scholarly journals PFKFB3 Promotes Liver Fibrosis by Regulating Aerobic Glycolysis of Hepatic Stellate Cells

2021 ◽  
Vol 21 (5) ◽  
Author(s):  
Ming-yu Zhou ◽  
Xue-ke Zhao ◽  
Tao Huang ◽  
Gao-liang Zou ◽  
Rui-Han Hu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Liver Tissue ◽  
Aerobic Glycolysis ◽  
Glucose Consumption ◽  
Stellate Cells ◽  
Glycolytic Flux ◽  
Type I ◽  
Fibrotic Liver

Background: Hepatic stellate cells (HSCs) are the key effector cells in the occurrence and development of liver fibrosis, while aerobic glycolysis is one of the important metabolic characteristics of HSC activation. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a homodimeric bifunctional enzyme, which is a rate-limiting enzyme in glycolysis. This metabolite is important for the dynamic regulation of glycolytic flux. However, little is known about the role of PFKFB3 in liver fibrosis. Objectives: In this study, we aimed to explore the effects of PFKFB3 on aerobic glycolysis in the process of HSC trans-differentiation and liver fibrosis. Methods: Immunohistochemical (IHC) staining and immunofluorescence assays were used to examine PFKFB3 expression in mice fibrotic liver tissue. The determination of extracellular acidification rate was used to examine changes in aerobic glycolytic flux, lactate production levels, and glucose consumption levels in HSCs upon TGF-β1 stimulation. Western blot analysis of the expression of PFKFB3, α-SMA protein, and type I collagen was done. Liver histopathology was also examined. Besides, glycolytic inhibition by pharmacologic approaches was used to demonstrate the critical role of glycolysis in liver fibrosis. Results: The PFKFB3 protein expression was increased in mouse fibrotic liver tissue. In addition, immunofluorescence revealed the colocalization of PFKFB3 and alpha-smooth muscle actin (α-SMA) protein. In vitro experiments showed that PFKFB3 could promote glycolysis flux, lactic acid production, and glucose consumption of hepatic stellate cells. The PFKFB3 inhibitor was used in a mouse model of liver fibrosis, and the inhibition of PFKFB3 reduced the degree of liver inflammation and liver fibrosis. Conclusions: PFKFB3 can promote HSC aerobic glycolysis, which, in turn, promotes HSC activation and liver fibrosis.

scholarly journals The role of Mesothelin signaling in Portal Fibroblasts in the pathogenesis of cholestatic liver fibrosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Hiroaki Fuji ◽  
Grant Miller ◽  
Takahiro Nishio ◽  
Yukinori Koyama ◽  
Kevin Lam ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Hepatic Stellate Cells ◽  
Inflammatory Responses ◽  
Stellate Cells ◽  
Collagen Type I ◽  
Type I ◽  
Fibrotic Liver ◽  
Portal Fibroblasts

Liver fibrosis develops in response to chronic toxic or cholestatic injury, and is characterized by apoptosis of damaged hepatocytes, development of inflammatory responses, and activation of Collagen Type I producing myofibroblasts that make liver fibrotic. Two major cell types, Hepatic Stellate Cells (HSCs) and Portal Fibroblasts (PFs) are the major source of hepatic myofibroblasts. Hepatotoxic liver injury activates Hepatic Stellate Cells (aHSCs) to become myofibroblasts, while cholestatic liver injury activates both aHSCs and Portal Fibroblasts (aPFs). aPFs comprise the major population of myofibroblasts at the onset of cholestatic injury, while aHSCs are increasingly activated with fibrosis progression. Here we summarize our current understanding of the role of aPFs in the pathogenesis of cholestatic fibrosis, their unique features, and outline the potential mechanism of targeting aPFs in fibrotic liver.

Possible Therapeutic Uses of Extracellular Vesicles for Reversion of Activated Hepatic Stellate Cells: Context and Future Perspectives

2021 ◽  
Vol 21 ◽  
Author(s):  
Fahim Rejanur Tasin ◽  
Debasish Halder ◽  
Chanchal Mandal
Keyword(s):  
Liver Fibrosis ◽  
Extracellular Vesicles ◽  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Target Cells ◽  
Fibrotic Liver ◽  
Paracrine Effects ◽  
Cell Therapies

: Liver fibrosis is one of the leading causes for cirrhotic liver disease and the lack of therapies to treat fibrotic liver is a major concern. Liver fibrosis is mainly occurred by activation of hepatic stellate cells and some stem cell therapies had previously reported for treatment. However, due to some problems with cell-based treatment, a safe therapeutic agent is vehemently sought by the researchers. Extracellular vesicles are cell-derived nanoparticles that are employed in several therapeutic approaches, including fibrosis, for their ability to transfer specific molecules in the target cells. In this review the possibilities of extracellular vesicles to inactivate stellate cells are summarized and discussed. According to several studies, extracellular vesicles from different sources can either put beneficial or detrimental effects by regulating the activation of stellate cells. Therefore, targeting extracellular vesicles for maximizing or inhibiting their production is a potential approach for fibrotic liver treatment. Extracellular vesicles from different cells can also inactivate stellate cells by carrying out the paracrine effects of those cells, working as the agents. They are also implicated as smart carrier of anti-fibrotic molecules when their respective parent cells are engineered to produce specific stellate cell-regulating substances. A number of studies showed stellate cell activation can be regulated by up/downregulation of specific proteins, and extracellular vesicle-based therapies can be an effective move to exploit these mechanisms. In conclusion, EVs are advantageous nano-carriers with the potential to treat fibrotic liver by inactivating activated stellate cells by various mechanisms.

scholarly journals Identification of GDF15 as A Pro-Fibrotic Factor in Mouse Liver Fibrosis Progression

2021 ◽  
Author(s):  
Peng Qi ◽  
Ming-Ze Ma ◽  
Jing-Hua Kuai
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Hepatic Stellate Cells ◽  
Liver Tissue ◽  
Cell Activation ◽  
Stellate Cell ◽  
Neutralizing Antibody ◽  
Stellate Cells ◽  
Fibrosis Progression

Abstract Aim:To elucidate the inhibitory role of growth differentiation factor 15 (GDF15) in liver fibrosis and its possible activation mechanism in hepatic stellate cells of mice.Methods:We generated a GDF15-neutralizing antibody that can inhibit TGF-β1-induced activation of the TGF-β/Smad2/3 pathway in LX-2 cells. All the mice in this study were induced by carbon tetrachloride and thioacetamide. In addition, primary hepatic stellate cells from mice were isolated from fresh livers using Nycodenz density gradient separation. The severity and extent of liver fibrosis in mice were evaluated by Sirius Red and Masson staining. The effect of GDF15 on the activation of the TGF-β pathway was detected using dual-luciferase reporter assays and Western blotting assays.Results:The expression of GDF15 in cirrhotic liver tissue was higher than that in normal liver tissue. Blocking GDF15 with a neutralizing antibody resulted in a delay in primary hepatic stellate cell activation and remission of liver fibrosis induced by carbon tetrachloride or thioacetamide. Meanwhile, TGF-β pathway activation was partly inhibited by a GDF15-neutralizing antibody in primary hepatic stellate cells. These results indicated that GDF15 plays an important role in regulating HSC activation and liver fibrosis progression.Conclusions:The inhibition of GDF15 attenuates chemical-inducible liver fibrosis and delays hepatic stellate cell activation, and this effect is probably mainly attributed to its regulatory role in TGF-β signalling.

scholarly journals EFFECT OF COLLAGEN I GEL ON APOPTOSIS OF RAT HEPATIC STELLATE CELLS

2013 ◽  
Vol 56 (2) ◽  
pp. 73-79
Author(s):  
Lenka Bittnerová ◽  
Alena Jiroutová ◽  
Emil Rudolf ◽  
Martina Řezáčová ◽  
Jiří Kanta
Keyword(s):  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Collagen Gel ◽  
Stellate Cells ◽  
Type I ◽  
Function Type ◽  
Fibrotic Liver ◽  
Normal Rat ◽  
And Function

Activated hepatic stellate cells (HSC) are a major source of fibrous proteins in cirrhotic liver. Inducing or accelerating their apoptosis is a potential way of liver fibrosis treatment. Extracellular matrix (ECM) surrounding cells in tissue affects their differentiation, migration, proliferation and function. Type I collagen is the main ECM component in fibrotic liver. We have examined how this protein modifies apoptosis of normal rat HSC induced by gliotoxin, cycloheximide and cytochalasin D in vitro and spontaneous apoptosis of HSC isolated from CCl4-damaged liver. We have found that type I collagen gel enhances HSC apoptosis regardless of the agent triggering this process.

scholarly journals The Role of Signal Transducer and Activator of Transcription 5 and Transforming Growth Factor-β1 in Hepatic Fibrosis Induced by Chronic Hepatitis C Virus Infection in Egyptian Patients

2018 ◽  
Vol 27 (2) ◽  
pp. 115-121
Author(s):  
Mona A. Abu El Makarem ◽  
Ghada M. El-Sagheer ◽  
Moustafa A. Abu El-Ella
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Serum Levels ◽  
Signal Transducer ◽  
Egyptian Patients ◽  
Tgf Β1

Objective: To investigate the possible role of signal transducer and activator of transcription 5 (STAT5) in the pathogenesis of liver fibrosis in Egyptian patients with chronic hepatitis C (CHC) virus infection and its relation to hepatic stellate cells (HSC). Subjects and Methods: Sixty-five patients (46 males and 19 females) were divided into 4 groups based on the severity of fibrosis as detected by Fibroscan as follows: F1, n = 15; F2, n = 21; F3, n = 13; and F4, n = 16. Twenty age- and gender-matched healthy persons volunteered as controls. The serum levels of STAT5, TGF-β1, α-smooth muscle actin (α-SMA), fasting blood sugar, and fasting insulin, as well as homeostasis model assessment of insulin resistance (HOMA-IR), were determined and compared for all groups. The usefulness of the studied serum biomarkers for predicting liver fibrosis was evaluated using a receiver operating characteristic curve. Results: Serum levels of STAT5 were significantly lower in patients compared to controls (9.69 ± 5.62 vs. 14.73 ± 6.52, p ≤ 0.001); on the contrary, TGF-β1, α-SMA, and HOMA-IR were significantly higher in patients compared to controls (mean: 1,796.04 vs. 1,636.94; 14.94 vs. 8.1; and 7.91 vs. 4.18; p ≤ 0.01 and 0.001, respectively). TGF-β1 and α-SMA showed a progressive increase with advancing severity of hepatic fibrosis (mean TGF-β1: 2,058.4 in F1-F2 and 1,583.8 in F3-F4, p ≤ 0.04; mean α-SMA: 13.59 in F1-F2 and 16.62 in F3-F4, p ≤ 0.05). STAT5 had a significant negative correlation with TGF-β1 (p ≤ 0.001), while no correlation was detected with α-SMA (p ≤ 0.8). Conclusions: STAT5 may play a significant role in hepatic fibrogenesis through the induction of TGF-β1 but not through the activation of hepatic stellate cells.

Molecular basis for calcium signaling in hepatic stellate cells

2007 ◽  
Vol 292 (4) ◽  
pp. G975-G982 ◽  
Author(s):  
Emma A. Kruglov ◽  
Paulo R. A. V. Correa ◽  
Gaurav Arora ◽  
Jin Yu ◽  
Michael H. Nathanson ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
P2y Receptors ◽  
Type I ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor ◽  
Healthy Liver ◽  
Organ Fibrosis ◽  
Injured Liver

Progressive liver fibrosis (with the resultant cirrhosis) is the primary cause of chronic liver failure. Hepatic stellate cells (HSCs) are critically important mediators of liver fibrosis. In the healthy liver, HSCs are quiescent lipid-storing cells limited to the perisinusoidal endothelium. However, in the injured liver, HSCs undergo myofibroblastic transdifferentiation (activation), which is a critical step in the development of organ fibrosis. HSCs express P2Y receptors linking extracellular ATP to inositol (1,4,5)-trisphosphate-mediated cytosolic Ca2+ signals. Here, we report that HSCs express only the type I inositol (1,4,5)-trisphosphate receptor and that the receptor shifts into the nucleus and cell extensions upon activation. These cell extensions, furthermore, express sufficient machinery to enable local application of ATP to evoke highly localized Ca2+ signals that induce localized contractions. These autonomous units of subcellular signaling and response reveal a new level of subcellular organization, which, in turn, establishes a novel paradigm for the local control of fibrogenesis in the liver.

scholarly journals miR-139-5p sponged by LncRNA NEAT1 regulates liver fibrosis via targeting β-catenin/SOX9/TGF-β1 pathway

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qi Wang ◽  
Song Wei ◽  
Lei Li ◽  
Qingfa Bu ◽  
Haoming Zhou ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Hepatic Carcinoma ◽  
Fibrotic Liver ◽  
Fibrosis Progression ◽  
Murine Liver ◽  
Lncrna Neat1 ◽  
Tgf Β1

AbstractLiver fibrosis is a patho-physiological process which can develop into cirrhosis, and hepatic carcinoma without intervention. Our study extensively investigated the mechanisms of lncRNA NEAT1 and miR-139-5p in regulating liver fibrosis progression. Our results demonstrated that the expression of lncRNA NEAT1 was increased and the expression of miR-139-5p was decreased in fibrotic liver tissues. LncRNA NEAT1 could sponge miR-139-5p and promoted hepatic stellate cells (HSCs) activation by directly inhibiting the expression of miR-139-5p. The co-localization of lncRNA NEAT1 with miR-139-5p was shown in the cytosols of activated HSCs. miR-139-5p upregulation could suppress the expression of β-catenin. The overexpression of β-catenin promoted HSCs activation. Moreover, we found that β-catenin could interact with SOX9 promoted HSCs activation. Our further studies demonstrated that SOX9 could bind with the TGF-β1 promoter and promoted the transcription activity of TGF-β1. The upregulation of TGF-β1 further promoted HSCs activation. In vivo study also suggested that lncRNA NEAT1 knockdown and miR-139-5p overexpression alleviated murine liver fibrosis. LncRNA NEAT1 exacerbated liver fibrosis by suppressing the expression of miR-139-5p. Collectively, our study suggested that miR-139-5p sponged by lncRNA NEAT1 regulated liver fibrosis via targeting β-catenin/SOX9/TGF-β1 Pathway.

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.

scholarly journals The role of hepatic stellate cells in fibrotic liver diseases

2020 ◽  
Vol 35 (2) ◽  
pp. 113-118
Author(s):  
Hye Jin Cho ◽  
Jae Young Jang ◽  
Tae Min Kim
Keyword(s):  
Hepatic Stellate Cells ◽  
Liver Diseases ◽  
Stellate Cells ◽  
Fibrotic Liver
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