scholarly journals Berberine Inhibition of Fibrogenesis in a Rat Model of Liver Fibrosis and in Hepatic Stellate Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Ning Wang ◽  
Qihe Xu ◽  
Hor Yue Tan ◽  
Ming Hong ◽  
Sha Li ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Rat Model ◽  
Hepatic Stellate Cells ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Molecular Approaches ◽  
Duct Ligation ◽  
High Doses ◽  
Induced Apoptosis ◽  
Amp Activated Protein Kinase

Aim.To examine the effect of berberine (BBR) on liver fibrosis and its possible mechanisms through direct effects on hepatic stellate cells (HSC).Methods.The antifibrotic effect of BBR was determined in a rat model of bile duct ligation- (BDL-) induced liver fibrosis. Multiple cellular and molecular approaches were introduced to examine the effects of BBR on HSC.Results.BBR potently inhibited hepatic fibrosis induced by BDL in rats. It exhibited cytotoxicity to activated HSC at doses nontoxic to hepatocytes. High doses of BBR induced apoptosis of activated HSC, which was mediated by loss of mitochondrial membrane potential and Bcl-2/Bax imbalance. Low doses of BBR suppressed activation of HSC as evidenced by the inhibition ofα-smooth muscle actin (α-SMA) expression and cell motility. BBR did not affect Smad2/3 phosphorylation but significantly activated 5′ AMP-activated protein kinase (AMPK) signalling, which was responsible for the transcriptional inhibition by BBR of profibrogenic factorsα-SMA and collagen in HSC.Conclusion.BBR is a promising agent for treating liver fibrosis through multiple mechanisms, at least partially by directly targeting HSC and by inhibiting the AMPK pathway. Its value as an antifibrotic drug in patients with liver disease deserves further investigation.

Transforming growth factor beta-induced Foxo3a acts as a profibrotic mediator in hepatic stellate cells

2020 ◽  
Author(s):  
Seung Jung Kim ◽  
Kyu Min Kim ◽  
Ji Hye Yang ◽  
Sam Seok Cho ◽  
Eun Hee Jeong ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Hepatic Stellate Cells ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Forkhead Transcription Factor ◽  
Hepatic Fibrogenesis ◽  
Duct Ligation ◽  
Nuclear Levels

Abstract Hepatic stellate cells (HSCs) are major contributors to hepatic fibrogenesis facilitating liver fibrosis. FoxO3a is a member of the forkhead transcription factor family, which mediates cell proliferation and differentiation. However, the expression and function of FoxO3a during HSC activation remain largely unknown. FoxO3a overexpression was related to fibrosis in patients, and its expression was colocalized with desmin or α-smooth muscle actin, representative HSC markers. We also observed upregulated FoxO3a levels in two animal hepatic fibrosis models, a carbon tetrachloride (CCl4)-injected model and a bile duct ligation model. In addition, TGF-β treatment in mouse primary HSCs or LX-2 cells elevated FoxO3a expression. When FoxO3a was upregulated by TGF-β in LX-2 cells, both the cytosolic and nuclear levels of FoxO3a increased. In addition, we found that the induction of FoxO3a by TGF-β was due to both transcriptional and proteasome-dependent mechanisms. Moreover, FoxO3a overexpression promoted TGF-β-mediated Smad activation. Furthermore, FoxO3a increased fibrogenic gene expression, which was reversed by FoxO3a knockdown. TGF-β-mediated FoxO3a overexpression in HSCs facilitated hepatic fibrogenesis, suggesting that FoxO3a may be a novel target for liver fibrosis prevention and treatment.

scholarly journals Inflammasome-mediated regulation of hepatic stellate cells

2009 ◽  
Vol 296 (6) ◽  
pp. G1248-G1257 ◽  
Author(s):  
Azuma Watanabe ◽  
Muhammad Adnan Sohail ◽  
Dawidson Assis Gomes ◽  
Ardeshir Hashmi ◽  
Jun Nagata ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Immune Cells ◽  
Hepatic Stellate Cells ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Inflammasome Activation ◽  
Cellular Injury ◽  
Wild Type ◽  
Primary Mouse ◽  
Msu Crystals

The inflammasome is a cytoplasmic multiprotein complex that has recently been identified in immune cells as an important sensor of signals released by cellular injury and death. Analogous to immune cells, hepatic stellate cells (HSC) also respond to cellular injury and death. Our aim was to establish whether inflammasome components were present in HSC and could regulate HSC functionality. Monosodium urate (MSU) crystals (100 μg/ml) were used to experimentally induce inflammasome activation in LX-2 and primary mouse HSC. Twenty-four hours later primary mouse HSC were stained with α-smooth muscle actin and visualized by confocal microscopy, and TGF-β and collagen1 mRNA expression was quantified. LX-2 cells were further cultured with or without MSU crystals for 24 h in a transwell chemotaxis assay with PDGF as the chemoattractant. We also examined inhibition of calcium (Ca2+) signaling in LX-2 cells treated with or without MSU crystals using caged inositol 1,4,5-triphosphate (IP3). Finally, we confirmed an important role of the inflammasome in experimental liver fibrosis by the injection of carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild-type mice and mice lacking components of the inflammasome. Components of the inflammasome are expressed in LX-2 cells and primary HSC. MSU crystals induced upregulation of TGF-β and collagen1 mRNA and actin reorganization in HSCs from wild-type mice but not mice lacking inflammasome components. MSU crystals inhibited the release of Ca2+ via IP3 in LX-2 cells and also inhibited PDGF-induced chemotaxis. Mice lacking the inflammasome-sensing and adaptor molecules, NLRP3 and apoptosis-associated speck-like protein containing CARD, had reduced CCl4 and TAA-induced liver fibrosis. We concluded that inflammasome components are present in HSC, can regulate a variety of HSC functions, and are required for the development of liver fibrosis.

scholarly journals Structural Changes and Detection of Liver Fibrosis–Related Protein Levels in Coculture of Alveolar Echinococcosis-Protoscoleces and Human Hepatic Stellate Cells

2021 ◽  
Author(s):  
DEping cao ◽  
Emad Shamsan ◽  
Bofan Jiang ◽  
Zhang Yaogang ◽  
Mustafa Abdo Saif Dehwah
Keyword(s):  
Smooth Muscle ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Structural Changes ◽  
Alveolar Echinococcosis ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Muscle Actin ◽  
Related Protein

Abstract BackgroundEchinococcus multilocularis is a causative agent of human alveolar echinococcosis (AE). AE leads to cirrhosis in several organs, such as the liver, triggering severe conditions, including hepatic failure and encephalopathy. The main purpose of this study is to explore the interaction between treated hepatic stellate cells and AE-protoscoleces (AE-PSCs). The results of this study will be provided experimental basis for revealing the mechanisms of hepatic fibrosis after AE infection.MethodsWe investigated the role of alveolar echinococcosis-protoscoleces (AE-PSCs) in liver fibrosis and structural changes and liver fibrosis-related protein expression in a coculture of PSCs and human hepatic stellate cells (HSCs). Structural changes were detected by transmission electron microscopy, whereas liver fibrosis-related proteins, collagen I, alpha-smooth muscle actin, and osteopontin levels were measured by western blotting and enzyme-linked immunosorbent assay. ResultsPSCs exhibited morphological changes, specifically changes in shape, and showed slight changes in the cytoplasmic membrane, whereas structural modifications were observed in HSCs. Additionally, western blotting and enzyme-linked immunosorbent assay revealed that PSCs treated in vitro with HSC-LX2 showed significantly increased collagen-Ⅰ, α-smooth muscle actin, and osteopontin expression levels after 3–4 days of incubation in a coculture system. AE-PSCs induced liver fibrosis by inducing extracellular matrix expression and HSC activation.ConclusionsThese results provide insight into the pathogenesis of echinococcosis- induced hepatic fibrosis and introduce therapeutic targets and diagnostic criteria for managing echinococcosis-dependent liver fibrosis.

scholarly journals Suberoylanilide hydroxamic acid suppresses hepatic stellate cells activation by HMGB1 dependent reduction of NF-κB1

PeerJ ◽  
2015 ◽  
Vol 3 ◽  
pp. e1362 ◽  
Author(s):  
Wenwen Wang ◽  
Min Yan ◽  
Qiuhong Ji ◽  
Jinbiao Lu ◽  
Yuhua Ji ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Hydroxamic Acid ◽  
Molecular Mechanisms ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Cdna Array ◽  
Stellate Cells ◽  
Type I ◽  
Suberoylanilide Hydroxamic Acid

Hepatic stellate cells (HSCs) activation is essential to the pathogenesis of liver fibrosis. Exploring drugs targeting HSC activation is a promising anti-fibrotic strategy. In the present study, we found suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, prominently suppressed the activation phenotype of a human hepatic stellate cell line—LX2. The production of collagen type I andα-smooth muscle actin (α-SMA) as well as the proliferation and migration of LX2 cells were significantly reduced by SAHA treatment. To determine the molecular mechanisms underlying this suppression, genome wild gene regulation by SAHA was determined by Affymetrix 1.0 human cDNA array. Upon SAHA treatment, the abundance of 331 genes was up-regulated and 173 genes was down-regulated in LX2 cells. Bioinformatic analyses of these altered genes highlighted the high mobility group box 1 (HMGB1) pathway was one of the most relevant pathways that contributed to SAHA induced suppression of HSCs activation. Further studies demonstrated the increased acetylation of intracellular HMGB1 in SAHA treated HSCs, and this increasing is most likely to be responsible for SAHA induced down-regulation of nuclear factor kappa B1 (NF-κB1) and is one of the main underlying mechanisms for the therapeutic effect of SAHA for liver fibrosis.

MicroRNA-134 deactivates hepatic stellate cells by targeting TGF-β activated kinase 1-binding protein 1

2019 ◽  
Vol 97 (5) ◽  
pp. 505-512 ◽  
Author(s):  
Peiqin Wang ◽  
Shujuan Lei ◽  
Xiaohang Wang ◽  
Wenping Xu ◽  
Pingfang Hu ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Transforming Growth Factor ◽  
Bile Duct Ligation ◽  
Binding Protein ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Aberrant Expression ◽  
Duct Ligation ◽  
Liver Fibrogenesis

Aberrant expression of microRNAs is associated with liver fibrogenesis. We previously found that microRNA-134 (miR-134) expression was reduced in fibrosis-based hepatocarcinogenesis induced by diethylinitrosamine. Herein we investigate the role and mechanisms of miR-134 in hepatic fibrosis. Our data show that miR-134 expression is reduced in rat hepatic fibrogenesis induced by carbontetrachloride, bile duct ligation, and dimethylnitrosamine, as well as in activated hepatic stellate cells (HSCs). Moreover, miR-134 inhibited HSC proliferation, and decreased the expression of smooth muscle actin and collagen I in HSCs, whereas the miR-134 inhibitor increased HSC activation. MiR-134 also negatively regulated transforming growth factor-β-activated kinase 1-binding protein 1 (TAB1) expression in both human and rat HSCs by directly binding to its 3′ untranslated region. Importantly, TAB1 expression was significantly elevated during liver fibrogenesis and HSC activation. Knockdown of TAB1 inhibited the proliferation and fibrogenic behavior of HSCs, and significantly reduced the effect of the miR-134 inhibitor on HSC proliferation. Collectively, these data suggest that miR-134 inhibits the activation of HSCs via directly targeting TAB1, and the restoration of miR-134 or targeting TAB1 is of clinical significance in the treatment of liver fibrosis.

Interleukin-6 secreted by bipotential murine oval liver stem cells induces apoptosis of activated hepatic stellate cells by activating NF-κB-inducible nitric oxide synthase signaling

2017 ◽  
Vol 95 (2) ◽  
pp. 263-272 ◽  
Author(s):  
Palanivel Gajalakshmi ◽  
Syamantak Majumder ◽  
Cornelia S. Viebahn ◽  
Akila Swaminathan ◽  
George C. Yeoh ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Interleukin 6 ◽  
Hepatic Stellate Cells ◽  
Critical Role ◽  
In Vitro Study ◽  
Stellate Cells ◽  
Causative Factor ◽  
Activated Hepatic Stellate Cells ◽  
Induced Apoptosis

Liver fibrosis is now well recognized as the causative factor for increased mortality from complications associated with liver pathologies. Activated hepatic stellate cells (HSCs) play a critical role in the progression of liver fibrosis. Therefore, targeting these activated HSCs to prevent and (or) treat liver disease is a worthwhile approach to explore. In the present in vitro study, we investigated the use of bipotential murine oval liver cells (BMOL) in regulating the functions of activated HSCs to prevent progression of liver fibrosis. We used a conditioned medium-based approach to study the effect of BMOL cells on activated HSC survival and function. Our data showed that BMOL cells block the contraction of activated HSCs by inducing apoptosis of these cells. We demonstrated that BMOL cells secrete soluble factors, such as interleukin-6 (IL-6), which induced apoptosis of activated HSCs. Using both pharmacological and molecular inhibitor approaches, we further identified that IL-6-mediated activation of NF-κB–iNOS–NO–ROS signaling in activated HSCs plays a critical role in BMOL-cell-mediated apoptosis of activated HSCs. Thus, the present study provides an alternative cell-based therapeutic approach to treat liver fibrosis.

scholarly journals Role of TGF-β signaling in differentiation of mesothelial cells to vitamin A-poor hepatic stellate cells in liver fibrosis

2016 ◽  
Vol 310 (4) ◽  
pp. G262-G272 ◽  
Author(s):  
Yuchang Li ◽  
Ingrid Lua ◽  
Samuel W. French ◽  
Kinji Asahina
Keyword(s):  
Liver Fibrosis ◽  
Vitamin A ◽  
Hepatic Stellate Cells ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Mesothelial Cells ◽  
Mesenchymal Transition ◽  
Duct Ligation ◽  
Liver Surface

Mesothelial cells (MCs) form a single layer of the mesothelium and cover the liver surface. A previous study demonstrated that, upon liver injury, MCs migrate inward from the liver surface and give rise to hepatic stellate cells (HSCs) in biliary fibrosis induced by bile duct ligation (BDL) or myofibroblasts in CCl4-induced fibrosis. The present study analyzed the role of transforming growth factor-β (TGF-β) signaling in mesothelial-mesenchymal transition (MMT) and the fate of MCs during liver fibrosis and its regression. Deletion of TGF-β type II receptor ( Tgfbr2) gene in cultured MCs suppressed TGF-β-mediated myofibroblastic conversion. Conditional deletion of Tgfbr2 gene in MCs reduced the differentiation of MCs to HSCs and myofibroblasts in the BDL and CCl4 models, respectively, indicating that the direct TGF-β signaling in MCs is responsible to MMT. After BDL and CCl4 treatment, MC-derived HSCs and myofibroblasts were distributed near the liver surface and the thickness of collagen was increased in Glisson's capsule beneath the liver surface. Fluorescence-activated cell sorting analysis revealed that MC-derived HSCs and myofibroblasts store little vitamin A lipids and have fibrogenic phenotype in the fibrotic livers. MCs contributed to 1.4 and 2.0% of activated HSCs in the BDL and CCl4 models, respectively. During regression of CCl4-induced fibrosis, 20% of MC-derived myofibroblasts survived in the liver and deactivated to vitamin A-poor HSCs. Our data indicate that MCs participate in capsular fibrosis by supplying vitamin A-poor HSCs during a process of liver fibrosis and regression.

scholarly journals LincRNA-p21 Inhibits the Wnt/β-Catenin Pathway in Activated Hepatic Stellate Cells via Sponging MicroRNA-17-5p

2017 ◽  
Vol 41 (5) ◽  
pp. 1970-1980 ◽  
Author(s):  
Fujun Yu ◽  
Yong Guo ◽  
Bicheng Chen ◽  
Liang Shi ◽  
Peihong Dong ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Noncoding Rna ◽  
Type I Collagen ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Type I ◽  
Muscle Actin ◽  
Pathway Activity ◽  
Long Intergenic Noncoding Rna

Background/Aims: It is known that the activation of hepatic stellate cells (HSCs) is a pivotal step in the initiation and progression of liver fibrosis. Aberrant activated Wnt/β-catenin pathway is known to accelerate the development of liver fibrosis. microRNAs (miRNAs)-mediated Wnt/β-catenin pathway has been reported to be involved in HSC activation during liver fibrosis. However, whether long noncoding RNAs (lncRNAs) regulate Wnt/β-catenin pathway during HSC activation still remains unclear. Methods: Long intergenic noncoding RNA-p21 (lincRNA-p21) expression was detected in Salvianolic acid B (Sal B)-treated cells. Effects of lincRNA-p21 knockdown on HSC activation and Wnt/β-catenin pathway activity were analyzed in Sal B-treated cells. In lincRNA-p21-overexpressing cells, effects of miR-17-5p on HSC activation and Wnt/β-catenin pathway activity were examined. Results: LincRNA-p21 expression was up-regulated in HSCs after Sal B treatment. In primary HSCs, lincRNA-p21 expression was down-regulated at Day 5 relative to Day 2. Sal B-inhibited HSC activation including the reduction of cell proliferation, α-smooth muscle actin (α-SMA) and type I collagen was inhibited by lincRNA-p21 knockdown. Sal B-induced Wnt/β-catenin pathway inactivation was blocked down by loss of lincRNA-p21. Notably, lincRNA-p21, confirmed as a target of miR-17-5p, suppresses miR-17-5p level. Lack of the miR-17-5p binding site in lincRNA-p21 prevents the suppression of miR-17-5p expression. In addition, the suppression of HSC activation and Wnt/β-catenin pathway induced by lincRNA-p21 overexpression was almost inhibited by miR-17-5p. Conclusion: We demonstrate that lincRNA-p21-inhibited Wnt/β-catenin pathway is involved in the effects of Sal B on HSC activation and lincRNA-p21 suppresses HSC activation, at least in part, via miR-17-5p-mediated-Wnt/β-catenin pathway.

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