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12 pages, 659 KiB

Open AccessEditorial

Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis”

by Ralf Weiskirchen

Cells 2020, 9(5), 1105; https://doi.org/10.3390/cells9051105 - 29 Apr 2020

Cited by 6 | Viewed by 2891

Abstract

This Special issue contains 48 contributions highlighting novel findings and current concepts in basic and clinical liver fibrosis research. These articles emphasize issues on pathogenesis, cellular mediators, modulators, molecular pathways, disease-specific therapies, scoring systems, as well as novel preclinical animal models for the [...] Read more.

This Special issue contains 48 contributions highlighting novel findings and current concepts in basic and clinical liver fibrosis research. These articles emphasize issues on pathogenesis, cellular mediators, modulators, molecular pathways, disease-specific therapies, scoring systems, as well as novel preclinical animal models for the study of liver fibrogenesis. This editorial aims to briefly summarize the content of these papers. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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Research

Jump to: Editorial, Review

13 pages, 6470 KiB

Open AccessArticle

α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin

by Ute A. Schwinghammer, Magda M. Melkonyan, Lilit Hunanyan, Roman Tremmel, Ralf Weiskirchen, Erawan Borkham-Kamphorst, Elke Schaeffeler, Torgom Seferyan, Wolfgang Mikulits, Konstantin Yenkoyan, Matthias Schwab and Lusine Danielyan

Cells 2020, 9(2), 456; https://doi.org/10.3390/cells9020456 - 18 Feb 2020

Cited by 10 | Viewed by 4794

Abstract

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and β-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern [...] Read more.

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and β-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of α2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the α2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of α2a-, α2b-, and α2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only α2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in α-smooth muscle actin, transforming growth factor-β and α2a-AR expression, which was indicated by RT-qPCR, immunocytochemistry, and Western blot analyses. In a hLSEC line, an increased expression of endothelial nitric oxide synthase was detected along with downregulated transforming growth factor-β. In conclusion, we suggest that the α2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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22 pages, 8299 KiB

Open AccessArticle

Antifibrotic Effects of Amyloid-Beta and Its Loss in Cirrhotic Liver

by Gayane Hrachia Buniatian, Ralf Weiskirchen, Thomas S. Weiss, Ute Schwinghammer, Martin Fritz, Torgom Seferyan, Barbara Proksch, Michael Glaser, Ali Lourhmati, Marine Buadze, Erawan Borkham-Kamphorst, Frank Gaunitz, Christoph H. Gleiter, Thomas Lang, Elke Schaeffeler, Roman Tremmel, Holger Cynis, William H. Frey II, Rolf Gebhardt, Scott L. Friedman, Wolfgang Mikulits, Matthias Schwab and Lusine Danielyan Show full author list Hide full author list

Cells 2020, 9(2), 452; https://doi.org/10.3390/cells9020452 - 17 Feb 2020

Cited by 9 | Viewed by 5317

Abstract

The function and regulation of amyloid-beta (Aβ) in healthy and diseased liver remains unexplored. Because Aβ reduces the integrity of the blood-brain barrier we have examined its potential role in regulating the sinusoidal permeability of normal and cirrhotic liver. Aβ and key proteins [...] Read more.

The function and regulation of amyloid-beta (Aβ) in healthy and diseased liver remains unexplored. Because Aβ reduces the integrity of the blood-brain barrier we have examined its potential role in regulating the sinusoidal permeability of normal and cirrhotic liver. Aβ and key proteins that generate (beta-secretase 1 and presenilin-1) and degrade it (neprilysin and myelin basic protein) were decreased in human cirrhotic liver. In culture, activated hepatic stellate cells (HSC) internalized Aβ more efficiently than astrocytes and HSC degraded Aβ leading to suppressed expression of α-smooth muscle actin (α-SMA), collagen 1 and transforming growth factor β (TGFβ). Aβ also upregulated sinusoidal permeability marker endothelial NO synthase (eNOS) and decreased TGFβ in cultured human liver sinusoidal endothelial cells (hLSEC). Liver Aβ levels also correlate with the expression of eNOS in transgenic Alzheimer’s disease mice and in human and rodent cirrhosis/fibrosis. These findings suggest a previously unexplored role of Aβ in the maintenance of liver sinusoidal permeability and in protection against cirrhosis/fibrosis via attenuation of HSC activation. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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19 pages, 5227 KiB

Open AccessArticle

Dynamic Changes in Function and Proteomic Composition of Extracellular Vesicles from Hepatic Stellate Cells during Cellular Activation

by Xinlei Li, Ruju Chen, Sherri Kemper and David R Brigstock

Cells 2020, 9(2), 290; https://doi.org/10.3390/cells9020290 - 25 Jan 2020

Cited by 19 | Viewed by 3871

Abstract

During chronic liver injury, hepatic stellate cells (HSC) undergo activation and are the principal cellular source of collagenous scar. In this study, we found that activation of mouse HSC (mHSC) was associated with a 4.5-fold increase in extracellular vesicle (EV) production and that [...] Read more.

During chronic liver injury, hepatic stellate cells (HSC) undergo activation and are the principal cellular source of collagenous scar. In this study, we found that activation of mouse HSC (mHSC) was associated with a 4.5-fold increase in extracellular vesicle (EV) production and that fibrogenic gene expression (CCN2, Col1a1) was suppressed in Passage 1 (P1; activated) mHSC exposed to EVs from Day 4 (D4; relatively quiescent) mHSC but not to EVs from P1 mHSC. Conversely, gene expression (CCN2, Col1a1, αSMA) in D4 mHSC was stimulated by EVs from P1 mHSC but not by EVs from D4 mHSC. EVs from Day 4 mHSC contained only 46 proteins in which histones and keratins predominated, while EVs from P1 mHSC contained 337 proteins and these were principally associated with extracellular spaces or matrix, proteasome, collagens, vesicular transport, metabolic enzymes, ribosomes and chaperones. EVs from the activated LX-2 human HSC (hHSC) line also promoted fibrogenic gene expression in D4 mHSC in vitro and contained 524 proteins, many of which shared identity or had functional overlap with those in P1 mHSC EVs. The activation-associated changes in production, function and protein content of EVs from HSC likely contribute to the regulation of HSC function in vivo and to the fine-tuning of fibrogenic pathways in the liver. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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15 pages, 3383 KiB

Open AccessArticle

Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis

by Simon Hohenester, Veronika Kanitz, Andreas E. Kremer, Coen C. Paulusma, Ralf Wimmer, Helen Kuehn, Gerald Denk, David Horst, Ronald Oude Elferink and Ulrich Beuers

Cells 2020, 9(2), 281; https://doi.org/10.3390/cells9020281 - 23 Jan 2020

Cited by 26 | Viewed by 3998

Abstract

Hydrophobic bile salts are considered to promote liver fibrosis in cholestasis. However, evidence for this widely accepted hypothesis remains scarce. In established animal models of cholestasis, e.g., by Mdr2 knockout, cholestasis and fibrosis are both secondary to biliary damage. Therefore, to test the [...] Read more.

Hydrophobic bile salts are considered to promote liver fibrosis in cholestasis. However, evidence for this widely accepted hypothesis remains scarce. In established animal models of cholestasis, e.g., by Mdr2 knockout, cholestasis and fibrosis are both secondary to biliary damage. Therefore, to test the specific contribution of accumulating bile salts to liver fibrosis in cholestatic disease, we applied the unique model of inducible hepatocellular cholestasis in cholate-fed Atp8b1^G308V/G308V mice. Glycochenodeoxycholate (GCDCA) was supplemented to humanize the murine bile salt pool, as confirmed by HPLC. Biomarkers of cholestasis and liver fibrosis were quantified. Hepatic stellate cells (HSC) isolated from wild-type mice were stimulated with bile salts. Proliferation, cell accumulation, and collagen deposition of HSC were determined. In cholestatic Atp8b1^G308V/G308V mice, increased hepatic expression of αSMA and collagen1a mRNA and excess hepatic collagen deposition indicated development of liver fibrosis only upon GCDCA supplementation. In vitro, numbers of myofibroblasts and deposition of collagen were increased after incubation with hydrophobic but not hydrophilic bile salts, and associated with EGFR and MEK1/2 activation. We concluded that chronic hepatocellular cholestasis alone, independently of biliary damage, induces liver fibrosis in mice in presence of the human bile salt GCDCA. Bile salts may have direct pro-fibrotic effects on HSC, putatively involving EGFR and MEK1/2 signaling. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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12 pages, 2012 KiB

Open AccessArticle

Four-And-A-Half LIM-Domain Protein 2 (FHL2) Deficiency Aggravates Cholestatic Liver Injury

by Judith Sommer, Christoph Dorn, Erwin Gäbele, Frauke Bataille, Kim Freese, Tatjana Seitz, Wolfgang E. Thasler, Reinhard Büttner, Ralf Weiskirchen, Anja Bosserhoff and Claus Hellerbrand

Cells 2020, 9(1), 248; https://doi.org/10.3390/cells9010248 - 19 Jan 2020

Cited by 9 | Viewed by 3482

Abstract

Cholestasis occurs in different clinical circumstances and leads to severe hepatic disorders. The four-and-a-half LIM-domain protein 2 (FHL2) is a scaffolding protein that modulates multiple signal transduction pathways in a tissue- and cell context-specific manner. In this study, we aimed to gain insight [...] Read more.

Cholestasis occurs in different clinical circumstances and leads to severe hepatic disorders. The four-and-a-half LIM-domain protein 2 (FHL2) is a scaffolding protein that modulates multiple signal transduction pathways in a tissue- and cell context-specific manner. In this study, we aimed to gain insight into the function of FHL2 in cholestatic liver injury. FHL2 expression was significantly increased in the bile duct ligation (BDL) model in mice. In Fhl2-deficient (Fhl2-ko) mice, BDL caused a more severe portal and parenchymal inflammation, extended portal fibrosis, higher serum transaminase levels, and higher pro-inflammatory and pro-fibrogenic gene expression compared to wild type (wt) mice. FHL2 depletion in HepG2 cells with siRNA resulted in a higher expression of the bile acid transporter Na⁺-taurocholate cotransporting polypeptide (NTCP) gene. Furthermore, FHL2-depleted HepG2 cells showed higher expression of markers for oxidative stress, lower B-cell lymphoma 2 (Bcl2) expression, and higher Bcl2-associated X protein (BAX) expression after stimulation with deoxycholic acid (DCA). In hepatic stellate cells (HSCs), FHL2 depletion caused an increased expression of TGF-β and several pro-fibrogenic matrix metalloproteinases. In summary, our study shows that deficiency in FHL2 aggravates cholestatic liver injury and suggests FHL2-mediated effects on bile acid metabolisms and HSCs as potential mechanisms for pronounced hepatocellular injury and fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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17 pages, 4363 KiB

Open AccessArticle

Transcriptional Suppression of the NLRP3 Inflammasome and Cytokine Release in Primary Macrophages by Low-Dose Anthracyclines

by Nilay Köse-Vogel, Sven Stengel, Elena Gardey, Tatiana Kirchberger-Tolstik, Philipp A. Reuken, Andreas Stallmach and Tony Bruns

Cells 2020, 9(1), 79; https://doi.org/10.3390/cells9010079 - 28 Dec 2019

Cited by 8 | Viewed by 6653

Abstract

Tissue-resident macrophages play critical roles in controlling homeostasis, tissue repair, and immunity. Inflammatory macrophages can sustain tissue damage and promote the development of fibrosis during infections and sterile tissue injury. The NLRP3 inflammasome and its effector cytokine IL-1β have been identified as important [...] Read more.

Tissue-resident macrophages play critical roles in controlling homeostasis, tissue repair, and immunity. Inflammatory macrophages can sustain tissue damage and promote the development of fibrosis during infections and sterile tissue injury. The NLRP3 inflammasome and its effector cytokine IL-1β have been identified as important mediators of fibrosis. Epirubicin, an anthracycline topoisomerase II inhibitor, has been reported to inhibit myeloid inflammatory cytokine production and to promote tissue tolerance following bacterial infection. We investigated the anti-inflammatory properties of epirubicin on the NLRP3 inflammasome and TLR4-mediated inflammation in PMA-primed THP-1 and in primary human peritoneal macrophages (PM). Low-dose epirubicin at non-cytotoxic doses downregulated NLRP3 inflammasome components and reduced the release of cleaved caspase-1, bioactive IL-1β, and TNF-α following NLRP3 activation in a dose-dependent fashion. In addition, epirubicin attenuated inflammatory macrophage responses after TLR4 and TLR2 ligation. These anti-inflammatory effects were not mediated by the induction of autophagy or altered MAPK signaling, but as the result of a global transcriptional suppression of LPS-dependent genes. Epirubicin-treated macrophages displayed reduced acetylation of histone 3 lysine 9 (H3K9ac), suggesting anti-inflammatory epigenetic imprinting as one underlying mechanism. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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24 pages, 5863 KiB

Open AccessArticle

Oncostatin M, A Profibrogenic Mediator Overexpressed in Non-Alcoholic Fatty Liver Disease, Stimulates Migration of Hepatic Myofibroblasts

by Beatrice Foglia, Salvatore Sutti, Dario Pedicini, Stefania Cannito, Claudia Bocca, Marina Maggiora, Maria Rosaria Bevacqua, Chiara Rosso, Elisabetta Bugianesi, Emanuele Albano, Erica Novo and Maurizio Parola

Cells 2020, 9(1), 28; https://doi.org/10.3390/cells9010028 - 20 Dec 2019

Cited by 24 | Viewed by 4729

Abstract

Background: Hepatic myofibroblasts (MFs) can originate from hepatic stellate cells, portal fibroblasts, or bone marrow-derived mesenchymal stem cells and can migrate towards the site of injury by aligning with nascent and established fibrotic septa in response to several mediators. Oncostatin M (OSM) is [...] Read more.

Background: Hepatic myofibroblasts (MFs) can originate from hepatic stellate cells, portal fibroblasts, or bone marrow-derived mesenchymal stem cells and can migrate towards the site of injury by aligning with nascent and established fibrotic septa in response to several mediators. Oncostatin M (OSM) is known to orchestrate hypoxia-modulated hepatic processes involving the hypoxia-inducible factor 1 (HIF-1). Methods. In vivo and in vitro experiments were performed to analyze the expression of OSM and OSM-receptor (OSMR) in three murine models of non-alcoholic-fatty liver disease (NAFLD) and -steatohepatitis (NASH) and in human NASH patients as well as the action of OSM on phenotypic responses of human MFs. Results: Hepatic OSM and OSMR levels were overexpressed in three murine NASH models and in NASH patients. OSM stimulates migration in human MFs by involving early intracellular ROS generation and activation of Ras/Erk, JNK1/2, PI3K/Akt as well as STAT1/STAT3 pathways and HIF-1α. OSM-dependent migration relies on a biphasic mechanism requiring early intracellular generation of reactive oxygen species (ROS) and late HIF1-dependent expression and release of VEGF. Conclusion: OSM is overexpressed in experimental and human progressive NAFLD and can act as a profibrogenic factor by directly stimulating migration of hepatic MFs. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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21 pages, 8497 KiB

Open AccessFeature PaperArticle

Influence of Liver Fibrosis on Lobular Zonation

by Ahmed Ghallab, Maiju Myllys, Christian H. Holland, Ayham Zaza, Walaa Murad, Reham Hassan, Yasser A. Ahmed, Tahany Abbas, Eman A. Abdelrahim, Kai Markus Schneider, Madlen Matz-Soja, Jörg Reinders, Rolf Gebhardt, Marie-Luise Berres, Maximilian Hatting, Dirk Drasdo, Julio Saez-Rodriguez, Christian Trautwein and Jan G. Hengstler

Cells 2019, 8(12), 1556; https://doi.org/10.3390/cells8121556 - 2 Dec 2019

Cited by 48 | Viewed by 9499

Abstract

Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl₄ administration for 2, 6 and 12 months to induce pericentral damage, as well as bile duct ligation (21 [...] Read more.

Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl₄ administration for 2, 6 and 12 months to induce pericentral damage, as well as bile duct ligation (21 days) and mdr2^−/− mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl₄; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated ‘periportalization’ was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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21 pages, 4957 KiB

Open AccessArticle

The G Protein-Coupled Bile Acid Receptor TGR5 (Gpbar1) Modulates Endothelin-1 Signaling in Liver

by Caroline Klindt, Maria Reich, Birte Hellwig, Jan Stindt, Jörg Rahnenführer, Jan G. Hengstler, Karl Köhrer, Kristina Schoonjans, Dieter Häussinger and Verena Keitel

Cells 2019, 8(11), 1467; https://doi.org/10.3390/cells8111467 - 19 Nov 2019

Cited by 41 | Viewed by 5837

Abstract

TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs), and activated hepatic stellate cells (HSCs). Mice with targeted deletion of [...] Read more.

TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs), and activated hepatic stellate cells (HSCs). Mice with targeted deletion of TGR5 are more susceptible towards cholestatic liver injury induced by cholic acid-feeding and bile duct ligation, resulting in a reduced proliferative response and increased liver injury. Conjugated lithocholic acid (LCA) represents the most potent TGR5 BA ligand and LCA-feeding has been used as a model to rapidly induce severe cholestatic liver injury in mice. Thus, TGR5 knockout (KO) mice and wildtype (WT) littermates were fed a diet supplemented with 1% LCA for 84 h. Liver injury and gene expression changes induced by the LCA diet revealed an enrichment of pathways associated with inflammation, proliferation, and matrix remodeling. Knockout of TGR5 in mice caused upregulation of endothelin-1 (ET-1) expression in the livers. Analysis of TGR5-dependent ET-1 signaling in isolated LSECs and HSCs demonstrated that TGR5 activation reduces ET-1 expression and secretion from LSECs and triggers internalization of the ET-1 receptor in HSCs, dampening ET-1 responsiveness. Thus, we identified two independent mechanisms by which TGR5 inhibits ET-1 signaling and modulates portal pressure. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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12 pages, 5782 KiB

Open AccessArticle

Clusterin Attenuates Hepatic Fibrosis by Inhibiting Hepatic Stellate Cell Activation and Downregulating the Smad3 Signaling Pathway

by Hye-Young Seo, So-Hee Lee, Ji-Ha Lee, Yu Na Kang, Young-Keun Choi, Jae Seok Hwang, Keun-Gyu Park, Byoung Kuk Jang and Mi Kyung Kim

Cells 2019, 8(11), 1442; https://doi.org/10.3390/cells8111442 - 14 Nov 2019

Cited by 18 | Viewed by 4440

Abstract

Clusterin is a glycoprotein that is expressed in most human tissues and found in body fluids. In our previous studies we demonstrated that clusterin has a protective effect against hepatic lipid accumulation and renal fibrosis; however, the role of clusterin in hepatic fibrosis [...] Read more.

Clusterin is a glycoprotein that is expressed in most human tissues and found in body fluids. In our previous studies we demonstrated that clusterin has a protective effect against hepatic lipid accumulation and renal fibrosis; however, the role of clusterin in hepatic fibrosis is unknown. Here, we examined whether clusterin had protective effects against hepatic fibrosis using in vitro and in vivo models. Clusterin was upregulated in the livers of human cirrhotic patients and in thioacetamide (TAA)-induced and bile duct ligation mouse models of liver fibrosis. Loss and overexpression of clusterin promoted and attenuated hepatic fibrosis after TAA injection, respectively. In addition, we found that clusterin attenuates hepatic fibrosis by inhibiting the activation of hepatic stellate cells and Smad3 signaling pathways. Thus, clusterin plays an important role in hepatic fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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14 pages, 2721 KiB

Open AccessArticle

Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in HFE Knockout Mice

by Nurdan Guldiken, Karim Hamesch, Shari Malan Schuller, Mahmoud Aly, Cecilia Lindhauer, Carolin V. Schneider, Malin Fromme, Christian Trautwein and Pavel Strnad

Cells 2019, 8(11), 1415; https://doi.org/10.3390/cells8111415 - 9 Nov 2019

Cited by 5 | Viewed by 3691

Abstract

The presence of the homozygous ‘Pi*Z’ variant of alpha-1 antitrypsin (AAT) (‘Pi*ZZ’ genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene ( [...] Read more.

The presence of the homozygous ‘Pi*Z’ variant of alpha-1 antitrypsin (AAT) (‘Pi*ZZ’ genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene (HFE) as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. All underwent a comprehensive work-up and transient elastography to determine liver stiffness measurements (LSM). The corresponding mouse models (Pi*Z overexpressors, HFE knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on Pi*Z-induced liver injury. Compared to Pi*Z non-carriers, Pi*ZZ individuals had elevated serum iron, transferrin saturation, and ferritin levels, but relevant iron overload was rare. All these parameters were higher in individuals with signs of significant liver fibrosis (LSM ≥ 7.1 kPa) compared to those without signs of significant liver fibrosis. HFE knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of HFE did not alter the extent of AAT accumulation. In Pi*ZZ individuals, presence of HFE mutations was not associated with more severe liver fibrosis. Taken together, Pi*ZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of HFE mutations (C282Y and H63D) constitute a major contributor to liver fibrosis development. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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25 pages, 7153 KiB

Open AccessArticle

Hepatitis C Virus Enhances the Invasiveness of Hepatocellular Carcinoma via EGFR-Mediated Invadopodia Formation and Activation

by Liat Ninio, Abraham Nissani, Tomer Meirson, Tom Domovitz, Alessandro Genna, Shams Twafra, Kolluru D. Srikanth, Roba Dabour, Erez Avraham, Ateret Davidovich, Hava Gil-Henn and Meital Gal-Tanamy

Cells 2019, 8(11), 1395; https://doi.org/10.3390/cells8111395 - 5 Nov 2019

Cited by 22 | Viewed by 3772

Abstract

Hepatocellular carcinoma (HCC) represents the fifth most common cancer worldwide and the third cause of cancer-related mortality. Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which often results in liver fibrosis, cirrhosis, and eventually HCC. HCV is the most common [...] Read more.

Hepatocellular carcinoma (HCC) represents the fifth most common cancer worldwide and the third cause of cancer-related mortality. Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which often results in liver fibrosis, cirrhosis, and eventually HCC. HCV is the most common risk factor for HCC in western countries and leads to a more aggressive and invasive disease with poorer patient survival rates. However, the mechanism by which the virus induces the metastatic spread of HCC tumor cells through the regulation of invadopodia, the key features of invasive cancer, is still unknown. Here, the integration of transcriptome with functional kinome screen revealed that HCV infection induced invasion and invadopodia-related gene expression combined with activation of host cell tyrosine kinases, leading to invadopodia formation and maturation and consequent cell invasiveness in vitro and in vivo. The promotion of invadopodia following HCV infection was mediated by the sustained stimulation of epidermal growth factor receptor (EGFR) via the viral NS3/4A protease that inactivates the T-cell protein tyrosine phosphatase (TC-PTP), which inhibits EGFR signaling. Characterization of an invadopodia-associated gene signature in HCV-mediated HCC tumors correlated with the invasiveness of HCC and poor patient prognosis. These findings might lead to new prognostic and therapeutic strategies for virus-mediated invasive cancer. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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14 pages, 2127 KiB

Open AccessArticle

Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease

by Karina Reyes-Gordillo, Ruchi Shah, Jaime Arellanes-Robledo, Ying Cheng, Joseph Ibrahim and Pamela L. Tuma

Cells 2019, 8(11), 1337; https://doi.org/10.3390/cells8111337 - 29 Oct 2019

Cited by 50 | Viewed by 5098

Abstract

Akt kinase isoforms (Akt1, Akt2, and Akt3) have generally been thought to play overlapping roles in phosphoinositide 3-kinase (PI3K)-mediated-signaling. However, recent studies have suggested that they display isoform-specific roles in muscle and fat. To determine whether such isoform-specificity is observed with respect to [...] Read more.

Akt kinase isoforms (Akt1, Akt2, and Akt3) have generally been thought to play overlapping roles in phosphoinositide 3-kinase (PI3K)-mediated-signaling. However, recent studies have suggested that they display isoform-specific roles in muscle and fat. To determine whether such isoform-specificity is observed with respect to alcoholic liver disease (ALD) progression, we examined the role of Akt1, Akt2, and Akt3 in hepatic inflammation, and pro-fibrogenic proliferation and migration using Kupffer cells, hepatic stellate cells (HSC), and hepatocytes in an ethanol and lipopolysaccharide (LPS)-induced two-hit model in vitro and in vivo. We determined that siRNA-directed silencing of Akt2, but not Akt1, significantly suppressed cell inflammatory markers in HSC and Kupffer cells. Although both Akt1 and Akt2 inhibited cell proliferation in HSC, only Akt2 inhibited cell migration. Both Akt1 and Akt2, but not Akt3, inhibited fibrogenesis in hepatocytes and HSC. In addition, our in vivo results show that administration of chronic ethanol, binge ethanol and LPS (EBL) in wild-type C57BL/6 mice activated all three Akt isoforms with concomitant increases in activated forms of phosphoinositide dependent kinase-1 (PDK1), mammalian target-of-rapamycin complex 2 (mTORC2), and PI3K, resulting in upregulation in expression of inflammatory, proliferative, and fibrogenic genes. Moreover, pharmacological blocking of Akt2, but not Akt1, inhibited EBL-induced inflammation while blocking of both Akt1 and Akt2 inhibited pro-fibrogenic marker expression and progression of fibrosis. Our findings indicate that Akt isoforms play unique roles in inflammation, cell proliferation, migration, and fibrogenesis during EBL-induced liver injury. Thus, close attention must be paid when targeting all Akt isoforms as a therapeutic intervention. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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17 pages, 5279 KiB

Open AccessArticle

MicroRNA-29a Suppresses CD36 to Ameliorate High Fat Diet-Induced Steatohepatitis and Liver Fibrosis in Mice

by Hung-Yu Lin, Feng-Sheng Wang, Ya-Ling Yang and Ying-Hsien Huang

Cells 2019, 8(10), 1298; https://doi.org/10.3390/cells8101298 - 22 Oct 2019

Cited by 75 | Viewed by 7773

Abstract

MicroRNA-29 (miR-29) has been shown to play a critical role in reducing inflammation and fibrosis following liver injury. Non-alcoholic fatty liver disease (NAFLD) occurs when fat is deposited (steatosis) in the liver due to causes other than excessive alcohol use and is associated [...] Read more.

MicroRNA-29 (miR-29) has been shown to play a critical role in reducing inflammation and fibrosis following liver injury. Non-alcoholic fatty liver disease (NAFLD) occurs when fat is deposited (steatosis) in the liver due to causes other than excessive alcohol use and is associated with liver fibrosis. In this study, we asked whether miR-29a could reduce experimental high fat diet (HFD)-induced obesity and liver fibrosis in mice. We performed systematical expression analyses of miR-29a transgenic mice (miR-29aTg mice) and wild-type littermates subjected to HFD-induced NAFLD. The results demonstrated that increased miR-29a not only alleviated HFD-induced body weight gain but also subcutaneous, visceral, and intestinal fat accumulation and hepatocellular steatosis in mice. Furthermore, hepatic tissue in the miR-29aTg mice displayed a weak fibrotic matrix concomitant with low fibrotic collagen1α1 expression within the affected tissues compared to the wild-type (WT) mice fed the HFD diet. Increased miR-29a signaling also resulted in the downregulation of expression of the epithelial mesenchymal transition-executing transcription factor snail, mesenchymal markers vimentin, and such pro-inflammation markers as il6 and mcp1 within the liver tissue. Meanwhile, miR-29aTg-HFD mice exhibited significantly lower levels of peroxisome proliferator-activated receptor γ (PPARγ), mitochondrial transcription factor A TFAM, and mitochondria DNA content in the liver than the WT-HFD mice. An in vitro luciferase reporter assay further confirmed that miR-29a mimic transfection reduced fatty acid translocase CD36 expression in HepG2 cells. Conclusion: Our data provide new insights that miR-29a can improve HDF-induced obesity, hepatocellular steatosis, and fibrosis, as well as highlight the role of miR-29a in regulation of NAFLD. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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14 pages, 1738 KiB

Open AccessArticle

Increased Expression of RUNX1 in Liver Correlates with NASH Activity Score in Patients with Non-Alcoholic Steatohepatitis (NASH)

by Savneet Kaur, Preety Rawal, Hamda Siddiqui, Sumati Rohilla, Shvetank Sharma, Dinesh M Tripathi, Sukriti Baweja, Mohsin Hassan, Sebastian Vlaic, Reinhard Guthke, Maria Thomas, Rania Dayoub, Chaggan Bihari, Shiv K. Sarin and Thomas S. Weiss

Cells 2019, 8(10), 1277; https://doi.org/10.3390/cells8101277 - 18 Oct 2019

Cited by 28 | Viewed by 5684

Abstract

Given the important role of angiogenesis in liver pathology, the current study investigated the role of Runt-related transcription factor 1 (RUNX1), a regulator of developmental angiogenesis, in the pathogenesis of non-alcoholic steatohepatitis (NASH). Quantitative RT-PCRs and a transcription factor analysis of angiogenesis-associated differentially [...] Read more.

Given the important role of angiogenesis in liver pathology, the current study investigated the role of Runt-related transcription factor 1 (RUNX1), a regulator of developmental angiogenesis, in the pathogenesis of non-alcoholic steatohepatitis (NASH). Quantitative RT-PCRs and a transcription factor analysis of angiogenesis-associated differentially expressed genes in liver tissues of healthy controls, patients with steatosis and NASH, indicated a potential role of RUNX1 in NASH. The gene expression of RUNX1 was correlated with histopathological attributes of patients. The protein expression of RUNX1 in liver was studied by immunohistochemistry. To explore the underlying mechanisms, in vitro studies using RUNX1 siRNA and overexpression plasmids were performed in endothelial cells (ECs). RUNX1 expression was significantly correlated with inflammation, fibrosis and NASH activity score in NASH patients. Its expression was conspicuous in liver non-parenchymal cells. In vitro, factors from steatotic hepatocytes and/or VEGF or TGF-β significantly induced the expression of RUNX1 in ECs. RUNX1 regulated the expression of angiogenic and adhesion molecules in ECs, including CCL2, PECAM1 and VCAM1, which was shown by silencing or over-expression of RUNX1. Furthermore, RUNX1 increased the angiogenic activity of ECs. This study reports that steatosis-induced RUNX1 augmented the expression of adhesion and angiogenic molecules and properties in ECs and may be involved in enhancing inflammation and disease severity in NASH. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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15 pages, 2499 KiB

Open AccessArticle

Inhibition of Rho-Kinase Downregulates Th17 Cells and Ameliorates Hepatic Fibrosis by Schistosoma japonicum Infection

by Wei Zhou, Yingying Yang, Congjin Mei, Panpan Dong, Shasha Mu, Hongchu Wu, Yonghua Zhou, Yi Zheng, Fukun Guo and Jun-Qi Yang

Cells 2019, 8(10), 1262; https://doi.org/10.3390/cells8101262 - 16 Oct 2019

Cited by 31 | Viewed by 3822

Abstract

Background: Schistosomiasis is an immunopathogenic disease in which Th17 cells play vital roles. Hepatic granuloma formation and subsequent fibrosis are its main pathologic manifestations and the leading causes of hepatic cirrhosis, and effective therapeutic interventions are lacking. In this study, we explored the [...] Read more.

Background: Schistosomiasis is an immunopathogenic disease in which Th17 cells play vital roles. Hepatic granuloma formation and subsequent fibrosis are its main pathologic manifestations and the leading causes of hepatic cirrhosis, and effective therapeutic interventions are lacking. In this study, we explored the effects of fasudil, a selective RhoA–Rho-associated kinase (ROCK) inhibitor, on Th17 cells and the pathogenesis of schistosomiasis. Methods: Mice were infected with Schistosoma japonicum and treated with fasudil. The worm burden, hepatic granuloma formation, and fibrosis were evaluated. The roles of fasudil on Th17, Treg, and hepatic stellate cells were analyzed. Results: Fasudil therapy markedly reduced the granuloma size and collagen deposit in livers from mice infected with S. japonicum. However, fasudil therapy did not affect the worm burden in infected mice. The underlying cellular and molecular mechanisms were investigated. Fasudil suppressed the activation and induced the apoptosis of CD4⁺ T cells. Fasudil inhibited the differentiation and effector cytokine secretion of Th17 cells, whereas it upregulated Treg cells in vitro. It also restrained the in vivo interleukin (IL)-4 and IL-17 levels in infected mice. Fasudil directly induced the apoptosis of hepatic stellate cells and downregulated the expressions of hepatic fibrogenic genes, such as collagen type I (Col-I), Col-III, and transforming growth factor-1 (TGF-β1). These effects may contribute to its anti-pathogenic roles in schistosomiasis. Conclusions: Fasudil inhibits hepatic granuloma formation and fibrosis with downregulation of Th17 cells. Fasudil might serve as a novel therapeutic agent for hepatic fibrosis due to schistosome infections and perhaps other disorders. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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14 pages, 3277 KiB

Open AccessArticle

A Diet Induced Maladaptive Increase in Hepatic Mitochondrial DNA Precedes OXPHOS Defects and May Contribute to Non-Alcoholic Fatty Liver Disease

by Afshan N Malik, Inês C.M. Simões, Hannah S. Rosa, Safa Khan, Agnieszka Karkucinska-Wieckowska and Mariusz R. Wieckowski

Cells 2019, 8(10), 1222; https://doi.org/10.3390/cells8101222 - 8 Oct 2019

Cited by 27 | Viewed by 6082

Abstract

Non-alcoholic fatty liver disease (NAFLD), an increasingly prevalent and underdiagnosed disease, is postulated to be caused by hepatic fat mediated pathological mechanisms. Mitochondrial dysfunction is proposed to be involved, but it is not known whether this is a pathological driver or a consequence [...] Read more.

Non-alcoholic fatty liver disease (NAFLD), an increasingly prevalent and underdiagnosed disease, is postulated to be caused by hepatic fat mediated pathological mechanisms. Mitochondrial dysfunction is proposed to be involved, but it is not known whether this is a pathological driver or a consequence of NAFLD. We postulate that changes to liver mitochondrial DNA (mtDNA) are an early event that precedes mitochondrial dysfunction and irreversible liver damage. To test this hypothesis, we evaluated the impact of diet on liver steatosis, hepatic mtDNA content, and levels of key mitochondrial proteins. Liver tissues from C57BL/6 mice fed with high fat (HF) diet (HFD) and Western diet (WD, high fat and high sugar) for 16 weeks were used. Steatosis/fibrosis were assessed using haematoxylin and eosin (H&E) Oil Red and Masson’s trichome staining and collagen content. Total DNA was isolated, and mtDNA content was determined by quantifying absolute mtDNA copy number/cell using quantitative PCR. Selected mitochondrial proteins were analysed from a proteomics screen. As expected, both HFD and WD resulted in steatosis. Mouse liver contained a high mtDNA content (3617 ± 233 copies per cell), which significantly increased in HFD diet, but this increase was not functional, as indicated by changes in mitochondrial proteins. In the WD fed mice, liver dysfunction was accelerated alongside downregulation of mitochondrial oxidative phosphorylation (OXPHOS) and mtDNA replication machinery as well as upregulation of mtDNA-induced inflammatory pathways. These results demonstrate that diet induced changes in liver mtDNA can occur in a relatively short time; whether these contribute directly or indirectly to subsequent mitochondrial dysfunction and the development of NAFLD remains to be determined. If this hypothesis can be substantiated, then strategies to prevent mtDNA damage in the liver may be needed to prevent development and progression of NAFLD. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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17 pages, 5840 KiB

Open AccessArticle

Depletion of Bone Marrow-Derived Fibrocytes Attenuates TAA-Induced Liver Fibrosis in Mice

by Felix Hempel, Martin Roderfeld, Rajkumar Savai, Akylbek Sydykov, Karuna Irungbam, Ralph Schermuly, Robert Voswinckel, Kernt Köhler, Yury Churin, Ladislau Kiss, Jens Bier, Jörn Pons-Kühnemann and Elke Roeb

Cells 2019, 8(10), 1210; https://doi.org/10.3390/cells8101210 - 7 Oct 2019

Cited by 13 | Viewed by 4652

Abstract

Bone marrow-derived fibrocytes (FC) represent a unique cell type, sharing features of both mesenchymal and hematopoietic cells. FC were shown to specifically infiltrate the injured liver and participate in fibrogenesis. Moreover, FC exert a variety of paracrine functions, thus possibly influencing the disease [...] Read more.

Bone marrow-derived fibrocytes (FC) represent a unique cell type, sharing features of both mesenchymal and hematopoietic cells. FC were shown to specifically infiltrate the injured liver and participate in fibrogenesis. Moreover, FC exert a variety of paracrine functions, thus possibly influencing the disease progression. However, the overall contribution of FC to liver fibrosis remains unclear. We aimed to study the effect of a specific FC depletion, utilizing a herpes simplex virus thymidine kinase (HSV-TK)/Valganciclovir suicide gene strategy. Fibrosis was induced by oral thioacetamide (TAA) administration in C57BL/6J mice. Hepatic hydroxyproline content was assessed for the primary readout. The HSV-TK model enabled the specific depletion of fibrocytes. Hepatic hydroxyproline content was significantly reduced as a result of the fibrocyte ablation (−7.8%; 95% CI: 0.7–14.8%; p = 0.033), denoting a reduced deposition of fibrillar collagens. Lower serum alanine transaminase levels (−20.9%; 95% CI: 0.4–36.9%; p = 0.049) indicate a mitigation of liver-specific cellular damage. A detailed mode of action, however, remains yet to be identified. The present study demonstrates a relevant functional contribution of fibrocytes to chronic toxic liver fibrosis, contradicting recent reports. Our results emphasize the need to thoroughly study the biology of fibrocytes in order to understand their importance for hepatic fibrogenesis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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20 pages, 3454 KiB

Open AccessArticle

Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic Fibrogenesis

by Pei-Wen Wang, Tung-Ho Wu, Tung-Yi Lin, Mu-Hong Chen, Chau-Ting Yeh and Tai-Long Pan

Cells 2019, 8(10), 1184; https://doi.org/10.3390/cells8101184 - 1 Oct 2019

Cited by 23 | Viewed by 5003

Abstract

The activation of hepatic stellate cells (HSCs) manifested as proliferation and migration is the pivotal event involved in liver fibrogenesis. The vimentin network, an intermediate filament (IF) system, is one of the critical cascades by which the cell morphology, growth, and motility are [...] Read more.

The activation of hepatic stellate cells (HSCs) manifested as proliferation and migration is the pivotal event involved in liver fibrogenesis. The vimentin network, an intermediate filament (IF) system, is one of the critical cascades by which the cell morphology, growth, and motility are modulated. However, the vimentin-mediated cytoskeletal cross talk, as well as the signaling transduction, which further coordinates the cellular responses during hepatic fibrogenesis, is poorly understood. In the current study, both messenger RNA (mRNA) and the vimentin protein were significantly increased in a time-dependent manner in the dimethylnitrosamine (DMN)-exposed liver. In particular, vimentin was highly expressed in the activated HSCs. Again, the overexpressed vimentin was observed in the plasma samples derived from patients with hepatic fibrosis/cirrhosis, suggesting that vimentin may be a key factor in regulating the progression of liver fibrosis. Meanwhile, vimentin knockdown suppressed the migratory propensity, provoked morphological changes, and disturbed the focal adhesions in the HSCs due to the breakdown of associated cytoskeletal proteins. Western blotting showed that vimentin deletion inhibited proliferating cell nuclear antigen (PCNA) and arrested the Rho GTPase family, thereby impairing the HSCs’ growth as well as motility. The phosphorylated extracellular-signal regulated kinase (ERK) and AKT signals were also notably reduced in response to the silence of vimentin. Inhibitors of selected signaling pathways suppressed the migration and differentiation of activated HSCs by regulating specific serine phosphorylated sites on vimentin. Taken together, these findings revealed a novel mechanism of vimentin through which various signaling pathways controlled the proliferation, differentiation, and movement of the HSCs via the ERK/AKT and Rho cascades. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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18 pages, 3302 KiB

Open AccessArticle

TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats

by Daisuke Kaya, Kosuke Kaji, Yuki Tsuji, Satoko Yamashita, Koh Kitagawa, Takahiro Ozutsumi, Yukihisa Fujinaga, Hiroaki Takaya, Hideto Kawaratani, Kei Moriya, Tadashi Namisaki, Takemi Akahane and Hitoshi Yoshiji

Cells 2019, 8(10), 1153; https://doi.org/10.3390/cells8101153 - 26 Sep 2019

Cited by 12 | Viewed by 4946

Abstract

Hyperglycemia and hyperinsulinemia activate the proliferative potential of hepatic stellate cells (HSCs) and promote hepatic fibrosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic agents, reportedly inhibit the HSC proliferation. Additionally, Takeda G protein-coupled receptor 5 (TGR5) agonists induce the systemic release of glucagon-like peptides from [...] Read more.

Hyperglycemia and hyperinsulinemia activate the proliferative potential of hepatic stellate cells (HSCs) and promote hepatic fibrosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic agents, reportedly inhibit the HSC proliferation. Additionally, Takeda G protein-coupled receptor 5 (TGR5) agonists induce the systemic release of glucagon-like peptides from intestinal L cells, which maintains glycemic homeostasis. This study assessed the combined effect of TGR5 agonist and DPP-4 inhibitor on diabetes-based liver fibrosis development. Male diabetic rats received intraperitoneal injection of porcine serum (PS) to induce liver fibrosis, and they were orally administered the following agents: oleanolic acid (OA) as a TGR5 agonist, anagliptin (ANA) as a DPP-4 inhibitor, and a combination of both agents. Treatment with OA or ANA significantly improved glycemic status and attenuated intrahepatic steatosis and lipid peroxidation in diabetic rats. PS-induced liver fibrosis development was also drastically suppressed by treatment with either agent, and the combination of both reciprocally enhanced the antifibrotic effect. Fecal microbiome demonstrated that both agents inhibited the increase in the Firmicutes/Bacteroidetes ratio, an indicator of dysbiosis related to metabolic syndromes. Furthermore, ANA directly inhibited in vitro HSC proliferative and profibrogenic activities. Collectively, TGR5 agonist and DPP-4 inhibitor appears to be a novel strategy against liver fibrosis under diabetic conditions. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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15 pages, 1984 KiB

Open AccessArticle

New Rat Model of Advanced NASH Mimicking Pathophysiological Features and Transcriptomic Signature of The Human Disease

by Raquel Maeso-Díaz, Zoe Boyer-Diaz, Juan José Lozano, Martí Ortega-Ribera, Carmen Peralta, Jaime Bosch and Jordi Gracia-Sancho

Cells 2019, 8(9), 1062; https://doi.org/10.3390/cells8091062 - 10 Sep 2019

Cited by 18 | Viewed by 5946

Abstract

Non-alcoholic steatohepatitis (NASH) is a major cause of chronic liver disease. However, most available animal models fail to reflect the whole spectrum of the disease. Liver fibrosis and portal hypertension are the strongest prognostic markers in advanced NASH. We herein aimed at developing [...] Read more.

Non-alcoholic steatohepatitis (NASH) is a major cause of chronic liver disease. However, most available animal models fail to reflect the whole spectrum of the disease. Liver fibrosis and portal hypertension are the strongest prognostic markers in advanced NASH. We herein aimed at developing a new model of NASH in male rats, obtained using a multi-hit protocol that combines the administration of a high fat and high-cholesterol diet with CCl₄ and phenobarbital. Following this protocol, rats showed the full characteristics of advanced human NASH after 10 weeks and NASH with cirrhosis by 24 weeks. Specifically, our NASH rats exhibited: steatosis and metabolic syndrome, lipotoxicity, hepatocellular ballooning necrosis, inflammation and importantly, marked hepatic fibrosis and significant portal hypertension. Furthermore, a whole transcriptomic analysis of liver tissue from our rat model using next generation sequencing was compared with human NASH and illustrated the similarity of this pre-clinical model with the human disease. Pathway enrichment analysis showed that NASH animals shared a relevant number of central pathways involved in NASH pathophysiology, such as those related with cell death, as well as inflammatory or matrix remodeling. The present study defines a pre-clinical model of moderate and advanced NASH that mimics the human disease, including pathophysiologic characteristics and transcriptomic signature. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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19 pages, 2509 KiB

Open AccessArticle

The miRFIB-Score: A Serological miRNA-Based Scoring Algorithm for the Diagnosis of Significant Liver Fibrosis

by Joeri Lambrecht, Stefaan Verhulst, Hendrik Reynaert and Leo A. van Grunsven

Cells 2019, 8(9), 1003; https://doi.org/10.3390/cells8091003 - 29 Aug 2019

Cited by 22 | Viewed by 4585

Abstract

Background: The current diagnosis of early-stage liver fibrosis often relies on a serological or imaging-based evaluation of the stage of fibrosis, sometimes followed by an invasive liver biopsy procedure. Novel non-invasive experimental diagnostic tools are often based on markers of hepatocyte damage, [...] Read more.

Background: The current diagnosis of early-stage liver fibrosis often relies on a serological or imaging-based evaluation of the stage of fibrosis, sometimes followed by an invasive liver biopsy procedure. Novel non-invasive experimental diagnostic tools are often based on markers of hepatocyte damage, or changes in liver stiffness and architecture, which are late-stage characteristics of fibrosis progression, making them unsuitable for the diagnosis of early-stage liver fibrosis. miRNAs control hepatic stellate cell (HSC) activation and are proposed as relevant diagnostic markers. Methods: We investigated the possibility of circulating miRNAs, which we found to be dysregulated upon HSC activation, to mark the presence of significant liver fibrosis (F ≥ 2) in patients with chronic alcohol abuse, chronic viral infection (HBV/HCV), and non-alcoholic fatty liver disease (NAFLD). Results: miRNA-profiling identified miRNA-451a, miRNA-142-5p, Let-7f-5p, and miRNA-378a-3p to be significantly dysregulated upon in vitro HSC activation, and to be highly enriched in their extracellular vesicles, suggesting their potential use as biomarkers. Analysis of the plasma of patients with significant liver fibrosis (F ≥ 2) and no or mild fibrosis (F = 0–1), using miRNA-122-5p and miRNA-29a-3p as positive control, found miRNA-451a, miRNA-142-5p, and Let-7f-5p, but not miRNA-378a-3p, able to distinguish between the two patient populations. Using logistic regression analysis, combining all five dysregulated circulating miRNAs, we created the miRFIB-score with a predictive value superior to the clinical scores Fibrosis-4 (Fib-4), aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, and AST to platelet ratio index (APRI). The combination of the miRFIB-score with circulating PDGFRβ-levels further increased the predictive capacity for the diagnosis of significant liver fibrosis. Conclusions: The miRFIB- and miRFIB^p-scores are accurate tools for the diagnosis of significant liver fibrosis in a heterogeneous patient population. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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18 pages, 3168 KiB

Open AccessArticle

iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation

by Yanan Ming, Xingya Zhu, Sabine Tuma-Kellner, Alexandra Ganzha, Gerhard Liebisch, Hongying Gan-Schreier and Walee Chamulitrat

Cells 2019, 8(8), 879; https://doi.org/10.3390/cells8080879 - 12 Aug 2019

Cited by 7 | Viewed by 4885

Abstract

Background: Group VIA calcium-independent phospholipase A2 (iPla2β) regulates homeostasis and remodeling of phospholipids (PL). We previously showed that iPla2β^−/− mice fed with a methionine-choline-deficient diet (MCD) exhibited exaggerated liver fibrosis. As iPla2β is located in the endoplasmic reticulum (ER), we investigated the [...] Read more.

Background: Group VIA calcium-independent phospholipase A2 (iPla2β) regulates homeostasis and remodeling of phospholipids (PL). We previously showed that iPla2β^−/− mice fed with a methionine-choline-deficient diet (MCD) exhibited exaggerated liver fibrosis. As iPla2β is located in the endoplasmic reticulum (ER), we investigated the mechanisms for this by focusing on hepatic ER unfolded protein response (UPR), ER PL, and enterohepatic bile acids (BA). Methods: Female WT (wild-type) and iPla2β^−/− mice were fed with chow or MCD for 5 weeks. PL and BA profiles were measured by liquid chromatography-mass spectrometry. Gene expression analyses were performed. Results: MCD feeding of WT mice caused a decrease of ER PL subclasses, which were further decreased by iPla2β deficiency. This deficiency alone or combined with MCD downregulated the expression of liver ER UPR proteins and farnesoid X-activated receptor. The downregulation under MCD was concomitant with an elevation of BA in the liver and peripheral blood and an increase of biliary epithelial cell proliferation measured by cytokeratin 19. Conclusion: iPla2β deficiency combined with MCD severely disturbed ER PL composition and caused inactivation of UPR, leading to downregulated Fxr, exacerbated BA, and ductular proliferation. Our study provides insights into iPla2β inactivation for injury susceptibility under normal conditions and liver fibrosis and cholangiopathies during MCD feeding. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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10 pages, 2521 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Single Cell RNA Sequencing Identifies Subsets of Hepatic Stellate Cells and Myofibroblasts in Liver Fibrosis

by Oliver Krenkel, Jana Hundertmark, Thomas P. Ritz, Ralf Weiskirchen and Frank Tacke

Cells 2019, 8(5), 503; https://doi.org/10.3390/cells8050503 - 24 May 2019

Cited by 145 | Viewed by 16156

Abstract

Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, [...] Read more.

Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, and have biomechanical properties. We herein aimed to characterize the heterogeneity of these liver mesenchymal cells by single cell RNA sequencing. In vivo resting HSCs or activated MFB were isolated from C57BL6/J mice challenged by carbon tetrachloride (CCl₄) intraperitoneally for 3 weeks to induce liver fibrosis and compared to in vitro cultivated MFB. While resting HSCs formed a homogenous population characterized by high platelet derived growth factor receptor β (PDGFRβ) expression, in vivo and in vitro activated MFB split into heterogeneous populations, characterized by α-smooth muscle actin (α-SMA), collagens, or immunological markers. S100 calcium binding protein A6 (S100A6) was a universal marker of activated MFB on both the gene and protein expression level. Compared to the heterogeneity of in vivo MFB, MFB in vitro sequentially and only transiently expressed marker genes, such as chemokines, during culture activation. Taken together, our data demonstrate the heterogeneity of HSCs and MFB, indicating the existence of functionally relevant subsets in hepatic fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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13 pages, 1513 KiB

Open AccessArticle

Bone Morphogenetic Protein-8B Expression is Induced in Steatotic Hepatocytes and Promotes Hepatic Steatosis and Inflammation In Vitro

by Abdo Mahli, Tatjana Seitz, Tobias Beckröge, Kim Freese, Wolfgang Erwin Thasler, Matthias Benkert, Peter Dietrich, Ralf Weiskirchen, Anja Bosserhoff and Claus Hellerbrand

Cells 2019, 8(5), 457; https://doi.org/10.3390/cells8050457 - 15 May 2019

Cited by 16 | Viewed by 5606

Abstract

Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome. The bone morphogenetic protein-8B (BMP8B) has been shown to be expressed in brown adipose tissues and the hypothalamus and to affect thermogenesis and susceptibility to diet-induced obesity. [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome. The bone morphogenetic protein-8B (BMP8B) has been shown to be expressed in brown adipose tissues and the hypothalamus and to affect thermogenesis and susceptibility to diet-induced obesity. Here, we aimed to analyze BMP8B expression in NAFLD and to gain insight into BMP8B effects on pathophysiological steps of NAFLD progression. BMP8B mRNA and protein expression were dose-dependently induced in primary human hepatocytes in vitro upon incubation with fatty acids. Furthermore, hepatic BMP8B expression was significantly increased in a murine NAFLD model and in NAFLD patients compared with controls. Incubation with recombinant BMP8B further enhanced the fatty acid-induced cellular lipid accumulation as well as NFκB activation and pro-inflammatory gene expression in hepatocytes, while siRNA-mediated BMP8B depletion ameliorated these fatty acid-induced effects. Analysis of the expression of key factors of hepatocellular lipid transport and metabolisms indicated that BMP8B effects on fatty acid uptake as well as de novo lipogenesis contributed to hepatocellular accumulation of fatty acids leading to increased storage in the form of triglycerides and enhanced combustion by beta oxidation. In conclusion, our data indicate that BMP8B enhances different pathophysiological steps of NAFLD progression and suggest BMP8B as a promising prognostic marker and therapeutic target for NAFLD and, potentially, also for other chronic liver diseases. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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13 pages, 2919 KiB

Open AccessArticle

Therapeutic Application of Micellar Solubilized Xanthohumol in a Western-Type Diet-Induced Mouse Model of Obesity, Diabetes and Non-Alcoholic Fatty Liver Disease

by Abdo Mahli, Tatjana Seitz, Kim Freese, Jan Frank, Ralf Weiskirchen, Mona Abdel-Tawab, Dariush Behnam and Claus Hellerbrand

Cells 2019, 8(4), 359; https://doi.org/10.3390/cells8040359 - 17 Apr 2019

Cited by 35 | Viewed by 5890

Abstract

Xanthohumol (XN), a prenylated chalcone from hops, has been reported to exhibit a variety of health-beneficial effects. However, poor bioavailability may limit its application in the prevention and therapy of diseases. The objective of this study was to determine whether a micellar solubilization [...] Read more.

Xanthohumol (XN), a prenylated chalcone from hops, has been reported to exhibit a variety of health-beneficial effects. However, poor bioavailability may limit its application in the prevention and therapy of diseases. The objective of this study was to determine whether a micellar solubilization of xanthohumol could enhance the bioavailability and biological efficacy of xanthohumol in a Western-type diet (WTD) induced model of obesity, diabetes and non-alcoholic fatty liver disease (NAFLD). After 3 weeks feeding with WTD, XN was additionally applied per oral gavage as micellar solubilizate (s-XN) or native extract (n-XN) at a daily dose of 2.5 mg/kg body weight for a further 8 weeks. Control mice received vehicle only in addition to the WTD. WTD-induced body weight-gain and glucose intolerance were significantly inhibited by s-XN application. Furthermore, WTD-induced hepatic steatosis, pro-inflammatory gene expression (MCP-1 and CXCL1) and immune cell infiltration as well as activation of hepatic stellate cells (HSC) and expression of collagen alpha I were significantly reduced in the livers of s-XN-treated mice compared to WTD controls. In contrast, application of n-XN had no or only slight effects on the WTD-induced pathological effects. In line with this, plasma XN concentration ranged between 100–330 nmol/L in the s-XN group while XN was not detectable in the serum samples of n-XN-treated mice. In conclusion, micellar solubilization enhanced the bioavailability and beneficial effects of xanthohumol on different components of the metabolic syndrome including all pathological steps of NAFLD. Notably, this was achieved in a dose more than 10-fold lower than effective beneficial doses of native xanthohumol reported in previous in vivo studies. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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Review

Jump to: Editorial, Research

12 pages, 2783 KiB

Open AccessReview

The P2X7 Receptor and NLRP3 Axis in Non-Alcoholic Fatty Liver Disease: A Brief Review

by Marco Rossato, Angelo Di Vincenzo, Claudio Pagano, Hamza El Hadi and Roberto Vettor

Cells 2020, 9(4), 1047; https://doi.org/10.3390/cells9041047 - 22 Apr 2020

Cited by 29 | Viewed by 4573

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and its prevalence is reaching epidemic characteristics both in adults and in children. The increase of NAFLD prevalence parallels that of obesity, now representing the major cause of liver inflammation, increasing [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and its prevalence is reaching epidemic characteristics both in adults and in children. The increase of NAFLD prevalence parallels that of obesity, now representing the major cause of liver inflammation, increasing the risk of cirrhosis and hepatocarcinoma. Furthermore, NAFLD is a risk factor for cardiovascular diseases and type 2 diabetes, two of the major leading causes of morbidity and mortality in western countries. Thus a significant amount of studies have dealt with the evaluation of the possible molecular mechanisms leading to NAFLD and its inflammatory consequences within the liver, the non-alcoholic steatohepatitis, and cirrhosis. The inflammasome is a key player in the inflammation and fibrogenic responses in many different tissues, including the liver. The activation of the NLRP3 inflammasome requires the activation by extracellular adenosine tri-phosphate (ATP) of a specific purinergic receptor named P2X7 located in the target cells, although other pathways have been described. To this regard, extracellular ATP acts as an internal danger signal coming from damaged cells participating in the activation of the inflammatory process, a signaling pathway common to many different tissues. Here, we briefly review the involvement of the P2X7 receptor/inflammasome NLRP3 axis in the pathophysiological events leading to NAFLD and its inflammatory and fibrotic evolutions, reporting the possible therapeutical strategies targeting the P2X7 receptor/NLRP3 inflammasome. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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43 pages, 1301 KiB

Open AccessEditor’s ChoiceReview

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

by Natascha Roehlen, Emilie Crouchet and Thomas F. Baumert

Cells 2020, 9(4), 875; https://doi.org/10.3390/cells9040875 - 3 Apr 2020

Cited by 675 | Viewed by 36394

Abstract

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver [...] Read more.

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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18 pages, 930 KiB

Open AccessReview

Relationship between Heart Disease and Liver Disease: A Two-Way Street

by Hamza El Hadi, Angelo Di Vincenzo, Roberto Vettor and Marco Rossato

Cells 2020, 9(3), 567; https://doi.org/10.3390/cells9030567 - 28 Feb 2020

Cited by 99 | Viewed by 16652

Abstract

In clinical practice, combined heart and liver dysfunctions coexist in the setting of the main heart and liver diseases because of complex cardiohepatic interactions. It is becoming increasingly crucial to identify these interactions between heart and liver in order to ensure an effective [...] Read more.

In clinical practice, combined heart and liver dysfunctions coexist in the setting of the main heart and liver diseases because of complex cardiohepatic interactions. It is becoming increasingly crucial to identify these interactions between heart and liver in order to ensure an effective management of patients with heart or liver disease to provide an improvement in overall prognosis and therapy. In this review, we aim to summarize the cross-talk between heart and liver in the setting of the main pathologic conditions affecting these organs. Accordingly, we present the clinical manifestation, biochemical profiles, and histological findings of cardiogenic ischemic hepatitis and congestive hepatopathy due to acute and chronic heart failure, respectively. In addition, we discuss the main features of cardiac dysfunction in the setting of liver cirrhosis, nonalcoholic fatty liver disease, and those following liver transplantation. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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17 pages, 1472 KiB

Open AccessReview

Cellular Interplay as a Consequence of Inflammatory Signals Leading to Liver Fibrosis Development

by Simona-Rebeca Ignat, Sorina Dinescu, Anca Hermenean and Marieta Costache

Cells 2020, 9(2), 461; https://doi.org/10.3390/cells9020461 - 18 Feb 2020

Cited by 41 | Viewed by 6652

Abstract

Inflammation has been known to be an important driver of fibrogenesis in the liver and onset of hepatic fibrosis. It starts off as a process meant to protect the liver from further damage, but it can become the main promoter of liver fibrosis. [...] Read more.

Inflammation has been known to be an important driver of fibrogenesis in the liver and onset of hepatic fibrosis. It starts off as a process meant to protect the liver from further damage, but it can become the main promoter of liver fibrosis. There are many inflammation-related pathways activated during liver fibrosis that lead to hepatic stellate cells (HSCs) activation and collagen-deposition in the liver. Such events are mostly modulated upstream of HSCs and involve signals from hepatocytes and innate immune cells. One particular event is represented by cell death during liver injury that generates multiple inflammatory signals that further trigger sterile inflammation and enhancement of inflammatory response. The assembly of inflammasome that responds to danger-associated molecular patterns (DAMPs) stimulates the release of pro-inflammatory cytokines and at the same time, initiates programmed cell death called pyroptosis. This review focuses on cellular and molecular mechanisms responsible for initiation and progress of inflammation in the liver. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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22 pages, 1456 KiB

Open AccessReview

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

by Olga Khomich, Alexander V. Ivanov and Birke Bartosch

Cells 2020, 9(1), 24; https://doi.org/10.3390/cells9010024 - 20 Dec 2019

Cited by 144 | Viewed by 14556

Abstract

Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix [...] Read more.

Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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15 pages, 11581 KiB

Open AccessReview

Ubiquitin-Like Post-Translational Modifications (Ubl-PTMs): Small Peptides with Huge Impact in Liver Fibrosis

by Sofia Lachiondo-Ortega, Maria Mercado-Gómez, Marina Serrano-Maciá, Fernando Lopitz-Otsoa, Tanya B Salas-Villalobos, Marta Varela-Rey, Teresa C. Delgado and María Luz Martínez-Chantar

Cells 2019, 8(12), 1575; https://doi.org/10.3390/cells8121575 - 4 Dec 2019

Cited by 13 | Viewed by 4826

Abstract

Liver fibrosis is characterized by the excessive deposition of extracellular matrix proteins including collagen that occurs in most types of chronic liver disease. Even though our knowledge of the cellular and molecular mechanisms of liver fibrosis has deeply improved in the last years, [...] Read more.

Liver fibrosis is characterized by the excessive deposition of extracellular matrix proteins including collagen that occurs in most types of chronic liver disease. Even though our knowledge of the cellular and molecular mechanisms of liver fibrosis has deeply improved in the last years, therapeutic approaches for liver fibrosis remain limited. Profiling and characterization of the post-translational modifications (PTMs) of proteins, and more specifically NEDDylation and SUMOylation ubiquitin-like (Ubls) modifications, can provide a better understanding of the liver fibrosis pathology as well as novel and more effective therapeutic approaches. On this basis, in the last years, several studies have described how changes in the intermediates of the Ubl cascades are altered during liver fibrosis and how specific targeting of particular enzymes mediating these ubiquitin-like modifications can improve liver fibrosis, mainly in in vitro models of hepatic stellate cells, the main fibrogenic cell type, and in pre-clinical mouse models of liver fibrosis. The development of novel inhibitors of the Ubl modifications as well as novel strategies to assess the modified proteome can provide new insights into the overall role of Ubl modifications in liver fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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14 pages, 2091 KiB

Open AccessReview

Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins

by Masa-Ki Inoue, Yusuke Nakatsu, Takeshi Yamamotoya, Shun Hasei, Mayu Kanamoto, Miki Naitou, Yasuka Matsunaga, Hideyuki Sakoda, Midori Fujishiro, Hiraku Ono, Akifumi Kushiyama and Tomoichiro Asano

Cells 2019, 8(12), 1545; https://doi.org/10.3390/cells8121545 - 29 Nov 2019

Cited by 12 | Viewed by 5498

Abstract

Pin1 is one of the three known prolyl-isomerase types and its hepatic expression level is markedly enhanced in the obese state. Pin1 plays critical roles in favoring the exacerbation of both lipid accumulation and fibrotic change accompanying inflammation. Indeed, Pin1-deficient mice are highly [...] Read more.

Pin1 is one of the three known prolyl-isomerase types and its hepatic expression level is markedly enhanced in the obese state. Pin1 plays critical roles in favoring the exacerbation of both lipid accumulation and fibrotic change accompanying inflammation. Indeed, Pin1-deficient mice are highly resistant to non-alcoholic steatohepatitis (NASH) development by either a high-fat diet or methionine–choline-deficient diet feeding. The processes of NASH development can basically be separated into lipid accumulation and subsequent fibrotic change with inflammation. In this review, we outline the molecular mechanisms by which increased Pin1 promotes both of these phases of NASH. The target proteins of Pin1 involved in lipid accumulation include insulin receptor substrate 1 (IRS-1), AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase 1 (ACC1), while the p60 of the NF-kB complex and transforming growth factor β (TGF-β) pathway appear to be involved in the fibrotic process accelerated by Pin1. Interestingly, Pin1 deficiency does not cause abnormalities in liver size, appearance or function. Therefore, we consider the inhibition of increased Pin1 to be a promising approach to treating NASH and preventing hepatic fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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10 pages, 869 KiB

Open AccessReview

Porto-Sinusoidal Vascular Disease Associated to Oxaliplatin: An Entity to Think about It

by Angela Puente, Jose Ignacio Fortea, Carmen Del Pozo, Patricia Huelin, Maria Luisa Cagigal, Marina Serrano, Joaquin Cabezas, Maria Teresa Arias Loste, Paula Iruzubieta, Antonio Cuadrado, Susana Llerena, Carlos Lopez, Emilio Fábrega and Javier Crespo

Cells 2019, 8(12), 1506; https://doi.org/10.3390/cells8121506 - 24 Nov 2019

Cited by 23 | Viewed by 5753

Abstract

Portal sinusoidal vascular disease is a presinusoidal cause of portal hypertension (PHT) of unknown etiology, characterized by typical manifestations of PHT (esophageal varices, ascites, portosystemic collaterals), plaquetopenia and splenomegaly with a gradient of portal pressure slightly increased, according to the presinusoidal nature of [...] Read more.

Portal sinusoidal vascular disease is a presinusoidal cause of portal hypertension (PHT) of unknown etiology, characterized by typical manifestations of PHT (esophageal varices, ascites, portosystemic collaterals), plaquetopenia and splenomegaly with a gradient of portal pressure slightly increased, according to the presinusoidal nature of the PHT. A few cases in the literature have shown a relationship between oxaliplatin and the development of presinusoidal portal hypertension, years after the chemotherapy for colorectal cancer (therefore, different to sinusoidal obstruction syndrome). There are three mechanisms through which oxaliplatin can cause sinusoidal damage: (1) damage at the level of endothelial cells and stimulates the release of free radicals and depletion of glutathione transferase, with altering the integrity of the sinusoidal cells. The damage in the endothelial sinusoidal cells allows to erythrocytes to across into the Dissé space and formation of perisinusoidal fibrosis, (2) the appearance of nodular regenerative hyperplasia is favored by the chronic hypoxia of the centrilobular areas and, finally, (3) oxaliplatin can generate an obliteration of the blood capillaries and zones of parenchymal extinction. These three facts can develop, in a minority of cases, the appearance of a presinusoidal increase of portal pressure, which typically appears years after the completion of chemotherapy and sometimes is underdiagnosed until variceal bleeding, ascites or encephalopathy appear. The knowledge of this pathology is essential to be able to perform an early diagnostic and consult to the hepatologist. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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27 pages, 693 KiB

Open AccessReview

The Many Roles of Cell Adhesion Molecules in Hepatic Fibrosis

by Edith Hintermann and Urs Christen

Cells 2019, 8(12), 1503; https://doi.org/10.3390/cells8121503 - 24 Nov 2019

Cited by 47 | Viewed by 8056

Abstract

Fibrogenesis is a progressive scarring event resulting from disrupted regular wound healing due to repeated tissue injury and can end in organ failure, like in liver cirrhosis. The protagonists in this process, either liver-resident cells or patrolling leukocytes attracted to the site of [...] Read more.

Fibrogenesis is a progressive scarring event resulting from disrupted regular wound healing due to repeated tissue injury and can end in organ failure, like in liver cirrhosis. The protagonists in this process, either liver-resident cells or patrolling leukocytes attracted to the site of tissue damage, interact with each other by soluble factors but also by direct cell–cell contact mediated by cell adhesion molecules. Since cell adhesion molecules also support binding to the extracellular matrix, they represent excellent biosensors, which allow cells to modulate their behavior based on changes in the surrounding microenvironment. In this review, we focus on selectins, cadherins, integrins and members of the immunoglobulin superfamily of adhesion molecules as well as some non-classical cell adhesion molecules in the context of hepatic fibrosis. We describe their liver-specific contributions to leukocyte recruitment, cell differentiation and survival, matrix remodeling or angiogenesis and touch on their suitability as targets in antifibrotic therapies. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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33 pages, 2474 KiB

Open AccessFeature PaperReview

Mast Cells in Liver Fibrogenesis

by Ralf Weiskirchen, Steffen K. Meurer, Christian Liedtke and Michael Huber

Cells 2019, 8(11), 1429; https://doi.org/10.3390/cells8111429 - 13 Nov 2019

Cited by 35 | Viewed by 8147

Abstract

Mast cells (MCs) are immune cells of the myeloid lineage that are present in the connective tissue throughout the body and in mucosa tissue. They originate from hematopoietic stem cells in the bone marrow and circulate as MC progenitors in the blood. After [...] Read more.

Mast cells (MCs) are immune cells of the myeloid lineage that are present in the connective tissue throughout the body and in mucosa tissue. They originate from hematopoietic stem cells in the bone marrow and circulate as MC progenitors in the blood. After migration to various tissues, they differentiate into their mature form, which is characterized by a phenotype containing large granules enriched in a variety of bioactive compounds, including histamine and heparin. These cells can be activated in a receptor-dependent and -independent manner. Particularly, the activation of the high-affinity immunoglobulin E (IgE) receptor, also known as FcεRI, that is expressed on the surface of MCs provoke specific signaling cascades that leads to intracellular calcium influx, activation of different transcription factors, degranulation, and cytokine production. Therefore, MCs modulate many aspects in physiological and pathological conditions, including wound healing, defense against pathogens, immune tolerance, allergy, anaphylaxis, autoimmune defects, inflammation, and infectious and other disorders. In the liver, MCs are mainly associated with connective tissue located in the surrounding of the hepatic arteries, veins, and bile ducts. Recent work has demonstrated a significant increase in MC number during hepatic injury, suggesting an important role of these cells in liver disease and progression. In the present review, we summarize aspects of MC function and mediators in experimental liver injury, their interaction with other hepatic cell types, and their contribution to the pathogenesis of fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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20 pages, 1503 KiB

Open AccessReview

Metabolic Signature of Hepatic Fibrosis: From Individual Pathways to Systems Biology

by Ming-Ling Chang and Sien-Sing Yang

Cells 2019, 8(11), 1423; https://doi.org/10.3390/cells8111423 - 12 Nov 2019

Cited by 56 | Viewed by 7024

Abstract

Hepatic fibrosis is a major cause of morbidity and mortality worldwide, as it ultimately leads to cirrhosis, which is estimated to affect up to 2% of the global population. Hepatic fibrosis is confirmed by liver biopsy, and the erroneous nature of this technique [...] Read more.

Hepatic fibrosis is a major cause of morbidity and mortality worldwide, as it ultimately leads to cirrhosis, which is estimated to affect up to 2% of the global population. Hepatic fibrosis is confirmed by liver biopsy, and the erroneous nature of this technique necessitates the search for noninvasive alternatives. However, current biomarker algorithms for hepatic fibrosis have many limitations. Given that the liver is the largest organ and a major metabolic hub in the body, probing the metabolic signature of hepatic fibrosis holds promise for the discovery of new markers and therapeutic targets. Regarding individual metabolic pathways, accumulating evidence shows that hepatic fibrosis leads to alterations in carbohydrate metabolism, as aerobic glycolysis is aggravated in activated hepatic stellate cells (HSCs) and the whole fibrotic liver; in amino acid metabolism, as Fischer’s ratio (branched-chain amino acids/aromatic amino acids) decreases in patients with hepatic fibrosis; and in lipid metabolism, as HSCs lose vitamin A-containing lipid droplets during transdifferentiation, and cirrhotic patients have decreased serum lipids. The current review also summarizes recent findings of metabolic alterations relevant to hepatic fibrosis based on systems biology approaches, including transcriptomics, proteomics, and metabolomics in vitro, in animal models and in humans. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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19 pages, 2325 KiB

Open AccessReview

Hepatitis C Virus Downregulates Core Subunits of Oxidative Phosphorylation, Reminiscent of the Warburg Effect in Cancer Cells

by Gesche K. Gerresheim, Elke Roeb, Audrey M. Michel and Michael Niepmann

Cells 2019, 8(11), 1410; https://doi.org/10.3390/cells8111410 - 8 Nov 2019

Cited by 27 | Viewed by 5806

Abstract

Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, [...] Read more.

Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, the viral infection cannot be cleared by the immune system, but a chronic infection is established, often resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Induction of cancer in the host cells can be regarded to provide further advantages for ongoing virus replication. One adaptation in cancer cells is the enhancement of cellular carbohydrate flux in glycolysis with a reduction of the activity of the citric acid cycle and aerobic oxidative phosphorylation. To this end, HCV downregulates the expression of mitochondrial oxidative phosphorylation complex core subunits quite early after infection. This so-called aerobic glycolysis is known as the “Warburg Effect” and serves to provide more anabolic metabolites upstream of the citric acid cycle, such as amino acids, pentoses and NADPH for cancer cell growth. In addition, HCV deregulates signaling pathways like those of TNF-β and MAPK by direct and indirect mechanisms, which can lead to fibrosis and HCC. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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15 pages, 1102 KiB

Open AccessReview

Why Bile Acids Are So Important in Non-Alcoholic Fatty Liver Disease (NAFLD) Progression

by Aline Gottlieb and Ali Canbay

Cells 2019, 8(11), 1358; https://doi.org/10.3390/cells8111358 - 30 Oct 2019

Cited by 98 | Viewed by 13144

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a complex disease, affecting not just the liver, but also all other organs in the body. Despite an increasing amount of people worldwide developing NAFLD and having it progress to non-alcoholic steatohepatitis (NASH) and potentially cirrhosis, there [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease, affecting not just the liver, but also all other organs in the body. Despite an increasing amount of people worldwide developing NAFLD and having it progress to non-alcoholic steatohepatitis (NASH) and potentially cirrhosis, there is still no approved therapy. Therefore, huge efforts are being made to find and develop a successful treatment. One of the special interests is understanding the liver–gut axis and especially the role of bile acids in the progression of NAFLD. Farnesoid X receptor (FXR)-agonists have been approved und used in other liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and have shown signs of being able to decrease inflammation and potentially steatosis. This review will mainly focus on targets/ligands that play an important role in bile acid metabolism and give an overview of ongoing clinical as well as pre-clinical trials. With the complexity of the issue, we did not aim at giving a complete review, rather highlighting important targets and potential treatments that could be approved for NAFLD/NASH treatment within the next few years. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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19 pages, 2714 KiB

Open AccessReview

Natural Sulfur-Containing Compounds: An Alternative Therapeutic Strategy against Liver Fibrosis

by Alfonsina Milito, Mariarita Brancaccio, Giuseppe D’Argenio and Immacolata Castellano

Cells 2019, 8(11), 1356; https://doi.org/10.3390/cells8111356 - 30 Oct 2019

Cited by 46 | Viewed by 7347

Abstract

Liver fibrosis is a pathophysiologic process involving the accumulation of extracellular matrix proteins as collagen deposition. Advanced liver fibrosis can evolve in cirrhosis, portal hypertension and often requires liver transplantation. At the cellular level, hepatic fibrosis involves the activation of hepatic stellate cells [...] Read more.

Liver fibrosis is a pathophysiologic process involving the accumulation of extracellular matrix proteins as collagen deposition. Advanced liver fibrosis can evolve in cirrhosis, portal hypertension and often requires liver transplantation. At the cellular level, hepatic fibrosis involves the activation of hepatic stellate cells and their transdifferentiation into myofibroblasts. Numerous pro-fibrogenic mediators including the transforming growth factor-β1, the platelet-derived growth factor, endothelin-1, toll-like receptor 4, and reactive oxygen species are key players in this process. Knowledge of the cellular and molecular mechanisms underlying hepatic fibrosis development need to be extended to find novel therapeutic strategies. Antifibrotic therapies aim to inhibit the accumulation of fibrogenic cells and/or prevent the deposition of extracellular matrix proteins. Natural products from terrestrial and marine sources, including sulfur-containing compounds, exhibit promising activities for the treatment of fibrotic pathology. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans are largely unknown. This review aims to provide a reference collection on experimentally tested natural anti-fibrotic compounds, with particular attention on sulfur-containing molecules. Their chemical structure, sources, mode of action, molecular targets, and pharmacological activity in the treatment of liver disease will be discussed. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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30 pages, 895 KiB

Open AccessFeature PaperReview

Mechanisms Underlying Cell Therapy in Liver Fibrosis: An Overview

by Daphne Pinheiro, Isabelle Dias, Karina Ribeiro Silva, Ana Carolina Stumbo, Alessandra Thole, Erika Cortez, Lais de Carvalho, Ralf Weiskirchen and Simone Carvalho

Cells 2019, 8(11), 1339; https://doi.org/10.3390/cells8111339 - 29 Oct 2019

Cited by 28 | Viewed by 6681

Abstract

Fibrosis is a common feature in most pathogenetic processes in the liver, and usually results from a chronic insult that depletes the regenerative capacity of hepatocytes and activates multiple inflammatory pathways, recruiting resident and circulating immune cells, endothelial cells, non-parenchymal hepatic stellate cells, [...] Read more.

Fibrosis is a common feature in most pathogenetic processes in the liver, and usually results from a chronic insult that depletes the regenerative capacity of hepatocytes and activates multiple inflammatory pathways, recruiting resident and circulating immune cells, endothelial cells, non-parenchymal hepatic stellate cells, and fibroblasts, which become activated and lead to excessive extracellular matrix accumulation. The ongoing development of liver fibrosis results in a clinically silent and progressive loss of hepatocyte function, demanding the constant need for liver transplantation in clinical practice, and motivating the search for other treatments as the chances of obtaining compatible viable livers become scarcer. Although initially cell therapy has emerged as a plausible alternative to organ transplantation, many factors still challenge the establishment of this technique as a main or even additional therapeutic tool. Herein, the authors discuss the most recent advances and point out the corners and some controversies over several protocols and models that have shown promising results as potential candidates for cell therapy for liver fibrosis, presenting the respective mechanisms proposed for liver regeneration in each case. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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27 pages, 1367 KiB

Open AccessReview

The Role of Gut-Derived Microbial Antigens on Liver Fibrosis Initiation and Progression

by Dishen Chen, Thanh H. Le, Haleh Shahidipour, Scott A. Read and Golo Ahlenstiel

Cells 2019, 8(11), 1324; https://doi.org/10.3390/cells8111324 - 27 Oct 2019

Cited by 43 | Viewed by 5731

Abstract

Intestinal dysbiosis has recently become known as an important driver of gastrointestinal and liver disease. It remains poorly understood, however, how gastrointestinal microbes bypass the intestinal mucosa and enter systemic circulation to enact an inflammatory immune response. In the context of chronic liver [...] Read more.

Intestinal dysbiosis has recently become known as an important driver of gastrointestinal and liver disease. It remains poorly understood, however, how gastrointestinal microbes bypass the intestinal mucosa and enter systemic circulation to enact an inflammatory immune response. In the context of chronic liver disease (CLD), insults that drive hepatic inflammation and fibrogenesis (alcohol, fat) can drastically increase intestinal permeability, hence flooding the liver with gut-derived microbiota. Consequently, this may result in exacerbated liver inflammation and fibrosis through activation of liver-resident Kupffer and stellate cells by bacterial, viral, and fungal antigens transported to the liver via the portal vein. This review summarizes the current understanding of microbial translocation in CLD, the cell-specific hepatic response to intestinal antigens, and how this drives the development and progression of hepatic inflammation and fibrosis. Further, we reviewed current and future therapies targeting intestinal permeability and the associated, potentially harmful anti-microbial immune response with respect to their potential in terms of limiting the development and progression of liver fibrosis and end-stage cirrhosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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24 pages, 4593 KiB

Open AccessReview

Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis

by Pedro Melgar-Lesmes, Meritxell Perramon and Wladimiro Jiménez

Cells 2019, 8(11), 1311; https://doi.org/10.3390/cells8111311 - 24 Oct 2019

Cited by 27 | Viewed by 6420

Abstract

Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms. The hepatic endocannabinoid and apelin systems are two signalling pathways with a substantial role in the liver fibrosis [...] Read more.

Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms. The hepatic endocannabinoid and apelin systems are two signalling pathways with a substantial role in the liver fibrosis pathophysiology—both are upregulated in patients with advanced liver disease. Endogenous cannabinoids are lipid-signalling molecules derived from arachidonic acid involved in the pathogenesis of cardiovascular dysfunction, portal hypertension, liver fibrosis, and other processes associated with hepatic disease through their interactions with the CB₁ and CB₂ receptors. Apelin is a peptide that participates in cardiovascular and renal functions, inflammation, angiogenesis, and hepatic fibrosis through its interaction with the APJ receptor. The endocannabinoid and apelin systems are two of the multiple cell-signalling pathways involved in the transformation of quiescent hepatic stellate cells into myofibroblast like cells, the main matrix-producing cells in liver fibrosis. The mechanisms underlying the control of hepatic stellate cell activity are coincident despite the marked dissimilarities between the endocannabinoid and apelin signalling pathways. This review discusses the current understanding of the molecular and cellular mechanisms by which the hepatic endocannabinoid and apelin systems play a significant role in the pathophysiology of liver fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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26 pages, 1395 KiB

Open AccessReview

Magnetic-Assisted Treatment of Liver Fibrosis

by Kateryna Levada, Alexander Omelyanchik, Valeria Rodionova, Ralf Weiskirchen and Matthias Bartneck

Cells 2019, 8(10), 1279; https://doi.org/10.3390/cells8101279 - 19 Oct 2019

Cited by 26 | Viewed by 6548

Abstract

Chronic liver injury can be induced by viruses, toxins, cellular activation, and metabolic dysregulation and can lead to liver fibrosis. Hepatic fibrosis still remains a major burden on the global health systems. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are considered [...] Read more.

Chronic liver injury can be induced by viruses, toxins, cellular activation, and metabolic dysregulation and can lead to liver fibrosis. Hepatic fibrosis still remains a major burden on the global health systems. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are considered the main cause of liver fibrosis. Hepatic stellate cells are key targets in antifibrotic treatment, but selective engagement of these cells is an unresolved issue. Current strategies for antifibrotic drugs, which are at the critical stage 3 clinical trials, target metabolic regulation, immune cell activation, and cell death. Here, we report on the critical factors for liver fibrosis, and on prospective novel drugs, which might soon enter the market. Apart from the current clinical trials, novel perspectives for anti-fibrotic treatment may arise from magnetic particles and controlled magnetic forces in various different fields. Magnetic-assisted techniques can, for instance, enable cell engineering and cell therapy to fight cancer, might enable to control the shape or orientation of single cells or tissues mechanically. Furthermore, magnetic forces may improve localized drug delivery mediated by magnetism-induced conformational changes, and they may also enhance non-invasive imaging applications. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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20 pages, 4519 KiB

Open AccessReview

Potential Therapeutic Application of Estrogen in Gender Disparity of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

by Chanbin Lee, Jieun Kim and Youngmi Jung

Cells 2019, 8(10), 1259; https://doi.org/10.3390/cells8101259 - 15 Oct 2019

Cited by 73 | Viewed by 7161

Abstract

Nonalcoholic fatty liver disease (NAFLD) caused by fat accumulation in the liver is globally the most common cause of chronic liver disease. Simple steatosis can progress to nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD. The most potent driver for NASH is [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) caused by fat accumulation in the liver is globally the most common cause of chronic liver disease. Simple steatosis can progress to nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD. The most potent driver for NASH is hepatocyte death induced by lipotoxicity, which triggers inflammation and fibrosis, leading to cirrhosis and/or liver cancer. Despite the significant burden of NAFLD, there is no therapy for NAFLD/NASH. Accumulating evidence indicates gender-related NAFLD progression. A higher incidence of NAFLD is found in men and postmenopausal women than premenopausal women, and the experimental results, showing protective actions of estradiol in liver diseases, suggest that estrogen, as the main female hormone, is associated with the progression of NAFLD/NASH. However, the mechanism explaining the functions of estrogen in NAFLD remains unclear because of the lack of reliable animal models for NASH, the imbalance between the sexes in animal experiments, and subsequent insufficient results. Herein, we reviewed the pathogenesis of NAFLD/NASH focused on gender and proposed a feasible association of estradiol with NAFLD/NASH based on the findings reported thus far. This review would help to expand our knowledge of the gender differences in NAFLD and for developing gender-based treatment strategies for NAFLD/NASH. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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13 pages, 1040 KiB

Open AccessFeature PaperReview

Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis

by Mousumi Khatun and Ratna B. Ray

Cells 2019, 8(10), 1249; https://doi.org/10.3390/cells8101249 - 14 Oct 2019

Cited by 111 | Viewed by 9083

Abstract

Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of [...] Read more.

Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen fibers secreted by activated hepatic stellate cells (HSCs). Activation of HSCs from the quiescent stage is mediated by different mechanisms, including pro-inflammatory cytokines and chemokines released from HCV-infected hepatocytes and liver macrophages. HCV infection modulates the expression of different microRNAs that can be transported and delivered to the HSCs via exosomes released from infected cells, also leading to the development of advanced disease pathogenesis. Although recent advancements in direct-acting antiviral (DAA) treatment can efficiently control viremia, there are very few treatment strategies available that can be effective at preventing pathogenesis in advanced liver fibrosis or cirrhosis in patients. Assessment of fibrosis is considered to be the major part of proper patient care and decision making in clinical practice. In this review, we highlighted the current knowledge of molecular mechanisms responsible for the progression of liver fibrosis in chronically HCV-infected patients, and currently available methods for evaluation of fibrosis in patients. A detailed understanding of these aspects at the molecular level may contribute to the development of new therapies targeting HCV-related liver fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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16 pages, 1847 KiB

Open AccessReview

Regulation of Fibrotic Processes in the Liver by ADAM Proteases

by Dirk Schmidt-Arras and Stefan Rose-John

Cells 2019, 8(10), 1226; https://doi.org/10.3390/cells8101226 - 9 Oct 2019

Cited by 16 | Viewed by 4663

Abstract

Fibrosis in the liver is mainly associated with the activation of hepatic stellate cells (HSCs). Both activation and clearance of HSCs can be mediated by ligand–receptor interactions. Members of the a disintegrin and metalloprotease (ADAM) family are involved in the proteolytic release of [...] Read more.

Fibrosis in the liver is mainly associated with the activation of hepatic stellate cells (HSCs). Both activation and clearance of HSCs can be mediated by ligand–receptor interactions. Members of the a disintegrin and metalloprotease (ADAM) family are involved in the proteolytic release of membrane-bound ligands and receptor ectodomains and the remodelling of the extracellular matrix. ADAM proteases are therefore major regulators of intercellular signalling pathways. In the present review we discuss how ADAM proteases modulate pro- and anti-fibrotic processes and how ADAM proteases might be harnessed therapeutically in the future. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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23 pages, 2058 KiB

Open AccessEditor’s ChoiceReview

Current Status in Testing for Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)

by Hannah K. Drescher, Sabine Weiskirchen and Ralf Weiskirchen

Cells 2019, 8(8), 845; https://doi.org/10.3390/cells8080845 - 7 Aug 2019

Cited by 98 | Viewed by 17047

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with almost 25% affected adults worldwide. The growing public health burden is getting evident when considering that NAFLD-related liver transplantations are predicted to almost double within the next [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with almost 25% affected adults worldwide. The growing public health burden is getting evident when considering that NAFLD-related liver transplantations are predicted to almost double within the next 20 years. Typically, hepatic alterations start with simple steatosis, which easily progresses to more advanced stages such as nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. This course of disease finally leads to end-stage liver disease such as hepatocellular carcinoma, which is associated with increased morbidity and mortality. Although clinical trials show promising results, there is actually no pharmacological agent approved to treat NASH. Another important problem associated with NASH is that presently the liver biopsy is still the gold standard in diagnosis and for disease staging and grading. Because of its invasiveness, this technique is not well accepted by patients and the method is prone to sampling error. Therefore, an urgent need exists to find reliable, accurate and noninvasive biomarkers discriminating between different disease stages or to develop innovative imaging techniques to quantify steatosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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