Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility

Li, Changyong; Zheng, Sujun; You, Hong; Liu, Xihong; Mu, Lin; Yang, Lin; Li, Liying

doi:10.1016/j.jhep.2010.08.028

Cited by 113 publications

(110 citation statements)

References 43 publications

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“…Fortuitously, we identified that SK1 was up-regulated in ECs after FGF2 stimulation using an unbiased microarray-based approach. Additionally, prior studies have shown that active SK1 could be released from cells, although the mechanism and vehicle of release were not identified (1,24,25,29). Conceptually, the packaging of SK1 into exosomes could protect the enzyme from degradation and maintain its stability until reaching its target cell of action.…”

Section: Discussionmentioning

confidence: 99%

“…Transmission Electron Microscopy and Immunogold Labeling-EM and immuno-EM analysis of vesicles were performed as described previously (8,29). Briefly, the specimens were resuspended and fixed in 4% paraformaldehyde for 1 h. Subsequently, the samples were deposited onto formvar/carboncoated EM grids (5 l on each grid) and dried for 25 min.…”

Section: Methodsmentioning

confidence: 99%

“…Exosomal SK1 Promotes AKT Activation and HSC Migration-Because SK1/S1P have been implicated previously in cirrhosis (29,40), we examined the effect of SK1-containing exosomes on HSC migration, a key feature of HSC activation. Treatment of HSCs with serum-derived exosomes induced a prominent activation of AKT signaling within 15 min (Fig.…”

Section: Sk1 Is An Ec-derived Exosome Protein-becausementioning

confidence: 99%

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Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

Wang

Ding

Yaqoob

et al. 2015

Journal of Biological Chemistry

178

164

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Exosomes are cell-derived extracellular vesicles thought to promote intercellular communication by delivering specific content to target cells. The aim of this study was to determine whether endothelial cell (EC)-derived exosomes could regulate the phenotype of hepatic stellate cells (HSCs). Initial microarray studies showed that fibroblast growth factor 2 induced a 2.4-fold increase in mRNA levels of sphingosine kinase 1 (SK1). Exosomes derived from an SK1-overexpressing EC line increased HSC migration 3.2-fold. Migration was not conferred by the dominant negative SK1 exosome. Incubation of HSCs with exosomes was also associated with an 8.3-fold increase in phosphorylation of AKT and 2.5-fold increase in migration. Exosomes were found to express the matrix protein and integrin ligand fibronectin (FN) by Western blot analysis and transmission electron microscopy. Blockade of the FN-integrin interaction with a CD29 neutralizing antibody or the RGD peptide attenuated exosome-induced HSC AKT phosphorylation and migration. Inhibition of endocytosis with transfection of dynamin siRNA, the dominant negative dynamin GTPase construct Dyn2K44A, or the pharmacological inhibitor Dynasore significantly attenuated exosome-induced AKT phosphorylation. SK1 levels were increased in serum exosomes derived from mice with experimental liver fibrosis, and SK1 mRNA levels were up-regulated 2.5-fold in human liver cirrhosis patient samples. Finally, S1PR2 inhibition protected mice from CCl 4 -induced liver fibrosis. Therefore, EC-derived SK1-containing exosomes regulate HSC signaling and migration through FNintegrin-dependent exosome adherence and dynamin-dependent exosome internalization. These findings advance our understanding of EC/HSC cross-talk and identify exosomes as a potential target to attenuate pathobiology signals.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Sk1 Is An Ec-derived Exosome Protein-becausementioning

confidence: 99%

See 1 more Smart Citation

Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

Wang

Ding

Yaqoob

et al. 2015

Journal of Biological Chemistry

178

164

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“…For instance, recruitment of inflammatory macrophages in atherosclerosis appears to be mediated by S1P-driven chemotaxis [113]. It is also known to be important for the migration of other cell types including myofibroblasts [114], osteoclast precursors [115] and hepatic stellate cells [116]. S1P signaling is also thought to be important in multiple sclerosis provided the drugs modulating S1P receptor activity could be used as good therapeutic options for the relapsing disease [117,118].…”

Section: B) Sphingosine Derivatives: Sphingosine and S1pmentioning

confidence: 99%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

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“…Sphingosine 1-phosphate (S1P), as a bioactive lipid mediator, is involved in numerous signaling pathways and regulates a wide variety of cellular functions (12). It has been shown that the signaling axis with which S1P is involved, exerts a powerful migratory effect on hepatic myofibroblasts and is involved in the development of hepatic fibrosis (13). Therefore, it is hypothesized that sphingolipids may be associated with hepatic fibrogenesis.…”

Section: Introductionmentioning

confidence: 99%

Plasma sphingolipids: Potential biomarkers for severe hepatic fibrosis in chronic hepatitis C

Zheng

et al. 2012

Molecular Medicine Reports

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Abstract. The plasma profile of sphingolipids in hepatic fibrosis patients with chronic hepatitis C (CHC) is rarely considered at present. The association between plasma sphingolipids and severe fibrosis in CHC remains an obscure area of research. The aim of the present study was to assess the plasma profile of sphingolipids and to examine the association between plasma sphingolipids and severe fibrosis in CHC, in order to identify potential novel markers of severe fibrosis in CHC. A cohort of 120 treatment-naïve patients with CHC were included in the present study. Liver biopsies were performed and routine serological indicators were measured. Plasma sphingolipids were detected using high performance liquid chromatography tandem mass spectrometry. A total of 44 plasma sphingolipids were detected. Plasma hexosylceramide (HexCer; d18:1/12:0), HexCer (d18:1/16:0) and HexCer (d18:1/22:0) were shown to

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Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility

Cited by 113 publications

References 43 publications

Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Plasma sphingolipids: Potential biomarkers for severe hepatic fibrosis in chronic hepatitis C

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