprotein, HFD=high fat diet, LC-MS/MS=liquid chromatography-mass spectrometry, LDL=low density lipoprotein, LPD=lipoprotein depleted, S1P=sphingosine-1-phosphate, Tbg=thyroxin binding globulin, VLDL=very low density lipoprotein, WTD=western type diet ABSTRACTThe FoxO family of transcription factors play an important role in mediating insulin action on glucose, lipid, and lipoprotein metabolism. Liver-specific triple FoxO knockout mice (L-FoxO1,3,4) have defects in expression of genes related to glucose production, bile acid synthesis, and high density lipoprotein (HDL)-cholesterol uptake. We have now identified Apolipoprotein M (Apom) as a novel transcriptional target of liver FoxO. ApoM is a liver-secreted apolipoprotein that is bound to HDL in the circulation, and it serves as a chaperone for the bioactive lipid, sphingosine-1-phosphate (S1P). Several recent studies have demonstrated that S1P bound to ApoM induces unique effects, compared to S1P bound to albumin. We now show that liver FoxOs are required for ApoM mRNA and protein expression, and that ApoM is a transcriptional target of FoxOs. Moreover, while total plasma S1P levels are similar between control and L-FoxO1,3,4 mice, S1P is nearly absent from HDL in L-FoxO1,3,4 mice, and is instead increased in the lipoprotein depleted fraction. We also observed that leptin receptor deficient db/db mice have low hepatic Apom mRNA, and low levels of ApoM and S1P in HDL, without changes in total plasma S1P. These data demonstrate that FoxO transcription factors are novel regulators of the ApoM-S1P pathway, and indicate a potential link between hepatic insulin action and HDL function. METHODS Mice and diets.All experiments were approved by the Columbia University Institutional Animal Care and Use Committee. L-FoxO1,3,4 mice have been previously described 5,9 . Males at least 12 weeks old were studied, except in studies of 2-day-old pups, which were of mixed sex. For the acute FoxO depletion experiments, adult Foxo1 fl/fl , Foxo3 fl/fl , and Foxo4 fl/Y control mice were transduced with adeno-associated virus (serotype 8) expressing Cre recombinase driven by the hepatocyte-specific Tbg promoter (AAV8.Tbg. Cre) or control virus (AAV.GFP). Mice were injected intravenously with 1×10 11 virus particles/mouse, 4 weeks prior to euthanasia. AAV8.Tbg.Cre was a gift ). For the adenovirus experiments, adult male mice were injected intravenously with murine ApoM adenovirus (Welgen) 0.5 × 10 9 virus particles/gram of body weight, 8 days prior to euthanasia. For the db/db studies, male db/db and db/+ mice were purchased from Jackson Laboratory and were studied when they were 12, 13 or 25 weeks old. For the diet induced obesity studies, male C57BL/6J mice were purchased from Jackson Laboratory when they were 6 weeks old. Mice were fed either a standard chow diet (Purina) or a high fat diet ...

show abstract

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization

Cited by 37 publications

References 60 publications

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

Biological Redox Impact of Tocopherol Isomers Is Mediated by Fast Cytosolic Calcium Increases in Living Caco-2 Cells

Hepatic FoxOs induce apolipoprotein M and are required for sphingosine-1-phosphate to bind high density lipoproteins

Contact Info

Product

Resources

About

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization

Cited by 37 publications

References 60 publications

Cenerimod, a novel selective S1P1 receptor modulator with unique signaling properties

Cenerimod, a novel selective S1P1 receptor modulator with unique signaling properties

Biological Redox Impact of Tocopherol Isomers Is Mediated by Fast Cytosolic Calcium Increases in Living Caco-2 Cells

Hepatic FoxOs induce apolipoprotein M and are required for sphingosine-1-phosphate to bind high density lipoproteins

Contact Info

Product

Resources

About

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties

Cenerimod, a novel selective S1P₁ receptor modulator with unique signaling properties