Cellular and Molecular Mechanisms underlying the Pathogenesis of Hepatic Fibrosis II

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 119690

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Dear Colleagues,

The hallmark of hepatic fibrosis is the formation and deposition of excess fibrous connective tissue, leading to progressive architectural tissue remodeling. Irrespective of the underlying pathogenic cause (e.g., genetic disorders, viruses, alcohol, autoimmune attacks, metabolic disorders, cholestasis, venous obstruction, parasites), tissue damage induces an inflammatory response involving the local vascular system and the immune system and a systemic mobilization of endocrine and neurological mediators, ultimately leading to the activation of matrix-producing cell populations. In addition, excess fat and other lipotoxic mediators provoking endoplasmic reticulum stress, the alteration of mitochondrial function, oxidative stress, and modifications in the microbiota are associated with non-alcoholic fatty liver disease and, subsequently, the initiation and/or progression of hepatic fibrosis.

In this Special Issue of Cells, I invite you to contribute original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis”. Expert articles describing mechanistic, functional, cellular, biochemical, or general aspects of hepatic fibrogenesis are highly welcome. Relevant topics include but are not limited to:

  • Cytokine signaling;
  • Chemokine function;
  • In vitro and in vivo models;
  • Immunology in hepatic fibrosis;
  • Extracellular matrix;
  • Inflammation;
  • Fibrosis;
  • NASH/NAFLD;
  • Alcohol;
  • Hepatitis;
  • Microbiota;
  • Bioimaging;
  • Translational medicine.

Prof. Ralf Weiskirchen
Guest Editor

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Published Papers (22 papers)

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Editorial

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8 pages, 607 KiB  
Editorial
Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis II”
by Ralf Weiskirchen
Cells 2022, 11(15), 2403; https://doi.org/10.3390/cells11152403 - 4 Aug 2022
Cited by 1 | Viewed by 1436
Abstract
Hepatic fibrosis is a common type of liver disease that is attracting increasing attention of basic scientists and clinicians worldwide [...] Full article
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Research

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17 pages, 2765 KiB  
Article
Perilipin 5 Ameliorates Hepatic Stellate Cell Activation via SMAD2/3 and SNAIL Signaling Pathways and Suppresses STAT3 Activation
by Rafael Cierpka, Ralf Weiskirchen and Anastasia Asimakopoulos
Cells 2021, 10(9), 2184; https://doi.org/10.3390/cells10092184 - 24 Aug 2021
Cited by 9 | Viewed by 3396
Abstract
Comprehending the molecular mechanisms underlying hepatic fibrogenesis is essential to the development of treatment. The hallmark of hepatic fibrosis is the development and deposition of excess fibrous connective tissue forcing tissue remodeling. Hepatic stellate cells (HSC) play a major role in the pathogenesis [...] Read more.
Comprehending the molecular mechanisms underlying hepatic fibrogenesis is essential to the development of treatment. The hallmark of hepatic fibrosis is the development and deposition of excess fibrous connective tissue forcing tissue remodeling. Hepatic stellate cells (HSC) play a major role in the pathogenesis of liver fibrosis. Their activation via the transforming growth factor-β1 (TGF-β1) as a key mediator is considered the crucial event in the pathophysiology of hepatic fibrogenesis. It has been shown that Perilipin 5 (PLIN5), known as a lipid droplet structural protein that is highly expressed in oxidative tissue, can inhibit such activation through various mechanisms associated with lipid metabolism. This study aimed to investigate the possible influence of PLIN5 on TGF-β1 signaling. Our findings confirm the importance of PLIN5 in maintaining HSC quiescence in vivo and in vitro. PLIN5 overexpression suppresses the TGF-β1-SMAD2/3 and SNAIL signaling pathways as well as the activation of the signal transducers and activators of transcription 3 (STAT3). These findings derived from experiments in hepatic cell lines LX-2 and Col-GFP, in which overexpression of PLIN5 was able to downregulate the signaling pathways SMAD2/3 and SNAIL activated previously by TGF-β1 treatment. Furthermore, TGF-β1-mediatedinduction of extracellular matrix proteins, such as collagen type I (COL1), Fibronectin, and α-smooth muscle actin (α-SMA), was suppressed by PLIN5. Moreover, STAT3, which is interrelated with TGF-β1 was already basally activated in the cell lines and inhibited by PLIN5 overexpression, leading to a further reduction in HSC activity shown by lowered α-SMA expression. This extension of the intervening mechanisms presents PLIN5 as a potent and pleiotropic target in HSC activation. Full article
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14 pages, 3617 KiB  
Article
Death-Associated Protein 6 (Daxx) Alleviates Liver Fibrosis by Modulating Smad2 Acetylation
by Sung-Min Kim, Won-Hee Hur, Byung-Yoon Kang, Sung-Won Lee, Pu-Reun Roh, Dong-Jun Park, Pil-Soo Sung and Seung-Kew Yoon
Cells 2021, 10(7), 1742; https://doi.org/10.3390/cells10071742 - 9 Jul 2021
Cited by 8 | Viewed by 3363
Abstract
Transforming growth factor-β (TGF-β) has been identified as an inducer of hepatocyte epithelial–mesenchymal transition (EMT), which triggers liver fibrosis. Death-associated protein 6 (Daxx) is known to be associated with the TGF-β-induced apoptotic pathway, but the function of Daxx in liver fibrosis remains unknown. [...] Read more.
Transforming growth factor-β (TGF-β) has been identified as an inducer of hepatocyte epithelial–mesenchymal transition (EMT), which triggers liver fibrosis. Death-associated protein 6 (Daxx) is known to be associated with the TGF-β-induced apoptotic pathway, but the function of Daxx in liver fibrosis remains unknown. This study aimed to elucidate the role of Daxx in liver fibrosis. We used liver fibrosis tissues from humans and mice to assess Daxx expression. EMT properties and TGF-β signaling pathway activation were investigated in the Daxx-overexpressing FL83B cell line. The therapeutic effect of Daxx was investigated in a mouse model of liver fibrosis by the hydrodynamic injection of plasmids. The expression of Daxx was markedly decreased in hepatocytes from fibrotic human and mouse livers, as well as in hepatocytes treated with TGF-β in vitro. The overexpression of Daxx inhibited the EMT process by interfering with the TGF-β-induced phosphorylation of Smad2. Coimmunoprecipitation analysis confirmed that Daxx reduced the transcriptional activity of Smad2 by binding to its MH1 domain and interfering with Smad2 acetylation. In addition, the therapeutic delivery of Daxx alleviated liver fibrosis in a thioacetamide-induced fibrosis mouse model. Overall, our results indicate that Daxx could be a potential therapeutic target to modulate fibrogenesis, as well as a useful biomarker for liver fibrosis. Full article
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21 pages, 8273 KiB  
Article
Improved Recovery from Liver Fibrosis by Crenolanib
by Doreen Reichert, Louisa Adolph, Jan Philipp Köhler, Tobias Buschmann, Tom Luedde, Dieter Häussinger and Claus Kordes
Cells 2021, 10(4), 804; https://doi.org/10.3390/cells10040804 - 4 Apr 2021
Cited by 8 | Viewed by 4367
Abstract
Chronic liver diseases are associated with excessive deposition of extracellular matrix proteins. This so-called fibrosis can progress to cirrhosis and impair vital functions of the liver. We examined whether the receptor tyrosine kinase (RTK) class III inhibitor Crenolanib affects the behavior of hepatic [...] Read more.
Chronic liver diseases are associated with excessive deposition of extracellular matrix proteins. This so-called fibrosis can progress to cirrhosis and impair vital functions of the liver. We examined whether the receptor tyrosine kinase (RTK) class III inhibitor Crenolanib affects the behavior of hepatic stellate cells (HSC) involved in fibrogenesis. Rats were treated with thioacetamide (TAA) for 18 weeks to trigger fibrosis. After TAA treatment, the animals received Crenolanib for two weeks, which significantly improved recovery from liver fibrosis. Because Crenolanib predominantly inhibits the RTK platelet-derived growth factor receptor-β, impaired HSC proliferation might be responsible for this beneficial effect. Interestingly, blocking of RTK signaling by Crenolanib not only hindered HSC proliferation but also triggered their specification into hepatic endoderm. Endodermal specification was mediated by p38 mitogen-activated kinase (p38 MAPK) and c-Jun-activated kinase (JNK) signaling; however, this process remained incomplete, and the HSC accumulated lipids. JNK activation was induced by stress response-associated inositol-requiring enzyme-1α (IRE1α) in response to Crenolanib treatment, whereas β-catenin-dependent WNT signaling was able to counteract this process. In conclusion, the Crenolanib-mediated inhibition of RTK impeded HSC proliferation and triggered stress responses, initiating developmental processes in HSC that might have contributed to improved recovery from liver fibrosis in TAA-treated rats. Full article
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17 pages, 3146 KiB  
Article
Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations
by Daniel Heinrichs, Elisa F. Brandt, Petra Fischer, Janine Köhncke, Theresa H. Wirtz, Nurdan Guldiken, Sonja Djudjaj, Peter Boor, Daniela Kroy, Ralf Weiskirchen, Richard Bucala, Hermann E. Wasmuth, Pavel Strnad, Christian Trautwein, Jürgen Bernhagen and Marie-Luise Berres
Cells 2021, 10(2), 252; https://doi.org/10.3390/cells10020252 - 28 Jan 2021
Cited by 10 | Viewed by 4127
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF [...] Read more.
Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic Mif expression was strongly induced, an effect which was absent in Mifhep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif−/− and Mifhep mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury. Full article
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15 pages, 3057 KiB  
Article
Phosphate Groups in the Lipid A Moiety Determine the Effects of LPS on Hepatic Stellate Cells: A Role for LPS-Dephosphorylating Activity in Liver Fibrosis
by Marlies Schippers, Eduard Post, Ilse Eichhorn, Jitske Langeland, Leonie Beljaars, Madhu S. Malo, Richard A. Hodin, José Luis Millán, Yury Popov, Detlef Schuppan and Klaas Poelstra
Cells 2020, 9(12), 2708; https://doi.org/10.3390/cells9122708 - 17 Dec 2020
Cited by 10 | Viewed by 3783
Abstract
Alkaline phosphatase (AP) activity is highly upregulated in plasma during liver diseases. Previously, we demonstrated that AP is able to detoxify lipopolysaccharide (LPS) by dephosphorylating its lipid A moiety. Because a role of gut-derived LPS in liver fibrogenesis has become evident, we now [...] Read more.
Alkaline phosphatase (AP) activity is highly upregulated in plasma during liver diseases. Previously, we demonstrated that AP is able to detoxify lipopolysaccharide (LPS) by dephosphorylating its lipid A moiety. Because a role of gut-derived LPS in liver fibrogenesis has become evident, we now examined the relevance of phosphate groups in the lipid A moiety in this process. The effects of mono-phosphoryl and di-phosphoryl lipid A (MPLA and DPLA, respectively) were studied in vitro and LPS-dephosphorylating activity was studied in normal and fibrotic mouse and human livers. The effects of intestinal AP were studied in mice with CCL4-induced liver fibrosis. DPLA strongly stimulated fibrogenic and inflammatory activities in primary rat hepatic stellate cells (rHSCs) and RAW264.7 macrophages with similar potency as full length LPS. However, MPLA did not affect any of the parameters. LPS-dephosphorylating activity was found in mouse and human livers and was strongly increased during fibrogenesis. Treatment of fibrotic mice with intravenous intestinal-AP significantly attenuated intrahepatic desmin+− and αSMA+ −HSC and CD68+− macrophage accumulation. In conclusion, the lack of biological activity of MPLA, contrasting with the profound activities of DPLA, shows the relevance of LPS-dephosphorylating activity. The upregulation of LPS-dephosphorylating activity in fibrotic livers and the protective effects of exogenous AP during fibrogenesis indicate an important physiological role of intestinal-derived AP during liver fibrosis. Full article
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15 pages, 2450 KiB  
Article
Simultaneous Induction of Glycolysis and Oxidative Phosphorylation during Activation of Hepatic Stellate Cells Reveals Novel Mitochondrial Targets to Treat Liver Fibrosis
by Natalia Smith-Cortinez, Karen van Eunen, Janette Heegsma, Sandra Alejandra Serna-Salas, Svenja Sydor, Lars P. Bechmann, Han Moshage, Barbara M. Bakker and Klaas Nico Faber
Cells 2020, 9(11), 2456; https://doi.org/10.3390/cells9112456 - 11 Nov 2020
Cited by 32 | Viewed by 3981
Abstract
Upon liver injury, hepatic stellate cells (HSCs) transdifferentiate to migratory, proliferative and extracellular matrix-producing myofibroblasts (e.g., activated HSCs; aHSCs) causing liver fibrosis. HSC activation is associated with increased glycolysis and glutaminolysis. Here, we compared the contribution of glycolysis, glutaminolysis and mitochondrial oxidative phosphorylation [...] Read more.
Upon liver injury, hepatic stellate cells (HSCs) transdifferentiate to migratory, proliferative and extracellular matrix-producing myofibroblasts (e.g., activated HSCs; aHSCs) causing liver fibrosis. HSC activation is associated with increased glycolysis and glutaminolysis. Here, we compared the contribution of glycolysis, glutaminolysis and mitochondrial oxidative phosphorylation (OXPHOS) in rat and human HSC activation. Basal levels of glycolysis (extracellular acidification rate ~3-fold higher) and particularly mitochondrial respiration (oxygen consumption rate ~5-fold higher) were significantly increased in rat aHSCs, when compared to quiescent rat HSC. This was accompanied by extensive mitochondrial fusion in rat and human aHSCs, which occurred without increasing mitochondrial DNA content and electron transport chain (ETC) components. Inhibition of glycolysis (by 2-deoxy-D-glucose) and glutaminolysis (by CB-839) did not inhibit rat aHSC proliferation, but did reduce Acta2 (encoding α-SMA) expression slightly. In contrast, inhibiting mitochondrial OXPHOS (by rotenone) significantly suppressed rat aHSC proliferation, as well as Col1a1 and Acta2 expression. Other than that observed for rat aHSCs, human aHSC proliferation and expression of fibrosis markers were significantly suppressed by inhibiting either glycolysis, glutaminolysis or mitochondrial OXPHOS (by metformin). Activation of HSCs is marked by simultaneous induction of glycolysis and mitochondrial metabolism, extending the possibilities to suppress hepatic fibrogenesis by interfering with HSC metabolism. Full article
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17 pages, 2703 KiB  
Article
Discovery and Targeting of the Signaling Controls of PNPLA3 to Effectively Reduce Transcription, Expression, and Function in Pre-Clinical NAFLD/NASH Settings
by Brian E. Schwartz, Vaishnavi Rajagopal, Cynthia Smith, Evan Cohick, Gavin Whissell, Mario Gamboa, Rutuja Pai, Alla Sigova, Iris Grossman, David Bumcrot, Kavitha Sasidharan, Stefano Romeo, Alfica Sehgal and Piero Pingitore
Cells 2020, 9(10), 2247; https://doi.org/10.3390/cells9102247 - 7 Oct 2020
Cited by 27 | Viewed by 5062
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging worldwide epidemics, projected to become the leading cause of liver transplants. The strongest genetic risk factor for NAFLD/NASH susceptibility and progression is a single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging worldwide epidemics, projected to become the leading cause of liver transplants. The strongest genetic risk factor for NAFLD/NASH susceptibility and progression is a single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 gene (PNPLA3), rs738409, encoding the missense mutation I148M. This aminoacidic substitution interferes with the normal remodeling of lipid droplets in hepatocytes. It is also thought to play a key role in promoting liver fibrosis by inhibiting the release of retinol from hepatic stellate cells. Reducing PNPLA3 levels in individuals homozygous for 148M may be an effective treatment for the entire spectrum of NAFLD, based on gene dosage analysis in the human population, as well as the protective effect of another naturally occurring SNP (rs2294918) in PNPLA3 which, when co-inherited, reduces PNPLA3 mRNA levels to 50% and counteracts disease risk. By screening a clinical compound library targeting specific signaling pathways active in primary human hepatocytes, we identified momelotinib, a drug evaluated in clinical trials to treat myelofibrosis, as a potent down-regulator of PNPLA3 expression, across all genotypes. We found that momelotinib treatment yielded >80% reduction in PNPLA3 mRNA in human primary hepatocytes and stellate cells, as well as in vivo via acute and chronic treatment of WT mice. Using a human multilineage 3D spheroid model of NASH homozygous for the PNPLA3 mutant protein, we additionally show that it decreases PNPLA3 mRNA as well as intracellular lipid content. Furthermore, we show that the effects on PNPLA3 coincide with changes in chromatin accessibility within regulatory regions of the PNPLA3 locus, consistent with inhibition occurring at the level of transcription. In addition to its primary reported targets, the JAK kinases, momelotinib inhibits several non-JAK kinases, including ACVR1. Using a combination of targeted siRNA knockdowns and signaling pathway perturbations, we show that momelotinib reduces the expression of the PNPLA3 gene largely through the inhibition of BMP signaling rather than the JAK/STAT pathway. Overall, our work identified momelotinib as a potential NASH therapeutic and uncovered previously unrecognized connections between signaling pathways and PNPLA3. These pathways may be exploited by drug modalities to “tune down” the level of gene expression, and therefore offer a potential therapeutic benefit to a high at-risk subset of NAFLD/NASH patients. Full article
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20 pages, 4550 KiB  
Article
IL-13 as Target to Reduce Cholestasis and Dysbiosis in Abcb4 Knockout Mice
by Luisa Hahn, Nora Helmrich, Diran Herebian, Ertan Mayatepek, Uta Drebber, Eugen Domann, Stefan Olejniczak, Markus Weigel, Torsten Hain, Timo Rath, Stefan Wirtz, Hans-Joachim Mollenkopf, Nadine Schmidt, Christa Ewers, Anne Baier, Yuri Churin, Anita Windhorst, Ralf Weiskirchen, Ulrich Steinhoff, Elke Roeb and Martin Roderfeldadd Show full author list remove Hide full author list
Cells 2020, 9(9), 1949; https://doi.org/10.3390/cells9091949 - 24 Aug 2020
Cited by 4 | Viewed by 3098
Abstract
The Th2 cytokine IL-13 is involved in biliary epithelial injury and liver fibrosis in patients as well as in animal models. The aim of this study was to investigate IL-13 as a therapeutic target during short term and chronic intrahepatic cholestasis in an [...] Read more.
The Th2 cytokine IL-13 is involved in biliary epithelial injury and liver fibrosis in patients as well as in animal models. The aim of this study was to investigate IL-13 as a therapeutic target during short term and chronic intrahepatic cholestasis in an Abcb4-knockout mouse model (Abcb4−/−). Lack of IL-13 protected Abcb4−/− mice transiently from cholestasis. This decrease in serum bile acids was accompanied by an enhanced excretion of bile acids and a normalization of fecal bile acid composition. In Abcb4−/−/IL-13−/− double knockout mice, bacterial translocation to the liver was significantly reduced and the intestinal microbiome resembled the commensal composition in wild type animals. In addition, 52-week-old Abcb4−/−IL-13−/− mice showed significantly reduced hepatic fibrosis. Abcb4−/− mice devoid of IL-13 transiently improved cholestasis and converted the composition of the gut microbiota towards healthy conditions. This highlights IL-13 as a potential therapeutic target in biliary diseases. Full article
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17 pages, 3700 KiB  
Article
Deletion of Perilipin 5 Protects against Hepatic Injury in Nonalcoholic Fatty Liver Disease via Missing Inflammasome Activation
by Anastasia Asimakopoulou, Kathrin M. Engel, Nikolaus Gassler, Thilo Bracht, Barbara Sitek, Eva M. Buhl, Stavroula Kalampoka, Manuela Pinoé-Schmidt, Josef van Helden, Jürgen Schiller and Ralf Weiskirchen
Cells 2020, 9(6), 1346; https://doi.org/10.3390/cells9061346 - 28 May 2020
Cited by 17 | Viewed by 4757
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver diseases with an increasing prevalence due to rising rates of obesity, metabolic syndrome and type II diabetes. Untreated NAFLD may progress to steatohepatitis (NASH) and ultimately liver cirrhosis. NAFLD is characterized [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver diseases with an increasing prevalence due to rising rates of obesity, metabolic syndrome and type II diabetes. Untreated NAFLD may progress to steatohepatitis (NASH) and ultimately liver cirrhosis. NAFLD is characterized by lipid accumulation, and when sufficient excess lipids are obtained, irreversible liver injury may follow. Perilipin 5 (PLIN5), a known lipid droplet coating protein and triglyceride metabolism regulator, is highly expressed in oxidatively modified tissues but it is still unclear how it affects NAFLD/NASH progress. We here studied how PLIN5 affects NAFLD development induced by a 30-week high-fat diet (HFD) administration in wild type and PLIN5 knock out (Plin5−/−) mice. The disruption of PLIN5 induced differences in lipid metabolism during HFD feeding and was associated with reduced hepatic fat accumulation. Surprisingly, Plin5−/− mice showed mitigated activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, leading to minor hepatic damage. We conclude that PLIN5 is a pleiotropic regulator of hepatic homeostasis in NASH development. Targeting the PLIN5 expression appears critical for protecting the liver from inflammatory activation during chronic NAFLD. Full article
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24 pages, 2114 KiB  
Article
L-Selectin/CD62L Is a Key Driver of Non-Alcoholic Steatohepatitis in Mice and Men
by Hannah K. Drescher, Angela Schippers, Stefanie Rosenhain, Felix Gremse, Laura Bongiovanni, Alain de Bruin, Sreepradha Eswaran, Suchira U. Gallage, Dominik Pfister, Marta Szydlowska, Mathias Heikenwalder, Sabine Weiskirchen, Norbert Wagner, Christian Trautwein, Ralf Weiskirchen and Daniela C. Kroy
Cells 2020, 9(5), 1106; https://doi.org/10.3390/cells9051106 - 29 Apr 2020
Cited by 19 | Viewed by 5403
Abstract
CD62L (L-Selectin) dependent lymphocyte infiltration is known to induce inflammatory bowel disease (IBD), while its function in the liver, especially in non-alcoholic steatohepatitis (NASH), remains unclear. We here investigated the functional role of CD62L in NASH in humans as well as in two [...] Read more.
CD62L (L-Selectin) dependent lymphocyte infiltration is known to induce inflammatory bowel disease (IBD), while its function in the liver, especially in non-alcoholic steatohepatitis (NASH), remains unclear. We here investigated the functional role of CD62L in NASH in humans as well as in two mouse models of steatohepatitis. Hepatic expression of a soluble form of CD62L (sCD62L) was measured in patients with steatosis and NASH. Furthermore, CD62L−/− mice were fed with a methionine and choline deficient (MCD) diet for 4 weeks or with a high fat diet (HFD) for 24 weeks. Patients with NASH displayed increased serum levels of sCD62L. Hepatic CD62L expression was higher in patients with steatosis and increased dramatically in NASH patients. Interestingly, compared to wild type (WT) mice, MCD and HFD-treated CD62L−/− mice were protected from diet-induced steatohepatitis. This was reflected by less fat accumulation in hepatocytes and a dampened manifestation of the metabolic syndrome with an improved insulin resistance and decreased cholesterol and triglyceride levels. Consistent with ameliorated disease, CD62L−/− animals exhibited an enhanced hepatic infiltration of Treg cells and a strong activation of an anti-oxidative stress response. Those changes finally resulted in less fibrosis in CD62L−/− mice. Additionally, this effect could be reproduced in a therapeutic setting by administrating an anti-CD62L blocking antibody. CD62L expression in humans and mice correlates with disease activity of steatohepatitis. CD62L knockout and anti-CD62L-treated mice are protected from diet-induced steatohepatitis suggesting that CD62L is a promising target for therapeutic interventions in NASH. Full article
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23 pages, 8952 KiB  
Article
EX-527 Prevents the Progression of High-Fat Diet-Induced Hepatic Steatosis and Fibrosis by Upregulating SIRT4 in Zucker Rats
by Amit Kundu, Prasanta Dey, Jae Hyeon Park, In Su Kim, Seung Jun Kwack and Hyung Sik Kim
Cells 2020, 9(5), 1101; https://doi.org/10.3390/cells9051101 - 29 Apr 2020
Cited by 32 | Viewed by 4602
Abstract
Sirtuin (SIRT) is known to prevent nonalcoholic fatty liver disease (NAFLD); however, the role of SIRT4 in the progression of hepatic fibrosis remains unknown. We hypothesize that EX-527, a selective SIRT1 inhibitor, can inhibit the progression of high-fat diet (HFD)-induced hepatic fibrosis. We [...] Read more.
Sirtuin (SIRT) is known to prevent nonalcoholic fatty liver disease (NAFLD); however, the role of SIRT4 in the progression of hepatic fibrosis remains unknown. We hypothesize that EX-527, a selective SIRT1 inhibitor, can inhibit the progression of high-fat diet (HFD)-induced hepatic fibrosis. We found that SIRT4 expression in the liver of NAFLD patients is significantly lower than that in normal subjects. In this study, EX-527 (5 µg/kg), administered to HFD rats twice a week for ten weeks, reduced the serum levels of triglyceride (TG), total cholesterol, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) and attenuated hepatic fibrosis evidenced by Masson’s trichrome and hepatic fat by oil red-O staining. EX-527 upregulated SIRT2, SIRT3, and SIRT4 expression in the liver of HFD fed rats but downregulated transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) expression. It decreased proinflammatory cytokine production and hydroxyproline levels in the serum and SMAD4 expression and restored apoptotic protein (Bcl-2, Bax, and cleaved caspase-3) expression. These data propose a critical role for the SIRT4/SMAD4 axis in hepatic fibrogenesis. SIRT4 upregulation has the potential to counter HFD-induced lipid accumulation, inflammation, and fibrogenesis. We demonstrate that EX-527 is a promising candidate in inhibiting the progression of HFD-induced liver fibrosis. Full article
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Review

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22 pages, 1040 KiB  
Review
Metabolic Reprogramming of Liver Fibrosis
by M. Eugenia Delgado, Beatriz I. Cárdenas, Núria Farran and Mercedes Fernandez
Cells 2021, 10(12), 3604; https://doi.org/10.3390/cells10123604 - 20 Dec 2021
Cited by 27 | Viewed by 5672
Abstract
Liver fibrosis is an excessive and imbalanced deposition of fibrous extracellular matrix (ECM) that is associated with the hepatic wound-healing response. It is also the common mechanism that contributes to the impairment of the liver function that is observed in many chronic liver [...] Read more.
Liver fibrosis is an excessive and imbalanced deposition of fibrous extracellular matrix (ECM) that is associated with the hepatic wound-healing response. It is also the common mechanism that contributes to the impairment of the liver function that is observed in many chronic liver diseases (CLD). Despite the efforts, no effective therapy against fibrosis exists yet. Worryingly, due to the growing obesity pandemic, fibrosis incidence is on the rise. Here, we aim to summarize the main components and mechanisms involved in the progression of liver fibrosis, with special focus on the metabolic regulation of key effectors of fibrogenesis, hepatic stellate cells (HSCs), and their role in the disease progression. Hepatic cells that undergo metabolic reprogramming require a tightly controlled, fine-tuned cellular response, allowing them to meet their energetic demands without affecting cellular integrity. Here, we aim to discuss the role of ribonucleic acid (RNA)-binding proteins (RBPs), whose dynamic nature being context- and stimuli-dependent make them very suitable for the fibrotic situation. Thus, we will not only summarize the up-to-date literature on the metabolic regulation of HSCs in liver fibrosis, but also on the RBP-dependent post-transcriptional regulation of this metabolic switch that results in such important consequences for the progression of fibrosis and CLD. Full article
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26 pages, 3038 KiB  
Review
Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression
by Alessandra Caligiuri, Alessandra Gentilini, Mirella Pastore, Stefano Gitto and Fabio Marra
Cells 2021, 10(10), 2759; https://doi.org/10.3390/cells10102759 - 15 Oct 2021
Cited by 125 | Viewed by 9741
Abstract
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous [...] Read more.
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process. Full article
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22 pages, 1057 KiB  
Review
Fibrotic Events in the Progression of Cholestatic Liver Disease
by Hanghang Wu, Chaobo Chen, Siham Ziani, Leonard J. Nelson, Matías A. Ávila, Yulia A. Nevzorova and Francisco Javier Cubero
Cells 2021, 10(5), 1107; https://doi.org/10.3390/cells10051107 - 5 May 2021
Cited by 38 | Viewed by 5666
Abstract
Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic [...] Read more.
Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic liver disease remains elusive. Periductular fibroblasts located around the bile ducts seem biologically different from hepatic stellate cells (HSCs). The fibrotic events in these clinical conditions appear to be related to complex crosstalk between immune/inflammatory mechanisms, cytokine signalling, and perturbed homeostasis between cholangiocytes and mesenchymal cells. Several animal models including bile duct ligation (BDL) and the Mdr2-knockout mice have improved our understanding of mechanisms underlying chronic cholestasis. In the present review, we aim to elucidate the mechanisms of fibrosis in order to help to identify potential diagnostic and therapeutic targets. Full article
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22 pages, 684 KiB  
Review
Pathophysiology and Treatment Options for Hepatic Fibrosis: Can It Be Completely Cured?
by Arshi Khanam, Paul G. Saleeb and Shyam Kottilil
Cells 2021, 10(5), 1097; https://doi.org/10.3390/cells10051097 - 4 May 2021
Cited by 56 | Viewed by 12033
Abstract
Hepatic fibrosis is a dynamic process that occurs as a wound healing response against liver injury. During fibrosis, crosstalk between parenchymal and non-parenchymal cells, activation of different immune cells and signaling pathways, as well as a release of several inflammatory mediators take place, [...] Read more.
Hepatic fibrosis is a dynamic process that occurs as a wound healing response against liver injury. During fibrosis, crosstalk between parenchymal and non-parenchymal cells, activation of different immune cells and signaling pathways, as well as a release of several inflammatory mediators take place, resulting in inflammation. Excessive inflammation drives hepatic stellate cell (HSC) activation, which then encounters various morphological and functional changes before transforming into proliferative and extracellular matrix (ECM)-producing myofibroblasts. Finally, enormous ECM accumulation interferes with hepatic function and leads to liver failure. To overcome this condition, several therapeutic approaches have been developed to inhibit inflammatory responses, HSC proliferation and activation. Preclinical studies also suggest several targets for the development of anti-fibrotic therapies; however, very few advanced to clinical trials. The pathophysiology of hepatic fibrosis is extremely complex and requires comprehensive understanding to identify effective therapeutic targets; therefore, in this review, we focus on the various cellular and molecular mechanisms associated with the pathophysiology of hepatic fibrosis and discuss potential strategies to control or reverse the fibrosis. Full article
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22 pages, 1420 KiB  
Review
Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?
by Alex Claveria-Cabello, Leticia Colyn, Maria Arechederra, Jesus M. Urman, Carmen Berasain, Matias A. Avila and Maite G. Fernandez-Barrena
Cells 2020, 9(10), 2321; https://doi.org/10.3390/cells9102321 - 19 Oct 2020
Cited by 28 | Viewed by 4539
Abstract
Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of [...] Read more.
Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis. Full article
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22 pages, 2312 KiB  
Review
Playing Jekyll and Hyde—The Dual Role of Lipids in Fatty Liver Disease
by Martijn R. Molenaar, Louis C. Penning and J. Bernd Helms
Cells 2020, 9(10), 2244; https://doi.org/10.3390/cells9102244 - 6 Oct 2020
Cited by 4 | Viewed by 4209
Abstract
Lipids play Jekyll and Hyde in the liver. On the one hand, the lipid-laden status of hepatic stellate cells is a hallmark of healthy liver. On the other hand, the opposite is true for lipid-laden hepatocytes—they obstruct liver function. Neglected lipid accumulation in [...] Read more.
Lipids play Jekyll and Hyde in the liver. On the one hand, the lipid-laden status of hepatic stellate cells is a hallmark of healthy liver. On the other hand, the opposite is true for lipid-laden hepatocytes—they obstruct liver function. Neglected lipid accumulation in hepatocytes can progress into hepatic fibrosis, a condition induced by the activation of stellate cells. In their resting state, these cells store substantial quantities of fat-soluble vitamin A (retinyl esters) in large lipid droplets. During activation, these lipid organelles are gradually degraded. Hence, treatment of fatty liver disease is treading a tightrope—unsophisticated targeting of hepatic lipid accumulation might trigger problematic side effects on stellate cells. Therefore, it is of great importance to gain more insight into the highly dynamic lipid metabolism of hepatocytes and stellate cells in both quiescent and activated states. In this review, part of the special issue entitled “Cellular and Molecular Mechanisms underlying the Pathogenesis of Hepatic Fibrosis 2020”, we discuss current and highly versatile aspects of neutral lipid metabolism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Full article
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14 pages, 1759 KiB  
Review
MicroRNA-221: A Fine Tuner and Potential Biomarker of Chronic Liver Injury
by Jovana Markovic, Amar Deep Sharma and Asha Balakrishnan
Cells 2020, 9(8), 1767; https://doi.org/10.3390/cells9081767 - 23 Jul 2020
Cited by 24 | Viewed by 4045
Abstract
The last decade has witnessed significant advancements in our understanding of how small noncoding RNAs, such as microRNAs (miRNAs), regulate disease progression. One such miRNA, miR-221, has been shown to play a key role in the progression of liver fibrosis, a common feature [...] Read more.
The last decade has witnessed significant advancements in our understanding of how small noncoding RNAs, such as microRNAs (miRNAs), regulate disease progression. One such miRNA, miR-221, has been shown to play a key role in the progression of liver fibrosis, a common feature of most liver diseases. Many reports have demonstrated the upregulation of miR-221 in liver fibrosis caused by multiple etiologies such as viral infections and nonalcoholic steatohepatitis. Inhibition of miR-221 via different strategies has shown promising results in terms of the suppression of fibrogenic gene signatures in vitro, as well as in vivo, in independent mouse models of liver fibrosis. In addition, miR-221 has also been suggested as a noninvasive serum biomarker for liver fibrosis and cirrhosis. In this review, we discuss the biology of miR-221, its significance and use as a biomarker during progression of liver fibrosis, and finally, potential and robust approaches that can be utilized to suppress liver fibrosis via inhibition of miR-221. Full article
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20 pages, 1133 KiB  
Review
Matrix Metalloproteinases as Potential Biomarkers and Therapeutic Targets in Liver Diseases
by Eline Geervliet and Ruchi Bansal
Cells 2020, 9(5), 1212; https://doi.org/10.3390/cells9051212 - 13 May 2020
Cited by 105 | Viewed by 7579
Abstract
Chronic liver diseases, characterized by an excessive accumulation of extracellular matrix (ECM) resulting in scar tissue formation, are a growing health problem causing increasing morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only [...] Read more.
Chronic liver diseases, characterized by an excessive accumulation of extracellular matrix (ECM) resulting in scar tissue formation, are a growing health problem causing increasing morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only treatment for the end-stage liver diseases. During liver damage, injured hepatocytes release proinflammatory factors resulting in the recruitment and activation of immune cells that activate quiescent hepatic stellate cells (HSCs). Upon activation, HSCs transdifferentiate into highly proliferative, migratory, contractile and ECM-producing myofibroblasts. The disrupted balance between ECM deposition and degradation leads to the formation of scar tissue referred to as fibrosis. This balance can be restored either by reducing ECM deposition (by inhibition of HSCs activation and proliferation) or enhancing ECM degradation (by increased expression of matrix metalloproteinases (MMPs)). MMPs play an important role in ECM remodeling and represent an interesting target for therapeutic drug discovery. In this review, we present the current knowledge about ECM remodeling and role of the different MMPs in liver diseases. MMP expression patterns in different stages of liver diseases have also been reviewed to determine their role as biomarkers. Finally, we highlight MMPs as promising therapeutic targets for the resolution of liver diseases. Full article
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17 pages, 701 KiB  
Review
The Emerging Role of MicroRNAs in NAFLD: Highlight of MicroRNA-29a in Modulating Oxidative Stress, Inflammation, and Beyond
by Hung-Yu Lin, Ya-Ling Yang, Pei-Wen Wang, Feng-Sheng Wang and Ying-Hsien Huang
Cells 2020, 9(4), 1041; https://doi.org/10.3390/cells9041041 - 22 Apr 2020
Cited by 54 | Viewed by 6287
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and ranges from steatosis to steatohepatitis and to liver fibrosis. Lipotoxicity in hepatocytes, elevated oxidative stress and the activation of proinflammatory mediators of Kupffer cells, and fibrogenic pathways of activated [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and ranges from steatosis to steatohepatitis and to liver fibrosis. Lipotoxicity in hepatocytes, elevated oxidative stress and the activation of proinflammatory mediators of Kupffer cells, and fibrogenic pathways of activated hepatic stellate cells can contribute to the development of NAFLD. MicroRNAs (miRs) play a crucial role in the dysregulated metabolism and inflammatory signaling connected with NAFLD and its progression towards more severe stages. Of note, the protective effect of non-coding miR-29a on liver damage and its versatile action on epigenetic activity, mitochondrial homeostasis and immunomodulation may improve our perception of the pathogenesis of NAFLD. Herein, we review the biological functions of critical miRs in NAFLD, as well as highlight the emerging role of miR-29a in therapeutic application and the recent advances in molecular mechanisms underlying its liver protective effect. Full article
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26 pages, 2633 KiB  
Review
The Endothelium as a Driver of Liver Fibrosis and Regeneration
by Erica Lafoz, Maria Ruart, Aina Anton, Anna Oncins and Virginia Hernández-Gea
Cells 2020, 9(4), 929; https://doi.org/10.3390/cells9040929 - 10 Apr 2020
Cited by 92 | Viewed by 10490
Abstract
Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them [...] Read more.
Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided. Full article
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