scholarly journals The role of let-7b in the inhibition of hepatic stellate cell activation by rSjP40

2021 ◽  
Vol 15 (6) ◽  
pp. e0009472
Author(s):  
Xiaolei Sun ◽  
Li Zhang ◽  
Yuting Jiang ◽  
Aihong Li ◽  
Dandan Zhu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Direct Interaction ◽  
Collagen Type I ◽  
Collagen I ◽  
Luciferase Assay ◽  
Type I

Background Hepatic stellate cells (HSCs) are one of the main cell types involved in liver fibrosis induced by many factors, including schistosomes. Previous studies in our lab have shown that recombinant P40 protein from Schistosoma japonicum (rSjP40) can inhibit HSC activation in vitro. Let-7b is a member of the let-7 microRNA family and plays an inhibitory role in a variety of diseases and inflammatory conditions. In this study, we investigated the role of let-7b in the inhibition of HSC activation by rSjP40. Methods Expression of let-7b was detected by quantitative real-time PCR. A dual luciferase assay was used to confirm direct interaction between let-7b and collagen I. We also used western blot to assess protein levels of TGFβRI and collagen type I α1 (COL1A1). Results We found that rSjP40 up-regulates expression of let-7b in HSCs. Let-7b inhibits collagen I expression by directly targeting the 3’UTR region of the collagen I gene. Furthermore, we discovered that let-7b inhibitor partially restores the loss of collagen I expression caused by rSjP40. Conclusion Our research clarifies the role of let-7b in the inhibition of HSC activation by rSjP40 and will provide new insights and ideas for the inhibition of HSC activation and treatment of liver fibrosis.

scholarly journals WNT-5A regulates TGF-β-related activities in liver fibrosis

2017 ◽  
Vol 312 (3) ◽  
pp. G219-G227 ◽  
Author(s):  
Leonie Beljaars ◽  
Sara Daliri ◽  
Christa Dijkhuizen ◽  
Klaas Poelstra ◽  
Reinoud Gosens
Keyword(s):  
Liver Fibrosis ◽  
Functional Role ◽  
Collagen Type ◽  
Collagen Type I ◽  
Matrix Proteins ◽  
Type I ◽  
Human Livers

WNT-5A is a secreted growth factor that belongs to the noncanonical members of the Wingless-related MMTV-integration family. Previous studies pointed to a connection between WNT-5A and the fibrogenic factor TGF-β warranting further studies into the functional role of WNT-5A in liver fibrosis. Therefore, we studied WNT-5A expressions in mouse and human fibrotic livers and examined the relation between WNT-5A and various fibrosis-associated growth factors, cytokines, and extracellular matrix proteins. WNT-5A gene and protein expressions were significantly increased in fibrotic mouse and human livers compared with healthy livers. Regression or therapeutic intervention in mice resulted in decreased hepatic WNT-5A levels paralleled by lower collagen levels. Immunohistochemical analysis showed WNT-5A staining in fibrotic septa colocalizing with desmin staining indicating WNT-5A expression in myofibroblasts. In vitro studies confirmed WNT-5A expression in this cell type and showed that TGF-β significantly enhanced WNT-5A expression in contrast to PDGF-BB and proinflammatory cytokines IL-1β and TNF-α. Additionally, TGF-β induces the expression of the WNT receptors FZD2 and FZD8. After silencing of WNT-5A, reduced levels of collagen type I, vimentin, and fibronectin in TGF-β-stimulated myofibroblasts were measured compared with nonsilencing siRNA-treated controls. Interestingly, the antifibrotic cytokine IFNγ suppressed WNT-5A in vitro and in vivo. IFNγ-treated fibrotic mice showed significantly less WNT-5A expression compared with untreated fibrotic mice. In conclusion, WNT-5A paralleled collagen I levels in fibrotic mouse and human livers. WNT-5A expression in myofibroblasts is induced by the profibrotic factor TGF-β and plays an important role in TGF-β-induced regulation of fibrotic matrix proteins, whereas its expression can be reversed upon treatment, both in vitro and in vivo. NEW & NOTEWORTHY This study describes the localization and functional role of WNT-5A in human and mouse fibrotic livers. Hepatic WNT-5A expression parallels collagen type I expression. In vivo and in vitro, the myofibroblasts were identified as the key hepatic cells producing WNT-5A. WNT-5A is under control of TGF-β and its activities are primarily profibrotic.

scholarly journals Progranulin attenuates liver fibrosis by downregulating the inflammatory response

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Wonbeak Yoo ◽  
Jaemin Lee ◽  
Kyung Hee Noh ◽  
Sangmin Lee ◽  
Dana Jung ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Raw 264.7 Cells ◽  
Protective Effects ◽  
Deficient Diet ◽  
A Cell

Abstract Progranulin (PGRN) is a cysteine-rich secreted protein expressed in endothelial cells, immune cells, neurons, and adipocytes. It was first identified for its growth factor-like properties, being implicated in tissue remodeling, development, inflammation, and protein homeostasis. However, these findings are controversial, and the role of PGRN in liver disease remains unknown. In the current study, we examined the effect of PGRN in two different models of chronic liver disease, methionine‐choline‐deficient diet (MCD)-induced non-alcoholic steatohepatitis (NASH) and carbon tetrachloride (CCl4)-induced liver fibrosis. To induce long-term expression of PGRN, PGRN-expressing adenovirus was delivered via injection into the tibialis anterior. In the CCl4-induced fibrosis model, PGRN showed protective effects against hepatic injury, inflammation, and fibrosis via inhibition of nuclear transcription factor kappa B (NF-κB) phosphorylation. PGRN also decreased lipid accumulation and inhibited pro-inflammatory cytokine production and fibrosis in the MCD-induced NASH model. In vitro treatment of primary macrophages and Raw 264.7 cells with conditioned media from hepatocytes pre-treated with PGRN prior to stimulation with tumor necrosis factor (TNF)-α or palmitate decreased their expression of pro-inflammatory genes. Furthermore, PGRN suppressed inflammatory and fibrotic gene expression in a cell culture model of hepatocyte injury and primary stellate cell activation. These observations increase our understanding of the role of PGRN in liver injury and suggest PGRN delivery as a potential therapeutic strategy in chronic inflammatory liver disease.

scholarly journals Regulation of in vitro and in vivo Hepatic Stellate Cell Activation by the Ayrl Hydrocarbon Receptor

2020 ◽  
Author(s):  
Shivakumar Rayavara Veerabhadraiah
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Cell Activation ◽  
Stellate Cell ◽  
Pathological Condition ◽  
Matrix Material ◽  
Subsequent Development ◽  
Type I

Liver fibrosis is a pathological condition characterized by the excessive deposition of extracellular matrix material by activated hepatic stellate cells (HSCs). We recently reported that activation of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases HSC activation in vitro and in mouse models of experimental liver fibrosis. The goal of this project was to determine the mechanism by which AhR activation impacts HSC activation and the subsequent development of liver fibrosis. It is possible that HSCs are direct cellular targets for TCDD. Alternatively, TCDD could increase HSC activation indirectly by exacerbating hepatocyte damage and inflammation. To investigate this, we generated mice in which the AhR was selectively removed from either hepatocytes or HSCs to determine the ramifications on liver injury, inflammation, and HSC activation in an experimental model of liver fibrosis elicited by chronic administration of TCDD. Results from these studies indicate that TCDD does not directly activate HSCs in the mouse liver to produce fibrosis. Instead, it appears that TCDD-induced changes in hepatocytes, such as the development of steatosis, are what ultimately stimulate HSC activation and produce fibrosis. A second focus of this project was to investigate an endogenous role for AhR signaling in the regulation of HSC activation in the absence of liver injury and inflammation. To this end, I used CRISPR/Cas9 technology to knock down the AhR in the human HSC cell line, LX-2. I discovered that a functional AhR is required for optimal proliferation of activated HSCs. However, other endpoints of HSC activation, such as the production of collagen type I, were not impacted by the removal of AhR signaling. These findings are important because the AhR has been shown to be a druggable target, and there is growing interest in therapeutically modulating AhR activity to prevent or reverse HSC activation. Collectively, results from this project indicate that therapeutically targeting AhR signaling in hepatocytes, instead of AhR signaling in HSCs, might be a preferred approach for limiting HSC activation and preventing or diminishing liver fibrosis.

scholarly journals Thymosin-β4 Mediates Hepatic Stellate Cell Activation by Interfering with CircRNA-0067835/miR-155/FoxO3 Signaling Pathway

2018 ◽  
Vol 51 (3) ◽  
pp. 1389-1398 ◽  
Author(s):  
Lili Zhu ◽  
Tingting Ren ◽  
Zixin Zhu ◽  
Mingliang  Cheng ◽  
Qiuju Mou ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Circular Rna ◽  
Fine Tuning ◽  
Differentially Expressed ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
G1 Arrest

Background/Aims: Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrosis. Our study proved that thymosin beta 4 (Tβ4) has anti-fibrogenic effects in HSCs through PI3K/AKT pathway. However, the underlying mechanisms are not fully elucidated. Circular RNAs (circRNAs) play important roles in fine-tuning gene expression and are often deregulated in cancers. However, the expression profile and clinical significance of in liver fibrosis is still unknown. Therefore, we hypothesize that Tβ4 influences circRNAs in liver fibrosis. Methods: Circular RNA microarray was conducted to identify Tβ4-related circRNAs. Pathway analysis and miRNA response elements analysis was conducted to predict the potential roles of differentially expressed circRNAs in liver fibrosis. CCK8 assays and flow cytometric assays were conducted to clarify the role of circRNA in liver fibrosis. Bioinformatics analysis and in vitro experiments were conducted to clarify the mechanism of circRNA-mediated gene regulation in liver fibrosis. Results: A total of 644 differentially expressed circRNAs were identified between the Tβ4-depleted LX-2 cells and the control LX2 cells. The expression of circRNA-0067835 was significantly increased in the Tβ4-depleted LX-2 cells compared with control. Knockdown of circRNA-0067835 observably decreased LX-2 cell proliferation by causing G1 arrest and promoting apoptosis. Bioinformatics online programs predicted that circRNA-0067835 acted as miR-155 sponge to regulate FOXO3a expression, which was validated using luciferase reporter assay. Conclusion: Our experiments showed that circRNA-0067835 regulated liver fibrosis progression by acting as a sponge of miR-155 to promote FOXO3a expression, indicating that circRNA-0067835 may serve as a potential therapeutic target for patients with liver fibrosis.

The Role of Galectin-3 in Stellate Cell Activation and Liver Fibrosis

2012 ◽  
pp. 391-395 ◽  
Author(s):  
Joy X. Jiang ◽  
Xiangling Chen ◽  
Hiroo Fukada ◽  
Dan K. Hsu ◽  
Fu-tong Liu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Galectin 3

scholarly journals Role of cytoglobin, a novel radical scavenger, in stellate cell activation and hepatic fibrosis

2020 ◽  
Vol 26 (3) ◽  
pp. 280-293 ◽  
Author(s):  
Le Thi Thanh Thuy ◽  
Hoang Hai ◽  
Norifumi Kawada
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Radical Scavenger ◽  
History Of Research ◽  
Duct Ligation ◽  
History Of

Cytoglobin (Cygb), a stellate cell-specific globin, has recently drawn attention due to its association with liver fibrosis. In the livers of both humans and rodents, Cygb is expressed only in stellate cells and can be utilized as a marker to distinguish stellate cells from hepatic fibroblast-derived myofibroblasts. Loss of Cygb accelerates liver fibrosis and cancer development in mouse models of chronic liver injury including diethylnitrosamine-induced hepatocellular carcinoma, bile duct ligation-induced cholestasis, thioacetamide-induced hepatic fibrosis, and choline-deficient L-amino acid-defined diet-induced non-alcoholic steatohepatitis. This review focuses on the history of research into the role of reactive oxygen species and nitrogen species in liver fibrosis and discusses the current perception of Cygb as a novel radical scavenger with an emphasis on its role in hepatic stellate cell activation and fibrosis.

scholarly journals Targeting Follistatin like 1 ameliorates liver fibrosis induced by carbon tetrachloride through TGF-β1-miR29a in mice

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Xin-Yi Xu ◽  
Yan Du ◽  
Xue Liu ◽  
Yilin Ren ◽  
Yingying Dong ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Neutralizing Antibody ◽  
Transforming Growth Factor Β1 ◽  
Chemokine Ligand ◽  
Tgf Β1

Abstract Background Hepatic fibrosis is a pathological response of the liver to a variety of chronic stimuli. Hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. Follistatin like 1 (Fstl1) is a secreted glycoprotein induced by transforming growth factor-β1 (TGF-β1). However, the precise functions and regulation mechanisms of Fstl1 in liver fibrogenesis remains unclear. Methods Hepatic stellate cell (HSC) line LX-2 stimulated by TGF-β1, primary culture of mouse HSCs and a model of liver fibrosis induced by CCl4 in mice was used to assess the effect of Fstl1 in vitro and in vivo. Results Here, we found that Fstl1 was significantly up regulated in human and mouse fibrotic livers, as well as activated HSCs. Haplodeficiency of Fstl1 or blockage of Fstl1 with a neutralizing antibody 22B6 attenuated CCl4-induced liver fibrosis in vivo. Fstl1 modulates TGF-β1 classic Samd2 and non-classic JNK signaling pathways. Knockdown of Fstl1 in HSCs significantly ameliorated cell activation, cell migration, chemokines C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 8 (CXCL8) secretion and extracellular matrix (ECM) production, and also modulated microRNA-29a (miR29a) expression. Furthermore, we identified that Fstl1 was a target gene of miR29a. And TGF-β1 induction of Fstl1 expression was partially through down regulation of miR29a in HSCs. Conclusions Our data suggests TGF-β1-miR29a-Fstl1 regulatory circuit plays a key role in regulation the HSC activation and ECM production, and targeting Fstl1 may be a strategy for the treatment of liver fibrosis. Graphical abstract

scholarly journals Dioscin alleviates alcoholic liver fibrosis by attenuating hepatic stellate cell activation via the TLR4/MyD88/NF-κB signaling pathway

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Min Liu ◽  
Youwei Xu ◽  
Xu Han ◽  
Lianhong Yin ◽  
Lina Xu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Signaling Pathway ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Pyrrolidine Dithiocarbamate ◽  
Type I ◽  
Tgf Β1

Abstract The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF). In vivo liver fibrosis in mice was induced by an alcoholic liquid diet and in vitro studies were performed on activated HSC-T6 and LX2 cells treated with lipopolysaccharide. Our results showed that dioscin significantly attenuated hepatic stellate cells (HSCs) activation, improved collagen accumulation and attenuated inflammation through down-regulating the levels of myeloid differentiation factor 88 (MyD88), nuclear factor κB (NF-κB), interleukin (IL)-1, IL-6 and tumour necrosis factor-α by decreasing Toll-like receptor (TLR)4 expression both in vivo and in vitro. TLR4 overexpression was also decreased by dioscin, leading to the markedly down-regulated levels of MyD88, NF-κB, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) in cultured HSCs. Suppression of cellular MyD88 by ST2825 or abrogation of NF-κB by pyrrolidine dithiocarbamate eliminated the inhibitory effects of dioscin on the levels of TGF-β1, α-SMA and COL1A1. In a word, dioscin exhibited potent effects against ALF via altering TLR4/MyD88/NF-κB signaling pathway, which provided novel insights into the mechanisms of this compound as an antifibrogenic candidate for the treatment of ALF in the future.

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