Sphingosine kinase-1 inhibition protects primary rat hepatocytes against bile salt-induced apoptosis

Karimian, Golnar; Buist‐Homan, Manon; Schmidt, Martina; Tietge, Uwe J. F.; Boer, Jan Freark de; Klappe, Karin; Combettes, Laurent; Tordjmann, Thierry; Faber, Klaas Nico; Moshage, Han

doi:10.1016/j.bbadis.2013.06.011

Cited by 26 publications

(13 citation statements)

References 47 publications

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“…S1P is the natural ligand of the GPCRs, S1PR1‐5, which are differentially expressed in different tissues . Previously, we had shown that S1PR2 is highly expressed in the liver and that TCA activates ERK1/2 and Akt through S1PR2 in rat primary hepatocytes .…”

Section: Resultsmentioning

confidence: 99%

Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2

et al. 2014

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Cholangiocarcinoma (CCA) is an often fatal primary malignancy of the intra- and extrahepatic biliary tract that is commonly associated with chronic cholestasis and significantly elevated levels of primary and conjugated bile acids (CBAs), which are correlated with bile duct obstruction (BDO). BDO has also recently been shown to promote CCA progression. However, whereas there is increasing evidence linking chronic cholestasis and abnormal bile acid profiles to CCA development and progression, the specific mechanisms by which bile acids may be acting to promote cholangiocarcinogenesis and invasive biliary tumor growth have not been fully established. Recent studies have shown that CBAs, but not free bile acids, stimulate CCA cell growth, and that an imbalance in the ratio of free to CBAs may play an important role in the tumorigenesis of CCA. Also, CBAs are able to activate extracellular signal-regulated kinase (ERK)1/2- and phosphatidylinositol-3-kinase/protein kinase B (AKT)-signaling pathways through sphingosine 1-phosphate receptor 2 (S1PR2) in rodent hepatocytes. In the current study, we demonstrate S1PR2 to be highly expressed in rat and human CCA cells, as well as in human CCA tissues. We further show that CBAs activate the ERK1/2- and AKT-signaling pathways and significantly stimulate CCA cell growth and invasion in vitro. Taurocholate (TCA)-mediated CCA cell proliferation, migration, and invasion were significantly inhibited by JTE-013, a chemical antagonist of S1PR2, or by lentiviral short hairpin RNA silencing of S1PR2. In a novel organotypic rat CCA coculture model, TCA was further found to significantly increase the growth of CCA cell spheroidal/“duct-like” structures, which was blocked by treatment with JTE-013. Conclusion: Our collective data support the hypothesis that CBAs promote CCA cell-invasive growth through S1PR2.

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Section: Resultsmentioning

confidence: 99%

Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2

et al. 2014

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“…Adapted from [111]. S1PR, S1PR1 (formerly named as EDG1) in 1998 [163], a total of five GPCRs have been identified as S1P-specific receptors (S1PR1-5) [152,[164][165][166]. S1PRs are differentially expressed in different tissues and the expression levels vary under different physiological and pathological conditions [167].…”

Section: Sphingosine 1-phosphate Signalingmentioning

confidence: 99%

The role of sphingosine kinase 2 in alcoholic liver disease

Kwong

Liu

Zhao

et al. 2019

Digestive and Liver Disease

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Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide characterized by the accumulation of lipids within the liver, inflammation and the possibility of progressing to cirrhosis and liver failure. More importantly, there are currently no effective treatments for ALD and liver transplantation remains the only therapeutic option for end-stage liver disease. Previous studies have shown that ALD is a result of a combination of endoplasmic

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“…In addition, spinster homologue 2 (Spns2), a member of the major facilitator superfamily, has been shown to mediate S1P secretion 30 , 31 . Extracellular S1P exerts its function via activating five different G protein coupled receptors (S1PR1–5) on the cell membrane to induce various cellular responses 32 , 33 , 34 ( Fig. 2 ).…”

Section: Sphingosine-1-phosphate and Sphingosine-1-phosphate Receptormentioning

confidence: 99%

Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism

Kwong

Hylemon

et al. 2015

Acta Pharmaceutica Sinica B

102

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The liver is the central organ involved in lipid metabolism. Dyslipidemia and its related disorders, including non-alcoholic fatty liver disease (NAFLD), obesity and other metabolic diseases, are of increasing public health concern due to their increasing prevalence in the population. Besides their well-characterized functions in cholesterol homoeostasis and nutrient absorption, bile acids are also important metabolic regulators and function as signaling hormones by activating specific nuclear receptors, G-protein coupled receptors, and multiple signaling pathways. Recent studies identified a new signaling pathway by which conjugated bile acids (CBA) activate the extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) signaling pathway via sphingosine-1-phosphate receptor 2 (S1PR2). CBA-induced activation of S1PR2 is a key regulator of sphingosine kinase 2 (SphK2) and hepatic gene expression. This review focuses on recent findings related to the role of bile acids/S1PR2-mediated signaling pathways in regulating hepatic lipid metabolism.

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Sphingosine kinase-1 inhibition protects primary rat hepatocytes against bile salt-induced apoptosis

Cited by 26 publications

References 47 publications

Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2

Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2

The role of sphingosine kinase 2 in alcoholic liver disease

Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism

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