The role of sphingosine 1‐phosphate receptor 2 in bile‐acid–induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice

Wang, Yongqing; Aoki, Hiroaki; Yang, Jing; Peng, Kesong; Liu, Runping; Li, Xiaojiaoyang; Xiao, Qiang; Sun, Lixin; Gurley, Emily C.; Lai, Guan–Hua; Zhang, Luyong; Liang, Guang; Nagahashi, Masayuki; Takabe, Kazuaki; Pandak, William M.; Hylemon, Phillip B.; Zhou, Huiping

doi:10.1002/hep.29076

Cited by 158 publications

(111 citation statements)

References 48 publications

(131 reference statements)

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“…In contrast, others reported that the S1PR2 antagonist JTE-013 blocked liver fibrosis (Wang et al 2015). Similar results were observed in a bile duct ligation-induced model of liver fibrosis in which knockout of S1PR2 was protective (Wang et al 2017). Disruption of the hepatocyte–endothelium interaction in the injured liver frequently results in impaired regeneration and fibrosis.…”

Section: S1p Is An Important Mediator Of Liver Fibrosissupporting

confidence: 77%

Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology

Rohrbach

Maceyka

Spiegel

2017

Critical Reviews in Biochemistry and Molecular Biology

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Over 20 years ago, sphingosine-1-phosphate (S1P) was discovered to be a bioactive signaling molecule. Subsequent studies later identified two related kinases, sphingosine kinase 1 and 2, which are responsible for the phosphorylation of sphingosine to S1P. Many stimuli increase sphingosine kinase activity and S1P production and secretion. Outside the cell, S1P can bind to and activate five S1P-specific G protein-coupled receptors (S1PR1–5) to regulate many important cellular and physiological processes in an autocrine or paracrine manner. S1P is found in high concentrations in the blood where it functions to control vascular integrity and trafficking of lymphocytes. Obesity increases blood S1P levels in humans and mice. With the world wide increase in obesity linked to consumption of high-fat, high-sugar diets, S1P is emerging as an accomplice in liver pathobiology, including acute liver failure, metabolic syndrome, control of blood lipid and glucose homeostasis, nonalcoholic fatty liver disease, and liver fibrosis. Here, we review recent research on the importance of sphingosine kinases, S1P, and S1PRs in liver pathobiology, with a focus on exciting insights for new therapeutic modalities that target S1P signaling axes for a variety of liver diseases.

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Section: S1p Is An Important Mediator Of Liver Fibrosissupporting

confidence: 77%

Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology

Rohrbach

Maceyka

Spiegel

2017

Critical Reviews in Biochemistry and Molecular Biology

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“…A recent study has shown that S1PR2 expression is elevated in cholangiocytes during BDL, and taurocholate induces cholangiocyte proliferation by ERK1/2 activation and enhanced S1PR2 expression [97]. This study has also demonstrated that S1PR2 −/− mice show reduced bile acid secretion, bile duct mass, and liver fibrosis during BDL.…”

Section: Pathways Associated With Cholangiocyte Responses and Theimentioning

confidence: 53%

Mechanisms of cholangiocyte responses to injury

Sato

Meng²,

Giang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Cholangiocytes, epithelial cells that line the biliary epithelium, are the primary target cells for cholangiopathies including primary sclerosing cholangitis and primary biliary cholangitis. Quiescent cholangiocytes respond to biliary damage and acquire an activated neuroendocrine phenotype to maintain the homeostasis of the liver. The typical response of cholangiocytes is proliferation leading to bile duct hyperplasia, which is a characteristic of cholestatic liver diseases. Current studies have identified various signaling pathways that are associated with cholangiocyte proliferation/loss and liver fibrosis in cholangiopathies using human samples and rodent models. Although recent studies have demonstrated that extracellular vesicles and microRNAs could be mediators that regulate these messenger/receptor axes, further studies are required to confirm their roles. This review summarizes current studies of biliary response and cholangiocyte proliferation during cholestatic liver injury with particular emphasis on the secretin/secretin receptor axis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

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“…Wang et al recently present evidence that conjugated bile acids can activate the sphiinogsine-1-Receptor 2 in mouse cholangiocyte plasma membranes which initiates an AKT and ERK1/2 signaling pathway that elicits an inflammatory and fibrotic response. Total serum bile acid levels, ALP and liver fibrosis were greatly diminished in bile duct ligated mice where this receptor was deleted, although little evidence was provided for an attenuated inflammatory response in these mice other than an absence of COX-2 induction in isolated cholangiocytes (61). …”

Section: The Response Of Cholangiocytes To Cholestasismentioning

confidence: 99%

Mechanisms of bile acid mediated inflammation in the liver

Cai

Boyer

2017

Molecular Aspects of Medicine

182

109

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Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.

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The role of sphingosine 1‐phosphate receptor 2 in bile‐acid–induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice

Cited by 158 publications

References 48 publications

Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology

Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology

Mechanisms of cholangiocyte responses to injury

Mechanisms of bile acid mediated inflammation in the liver

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