scholarly journals Hepatic stellate cells activation and liver fibrosis after chronic administration of ethanol

2016 ◽  
Vol 29 (2) ◽  
pp. 66-70
Author(s):  
Katarzyna Kot-Bakiera ◽  
Ewelina Wawryk-Gawda ◽  
Beata Cichacz-Kwiatkowska ◽  
Barbara Jodlowska-Jedrych
Keyword(s):  
Alcohol Consumption ◽  
Liver Fibrosis ◽  
Kupffer Cells ◽  
Hepatic Stellate Cells ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Control Group ◽  
Chronic Alcohol ◽  
Chronic Alcohol Consumption ◽  
Group A

Abstract Hepatic stellate cells (HSC) are a nonparenchymal population of liver cells. In normal conditions, they store vitamin A, control the turnover of the extracellular matrix, and regulate the contractility of the sinusoids. Acute and chronic damage such as that brought about by alcohol activates the stellate cells and they are then responsible for the liver's inflammatory fibrotic response. Hence, alcohol consumption leads to hepatitis, steatosis, fibrosis and cirrhosis of liver by way of different mechanisms depending on effect upon the nonparenchymal cells of the liver. The aim of our study was to assess the histological changes in the liver of rats after chronic alcohol consumption. In our work, we evaluated the intensity of liver fibrosis and the number of Kupffer cells and active hepatic stellate cells present within a test population. In the experiment, we used 10 Wistar rats of 250 gram weight. The animals were placed within one of two groups: A (experimental) and C (control). Group A received alcohol for 4 weeks, while group C received just water. The rats of both groups were decapitated 24 hours after the end of the experiment. The samples of liver were then evaluated after H&E, Masson’s trichrome staining and an immunohistochemical reaction to desmin (a marker of quiescent HSC) and α-smooth muscle actin (marker of active HSC) antibody. In our work, we observed intensive fibrosis in the portal spaces and perivenular areas in group A samples. Moreover, Kupffer cells and stellate cells with positive α-SMA expression were more numerous in group A than in the group C, and these correlate with the area of intensive fibrosis. The expression of desmin in the HSC was seen in both groups to a similar level. Conclusion: Chronic alcohol consumption activates the transdifferentiation of hepatic stellate cells into the positive α-SMA myofibroblast-like cells which are responsible for fibrogenesis.

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.

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.

Pathological roles of bone marrow-derived stellate cells in a mouse model of alcohol-induced fatty liver

2009 ◽  
Vol 297 (3) ◽  
pp. G451-G460 ◽  
Author(s):  
Tatsuya Fujimiya ◽  
Jinyao Liu ◽  
Hideto Kojima ◽  
Seiko Shirafuji ◽  
Hiroshi Kimura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Alcohol Consumption ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Stellate Cells ◽  
Chronic Alcohol ◽  
Chronic Alcohol Consumption ◽  
Tnf Α ◽  
Tgf Β1 ◽  
Excess Alcohol Consumption

Chronic alcohol consumption activates hepatic stellate cells (HSCs) and causes fatty degeneration in the liver. However, the origin of HSCs and the mechanism of fatty changes of the liver have not been fully elucidated. Here, we examined the roles of bone marrow-derived cells (BMDCs) in a mouse model with chronic alcohol consumption. We performed bone marrow transplantation from transgenic mice expressing green fluorescence protein (GFP) to female wild-type and ROSA mice (B6.129S7-Gt 26Sor/J, transgenic mice expressing β-galactosidase, β-gal) and treated them with ethanol (EtOH) for 8 or 16 wk. GFP-expressing BMDCs increased in the liver with EtOH treatment in a time-dependent manner. In response to excess alcohol consumption, ≈68% of the BMDCs became activated HSCs in that they expressed α-smooth muscle actin. Meanwhile, ≈67% and ≈66% of these BMDCs expressed Tnf-α and transforming growth factor (Tgf)-β1, respectively, and the activities were further supported by the excessive mRNA expression of Tnf-α and Tgf-β1 in RT-PCR, respectively. Cell fusion occurs between BMDCs and nonparenchymal cells but scarcely occurs between BMDCs and hepatocytes, demonstrated by double staining of β-gal/GFP and further supported by the Y-chromosome staining. The EtOH withdrawal normalized most of the abnormalities produced by chronic alcohol consumption. These results indicate that excess alcohol consumption stimulates both the homing of HSCs from the bone marrow and their profibrogenic cytokine production in a mouse model of alcohol-induced fatty liver disease.

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.

scholarly journals Effect of High Concentrations of Fructose on the Expression of TGF-β and α-SMA Genes in Human Hepatic Stellate Cells

2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Elham Shakerian ◽  
Hamid Yaghooti ◽  
Alireza Kheirollah ◽  
Narges Mohammadtaghvaei
Keyword(s):  
Liver Fibrosis ◽  
Mrna Expression ◽  
Liver Damage ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Control Group ◽  
Chronic Liver Damage ◽  
Fructose Intake ◽  
High Fructose ◽  
Human Hscs

Background: Liver fibrosis is a reversible response to wound-healing that occurs in most forms of chronic liver damage, beginning with the activation of hepatic stellate cells (HSCs). The increased expression of genes, such as beta-converting growth factor (TGF-β) and actin-alpha smooth muscle (α-SMA) indicates the activation of HSCs. During liver damage, HSCs are activated and converted to myofibroblasts. As a result, the expression of TGF-β and αSMA genes in HSCs increases and leads to liver fibrosis. High fructose intake is known to have harmful effects on human health. Due to the persistent increase in high fructose intake via many beverages and foods in industrialized countries, much concern has been raised about the effect of fructose on liver damage, but its role in activating human HSCs has not been studied. Objectives: We aimed to investigate the effect of high fructose concentration on human HSCs activation by measuring the level of mRNA expression of TGF-β and α-SMA genes involved in liver fibrosis. Methods: Human HSCs were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) plus 10% Fetal Bovine Serum (FBS) at 37°C in 5% CO2. Cells were incubated in media containing 25 and 30 mM fructose for 48 h. The control group was incubated in DMEM without fructose. The cells were serum-starved for 24 h before treatment. Then, the total RNA was extracted, reversely transcribed into cDNA, and underwent Quantitative Real-time PCR (qRT-PCR). Results: The results indicated that the mRNA expression of TGF-β and αSMA genes significantly increased by treating with 25 and 30 mM fructose in HSCs when compared to the control group (P < 0.05). Conclusions: The increase in the mRNA of TGF-β and αSMA genes is used as a standard marker for HSC activation, leading to liver fibrosis. The results demonstrated that high fructose concentration could activate HSCs and increase the levels of TGF-β and αSMA in these cells. Thus, controlling fructose consumption and identifying the mechanism of fructose action is important to treat and reduce liver injury.

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.

scholarly journals Interleukin-17 Signaling in Inflammatory, Kupffer Cells, and Hepatic Stellate Cells Exacerbates Liver Fibrosis in Mice

2012 ◽  
Vol 143 (3) ◽  
pp. 765-776.e3 ◽  
Author(s):  
Fanli Meng ◽  
Kai Wang ◽  
Tomonori Aoyama ◽  
Sergei I. Grivennikov ◽  
YongHan Paik ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Kupffer Cells ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Interleukin 17

Chronic Alcohol Consumption Increased Bile Acid Levels in Enterohepatic Circulation and Reduced Efficacy of Irinotecan

2020 ◽  
Vol 55 (3) ◽  
pp. 264-277
Author(s):  
Xia Gong ◽  
Qisong Zhang ◽  
Yanjiao Ruan ◽  
Ming Hu ◽  
Zhongqiu Liu ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Liver Injury ◽  
Enterohepatic Circulation ◽  
Ethanol Intake ◽  
Mass Spectrometry Analysis ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Chronic Alcohol ◽  
Chronic Alcohol Consumption ◽  
Chronic Ethanol Consumption

Abstract Aims To investigate the effect of ethanol intake on the whole enterohepatic circulation (EHC) of bile acids (BAs) and, more importantly, on pharmacokinetics of irinotecan. Methods The present study utilized a mouse model administered by gavage with 0 (control), 240 mg/100 g (30%, v/v) and 390 mg/100 g (50%, v/v) ethanol for 6 weeks, followed by BA profiles in the whole EHC (including liver, gallbladder, intestine and plasma) and colon using ultra-high performance liquid chromatography with tandem mass spectrometry analysis. Pharmacokinetic parameters of irinotecan were measured after administration of irinotecan (i.v. 5 mg/kg) on alcohol-treated mice. Results The results showed that compared with the control group, concentrations of most free-BAs, total amount of the three main forms of BAs (free-BA, taurine-BA and glycine-BA) and total BAs (TBAs) in 50% ethanol intake group were significantly increased, which are mostly attributed to the augmentation of free-BAs and taurine-BAs. Additionally, the TBAs in liver and gallbladder and the BA pool were markedly increased in the 30% ethanol intake group. Importantly, ethanol intake upregulated the expression of BA-related enzymes (Cyp7a1, Cyp27a1, Cyp8b1 and Baat) and transporters (Bsep, Mrp2, P-gp and Asbt) and downregulated the expression of transporter Ntcp and nuclear receptor Fxr in the liver and ileum, respectively. Additionally, 50% ethanol intake caused fairly distinct liver injury. Furthermore, the AUC0–24 h of irinotecan and SN38 were significantly reduced but their clearance was significantly increased in the disrupted EHC of BA by 50% ethanol intake. Conclusions The present study demonstrated that ethanol intake altered the expression of BA-related synthetases and transporters. The BA levels, especially the toxic BAs (chenodeoxycholic acid, deoxycholic acid and lithocholic acid), in the whole EHC were significantly increased by ethanol intake, which may provide a potential explanation to illuminate the pathogenesis of alcoholic liver injury. Most importantly, chronic ethanol consumption had a significant impact on the pharmacokinetics (AUC0–24 h and clearance) of irinotecan and SN38; hence colon cancer patients with chronic alcohol consumption treated with irinotecan deserve our close attention.

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