scholarly journals Bivalent Ligand UDCA-LPE Inhibits Pro-Fibrogenic Integrin Signalling by Inducing Lipid Raft-Mediated Internalization

2018 ◽  
Vol 19 (10) ◽  
pp. 3254 ◽  
Author(s):  
Jie Su ◽  
Hongying Gan-Schreier ◽  
Benjamin Goeppert ◽  
Walee Chamulitrat ◽  
Wolfgang Stremmel ◽  
...  
Keyword(s):  
Focal Adhesion ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Inhibitory Effects ◽  
Integrin Β1 ◽  
Transport Pathway ◽  
Fatty Acid Chain ◽  
Embryonic Liver Cell

Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a synthetic bile acid-phospholipid conjugate with profound hepatoprotective and anti-fibrogenic functions in vitro and in vivo. Herein, we aimed to demonstrate the inhibitory effects of UDCA-LPE on pro-fibrogenic integrin signalling. UDCA-LPE treatment of human embryonic liver cell line CL48 and primary human hepatic stellate cells induced a non-classical internalization of integrin β1 resulting in dephosphorylation and inhibition of SRC and focal adhesion kinase (FAK). Signalling analyses suggested that UDCA-LPE may act as a heterobivalent ligand for integrins and lysophospholipid receptor1 (LPAR1) and co-immunoprecipitation demonstrated the bridging effect of UDCA-LPE on integrin β1 and LPAR1. The disruption of either the UDCA-moiety binding to integrins by RGD-containing peptide GRGDSP or the LPE-moiety binding to LPAR1 by LPAR1 antagonist Ki16425 reversed inhibitory functions of UDCA-LPE. The lack of inhibitory functions of UDCA-PE and UDCA-LPE derivatives (14:0 and 12:0, LPE-moiety containing shorter fatty acid chain) as well as the consistency of the translocation of UDCA-LPE and integrins, which co-fractionated with LPE but not UDCA, suggested that the observed UDCA-LPE-induced translocation of integrins was mediated by LPE endocytic transport pathway.

Erratum: Study on the in vitro and in vivo activation of rat hepatic stellate cells by Raman spectroscopy

2007 ◽  
Vol 12 (5) ◽  
pp. 059801
Author(s):  
Aiguo Shen ◽  
Zhangxiu Liao ◽  
Hui Wang ◽  
Iiho Goan ◽  
Yong Wu ◽  
...  
Keyword(s):  
Raman Spectroscopy ◽  
Hepatic Stellate Cells ◽  
Stellate Cells

scholarly journals Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Zhemin Shi ◽  
Kun Zhang ◽  
Ting Chen ◽  
Yu Zhang ◽  
Xiaoxiao Du ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
In Vitro Study ◽  
Stellate Cells ◽  
Protective Role ◽  
Activating Transcription Factor 3 ◽  
Dependent Manner ◽  
Liver Fibrogenesis

AbstractThe excessive accumulation of extracellular matrix (ECM) is a key feature of liver fibrosis and the activated hepatic stellate cells (HSCs) are the major producer of ECM proteins. However, the precise mechanisms and target molecules that are involved in liver fibrosis remain unclear. In this study, we reported that activating transcription factor 3 (ATF3) was over-expressed in mice and human fibrotic livers, in activated HSCs and injured hepatocytes (HCs). Both in vivo and in vitro study have revealed that silencing ATF3 reduced the expression of pro-fibrotic genes and inhibited the activation of HSCs, thus alleviating the extent of liver fibrosis, indicating a potential protective role of ATF3 knockdown. However, ATF3 was not involved in either the apoptosis or proliferation of HCs. In addition, our data illustrated that increased nuclear localization of ATF3 promoted the transcription of fibrogenic genes and lnc-SCARNA10, which functioned as a novel positive regulator of TGF-β signaling in liver fibrogenesis by recruiting SMAD3 to the promoter of these genes. Interestingly, further study also demonstrated that lnc-SCARNA10 promoted the expression of ATF3 in a TGF-β/SMAD3-dependent manner, revealing a TGF-β/ATF3/lnc-SCARNA10 axis that contributed to liver fibrosis by activating HSCs. Taken together, our data provide a molecular mechanism implicating induced ATF3 in liver fibrosis, suggesting that ATF3 may represent a useful target in the development of therapeutic strategies for liver fibrosis.

135 Jnk1 IN HEPATIC STELLATE CELLS MODULATES LIVER FIBROGENESIS IN VIVO AND IN VITRO

2013 ◽  
Vol 58 ◽  
pp. S59-S60
Author(s):  
F.J. Cubero ◽  
G. Zhao ◽  
M. Hatting ◽  
Y.A. Nevzorova ◽  
F. Schaefer ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Liver Fibrogenesis

Study on the in vitro and in vivo activation of rat hepatic stellate cells by Raman spectroscopy

2007 ◽  
Vol 12 (3) ◽  
pp. 034003 ◽  
Author(s):  
Aiguo Shen ◽  
Zhangxiu Liao ◽  
Hui Wang ◽  
Iiho Goan ◽  
Yong Wu ◽  
...  
Keyword(s):  
Raman Spectroscopy ◽  
Hepatic Stellate Cells ◽  
Stellate Cells

Inhibition of ASICs reduces rat hepatic stellate cells activity and liver fibrosis: An in vitro and in vivo study

2014 ◽  
pp. n/a-n/a ◽  
Author(s):  
Chun-xiao Pan ◽  
Fan-rong Wu ◽  
Xiao-yu Wang ◽  
Jie Tang ◽  
Wen-fan Gao ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
In Vivo Study

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

2003 ◽  
Vol 285 (3) ◽  
pp. G652-G660 ◽  
Author(s):  
H. Hendrickson ◽  
S. Chatterjee ◽  
S. Cao ◽  
M. Morales Ruiz ◽  
W. C. Sessa ◽  
...  
Keyword(s):  
Rat Liver ◽  
Hepatic Stellate Cells ◽  
Fluorescent Protein ◽  
Stellate Cell ◽  
Active Form ◽  
Stellate Cells ◽  
Liver Cells ◽  
No Production

Diminished endothelial nitric oxide (NO) synthase (eNOS)-derived NO production from the hepatic vascular endothelium contributes to hepatic vasoconstriction in portal hypertension. The aim of this study was to examine the mechanism of this process by testing the influence of a constitutively active form of eNOS (S1179DeNOS) in both primary and propagated liver cells in vitro and in the sham and bile duct ligated (BDL) rat liver in vivo, using an adenoviral vector encoding green fluorescent protein (AdGFP) and S1179DeNOS (AdS1179DeNOS). AdS1179DeNOS transduction augmented basal and agonist-stimulated NO generation in nonparenchymal liver cells. Sham rats transduced in vivo with AdS1179DeNOS evidenced a decreased pressor response to incremental doses of the vasoconstrictor methoxamine compared with sham rats transduced with AdGFP. However, BDL rats transduced with AdS1179DeNOS did not display improved vasodilatory responses as evidenced by similar flow-dependent pressure increases to that observed in BDL rats transduced with AdGFP, despite similar levels of viral transgene expression. We next examined the influence of the eNOS inhibitory protein caveolin on S1179DeNOS dysfunction in cirrhotic liver. Immunogold electron microscopic analysis of caveolin in BDL liver demonstrated prominent expression not only in liver endothelial cells, but also in hepatic stellate cells. In vitro studies in the LX2 hepatic stellate cell line demonstrate that caveolin precipitates recombinant S1179DeNOS in LX2 cells, that recombinant S1179DeNOS coprecipitates caveolin, and that binding is enhanced in the presence of overexpression of caveolin. Furthermore, caveolin overexpression inhibits recombinant S1179DeNOS activity. These studies indicate that recombinant S1179DeNOS protein functions appropriately in normal liver cells and tissue but evidences dysfunction in the cirrhotic rat liver and that caveolin expression and inhibition in BDL nonparenchymal cells, including hepatic stellate cells, may account for this dysfunction.

scholarly journals Reduction in SNAP-23 Alters Microfilament Organization in Myofibrobastic Hepatic Stellate Cells

2020 ◽  
Vol 20 (1) ◽  
pp. 25-37
Author(s):  
Haleigh B. Eubanks ◽  
Elise G. Lavoie ◽  
Jessica Goree ◽  
Jeffrey A. Kamykowski ◽  
Neriman Gokden ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Cell Movement ◽  
Stellate Cells ◽  
Snare Proteins ◽  
Actin Dynamics ◽  
Critical Feature ◽  
Effector Cells

Hepatic stellate cells (HSC) are critical effector cells of liver fibrosis. In the injured liver, HSC differentiate into a myofibrobastic phenotype. A critical feature distinguishing myofibroblastic from quiescent HSC is cytoskeletal reorganization. Soluble NSF attachment receptor (SNARE) proteins are important in trafficking of newly synthesized proteins to the plasma membrane for release into the extracellular environment. The goals of this project were to determine the expression of specific SNARE proteins in myofibroblastic HSC and to test whether their alteration changed the HSC phenotype in vitro and progression of liver fibrosis in vivo. We found that HSC lack the t-SNARE protein, SNAP-25, but express a homologous protein, SNAP-23. Downregulation of SNAP-23 in HSC induced reduction in polymerization and disorganization of the actin cytoskeleton associated with loss of cell movement. In contrast, reduction in SNAP-23 in mice by monogenic deletion delayed but did not prevent progression of liver fibrosis to cirrhosis. Taken together, these findings suggest that SNAP-23 is an important regular of actin dynamics in myofibroblastic HSC, but that the role of SNAP-23 in the progression of liver fibrosis in vivo is unclear.

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