The Role of Focal Adhesion Kinase-Phosphatidylinositol 3-Kinase-Akt Signaling in Hepatic Stellate Cell Proliferation and Type I Collagen Expression

Because human hepatic stellate cells (HSCs) perform a crucial role in the progress of hepatic fibrosis, it is of great value to establish an immortalized human cell line that exhibits HSC characteristics and grows well in tissue cultures for the development of antifibrotic therapies. Thus, we engineered an immortalized human hepatic stellate cell (HSC) line TWNT-4 by retrovirally inducing human telomerase reverse transcriptase (hTERT) into LI 90 cells established from a human liver mesenchymal tumor. Parental LI 90 entered replicative senescence, whereas TWNT-4 showed telomerase activity and proliferated for more than population doubling level (PDL) 200 without any crisis. TWNT-4 expressed platelet-derived growth factor-β receptor (PDGF-βR), α-smooth muscle actin (α-SMA), and type I collagen (α1) and was considered to be an activated form of HSCs. Treatment of TWNT-4 cells with either 100 U/ml of IFN-γ or 1 ng/ml of rapamycin (Rapa) for 14 days led to lower expression of type I collagen (α1) at RNA and protein levels. Exposure of TWNT-4 cells to both of IFN-γ (10 U/ml) and Rapa (0.1 ng/ml) for 14 days effectively decreased the expression of type I collagen (α1), PDGF-βR, and α-SMA expression and suppressed TGF-β1 secretion of TWNT-4 cells. We successfully induced apoptosis by transducing TNF-related apoptosis-inducing ligand (TRAIL) into TWNT-4 cells using adenovirus vectors Ad/GT-TRAIL and Ad/PGK-GV-17. These findings suggested that immortalized activated HSC line TWNT-4 would be a useful means to develop antifibrotic therapies.

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1059 CRITICAL ROLE OF TNF-RECEPTOR 1 BUT NOT 2 IN HEPATIC STELLATE CELL PROLIFERATION, EXTRACELLULAR MATRLX REMODELING AND LIVER FIBROGENESIS

Journal of Hepatology ◽

10.1016/s0168-8278(11)61061-1 ◽

2011 ◽

Vol 54 ◽

pp. S420

Author(s):

N. Tarrats ◽

A. Moles ◽

A. Morales ◽

C. Garcia-Ruiz ◽

J. Fernandez-Checa ◽

...

Keyword(s):

Cell Proliferation ◽

Hepatic Stellate Cell ◽

Stellate Cell ◽

Critical Role ◽

Tnf Receptor ◽

Liver Fibrogenesis

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Potential role of NF-kB in the negative regulation of human hepatic stellate cell proliferation

Journal of Hepatology ◽

10.1016/s0168-8278(98)80529-1 ◽

1998 ◽

Vol 28 ◽

pp. 83

Author(s):

C. Gallois ◽

A. Habib ◽

T. Jiangchuang ◽

J. Maclouf ◽

A. Mallat ◽

...

Keyword(s):

Cell Proliferation ◽

Hepatic Stellate Cell ◽

Potential Role ◽

Stellate Cell ◽

Negative Regulation ◽

Human Hepatic Stellate Cell

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NP603, a novel and potent inhibitor of FGFR1 tyrosine kinase, inhibits hepatic stellate cell proliferation and ameliorates hepatic fibrosis in rats

AJP Cell Physiology ◽

10.1152/ajpcell.00452.2010 ◽

2011 ◽

Vol 301 (2) ◽

pp. C469-C477 ◽

Cited By ~ 26

Author(s):

Nan Lin ◽

Si Chen ◽

Weidong Pan ◽

Linan Xu ◽

Kunpeng Hu ◽

...

Keyword(s):

Tyrosine Kinase ◽

Hepatic Fibrosis ◽

Hepatic Stellate Cell ◽

Type I Collagen ◽

Kinase Inhibitor ◽

Stellate Cell ◽

Smooth Muscle Actin ◽

Type I ◽

Promising Therapeutic Approach ◽

The Impact

Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of α-smooth muscle actin (α-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 μM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg·kg−1·day−1) administration significantly decreased hepatic collagen deposition and α-SMA expression in CCl4-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis.

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Dietary Flavonoid Hyperoside Induces Apoptosis of Activated Human LX-2 Hepatic Stellate Cell by Suppressing Canonical NF-κB Signaling

BioMed Research International ◽

10.1155/2016/1068528 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Liwen Wang ◽

Zhiwei Yue ◽

Mengzheng Guo ◽

Lianying Fang ◽

Liang Bai ◽

...

Keyword(s):

Hepatic Stellate Cell ◽

Type I Collagen ◽

Stellate Cell ◽

Smooth Muscle Actin ◽

Binding Activity ◽

Type I ◽

Altered Expression ◽

Dna Binding Activity ◽

Dietary Flavonoid ◽

Induced Apoptosis

Hyperoside, an active compound found in plants of the generaHypericumandCrataegus, is reported to exhibit antioxidant, anticancer, and anti-inflammatory activities. Induction of hepatic stellate cell (HSC) apoptosis is recognized as a promising strategy for attenuation of hepatic fibrosis. In this study, we investigated whether hyperoside treatment can exert antifibrotic effects in human LX-2 hepatic stellate cells. We found that hyperoside induced apoptosis in LX-2 cells and decreased levels ofα-smooth muscle actin (α-SMA), type I collagen, and intracellular reactive oxygen species (ROS). Remarkably, hyperoside also inhibited the DNA-binding activity of the transcription factor NF-κB and altered expression levels of NF-κB-regulated genes related to apoptosis, including proapoptotic genesBcl-Xs,DR4,Fas, andFasLand anti-apoptotic genesA20,c-IAP1,Bcl-XL, andRIP1. Our results suggest that hyperoside may have potential as a therapeutic agent for the treatment of liver fibrosis.

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