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Pathophysiology of Liver Fibrosis and Its Therapies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 31503

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Special Issue Editor

Dr. Pavel Strnad

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Guest Editor

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
Interests: internal medicine; liver diseases; liver cirrhosis; gastroenterology; chronic hepatitis C
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Liver fibrosis is a conserved response to chronic hepatocellular stress that results in cell death and activation of multiple signalling pathways. It is characterized by the activation of stellate cells and progressive deposition of the extracellular matrix. Alcoholic and non-alcoholic liver disease are the leading causes of liver fibrosis in the Western world, with lipotoxicity, an alteration of the gut–liver axis, and the resulting inflammation being among the well-known disease pathomechanisms. A better understanding of the transition process from a healthy liver to end-stage disease is needed to enable the prediction of individual disease courses. In advanced fibrosis, the development of portal hypertension and its associated complications are determinants of the patient´s prognosis, but these processes are still incompletely understood. This upcoming Special Issue of IJMS aims to reflect the diversity of this complex process and bring together biologists, immunologists, and bioinformaticians to highlight the progress in the field.

We invite authors to submit original research and review articles regarding the molecular/cellular aspects of liver fibrosis including, but not limited to, the following topics:

Hepatic stellate cells;
Non-alcoholic fatty liver disease;
Gut–liver axis;
Cell death;
Signaling;
Lipotoxicity;
Alcohol-related liver injury;
Phase transition;
Inflammation;
Portal hypertension;
Liver cirrhosis.

Dr. Pavel Strnad
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

hepatic stellate cell;
non-alcoholic fatty liver disease;
gut–liver axis;
cell death;
signaling;
lipotoxicity;
alcohol-related liver injury;
phase transition;
inflammation;
portal hypertension;
liver cirrhosis.

Published Papers (7 papers)

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Research

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16 pages, 3917 KiB

Open AccessArticle

Liver Fibrosis and Inflammation under the Control of ERK2

by Kuo-Shyang Jeng, Ssu-Jung Lu, Chih-Hsuan Wang and Chiung-Fang Chang

Int. J. Mol. Sci. 2020, 21(11), 3796; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113796 - 27 May 2020

Cited by 27 | Viewed by 3977

Abstract

Chronic liver injury could lead the formation of liver fibrosis, eventually some would develop to hepatocellular carcinoma (HCC), one of the leading malignancies worldwide. The aim of the study is to dissect the role of extracellular signal-regulated kinase 2 (ERK2) signaling in liver fibrosis and inflammation. The choline-deficient, ethionine-supplemented (CDE) diet could lead to fatty livers and generate oval cells, activate hepatocyte stellate cell (HSC) and recruit immune cells as the liver fibrosis model mice. WT and ERK2 deficient (ERK2^−/−) mice were compared in terms of liver weight/body weight, liver function, liver fibrosis markers and the differential gene expression in hepatotoxicity. ERK2^−/− mice display the less degree of liver fibrosis when compared to WT mice. The protein level of alpha smooth muscle (α-SMA) was reduced and several hepatocellular carcinoma-related genes such as MMP9, FoxM1 were down-regulated. In addition, the cell proliferation and the percentages of activated T cells were reduced in ERK2^−/− mice upon liver injury. Therefore, ERK2 plays an important role in regulating liver cirrhosis and inflammation. Full article

(This article belongs to the Special Issue Pathophysiology of Liver Fibrosis and Its Therapies)

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12 pages, 2121 KiB

Open AccessArticle

Exogenous Therapeutics of Microrna-29a Attenuates Development of Hepatic Fibrosis in Cholestatic Animal Model through Regulation of Phosphoinositide 3-Kinase p85 Alpha

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

Int. J. Mol. Sci. 2020, 21(10), 3636; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103636 - 21 May 2020

Cited by 19 | Viewed by 2660

Abstract

Recent studies have found that microRNA-29a (miR-29a) levels are significantly lower in fibrotic livers, as shown with human liver cirrhosis. Such downregulation influences the activation of hepatic stellate cells (HSC). Phosphoinositide 3-kinase p85 alpha (PI3KP85α) is implicated in the regulation of proteostasis mitochondrial integrity and unfolded protein response (UPR) and apoptosis in hepatocytes. This study aimed to investigate the potential therapeutic role of miR-29a in a murine bile duct ligation (BDL)-cholestatic injury and liver fibrosis model. Mice were assigned to four groups: sham, BDL, BDL + scramble miRs, and BDL + miR-29a-mimic. Liver fibrosis and inflammation were assessed by histological staining and mRNA/protein expression of representative markers. Exogenous therapeutics of miR-29a in BDL-stressed mice significantly attenuated glutamic oxaloacetic transaminase (GOT)/glutamic-pyruvic transaminase (GPT) and liver fibrosis, and caused a significant downregulation in markers related to inflammation (IL-1β), fibrogenesis (TGF-β1, α-SMA, and COL1α1), autophagy (p62 and LC3B II), mitochondrial unfolded protein response (UPR^mt; C/EBP homologous protein (CHOP), heat shock protein 60 (HSP60), and Lon protease-1 (LONP1, a mitochondrial protease), and PI3KP85α within the liver tissue. An in vitro luciferase reporter assay further confirmed that miR-29a mimic directly targets mRNA 3′ untranslated region (UTR) of PI3KP85α to suppress its expression in HepG2 cell line. Our data provide new insights that therapeutic miR-29a improves cholestasis-induced hepatic inflammation and fibrosis and proteotstasis via blocking PI3KP85α, highlighting the potential of miR-29a targeted therapy for liver injury. Full article

(This article belongs to the Special Issue Pathophysiology of Liver Fibrosis and Its Therapies)

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14 pages, 2922 KiB

Open AccessArticle

Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats

by Carla Cremonese, Robert Schierwagen, Frank Erhard Uschner, Sandra Torres, Olaf Tyc, Cristina Ortiz, Martin Schulz, Alexander Queck, Glen Kristiansen, Michael Bader, Tilman Sauerbruch, Ralf Weiskirchen, Thomas Walther, Jonel Trebicka and Sabine Klein

Int. J. Mol. Sci. 2020, 21(9), 3308; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093308 - 7 May 2020

Cited by 7 | Viewed by 4397

Abstract

Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity. Full article

(This article belongs to the Special Issue Pathophysiology of Liver Fibrosis and Its Therapies)

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22 pages, 5446 KiB

Open AccessArticle

Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti-Fibrotic Effects in Hepatic Stellate Cells In Vitro

by Anna Hübbers, Julia Hennings, Daniela Lambertz, Ute Haas, Christian Trautwein, Yulia A. Nevzorova, Roland Sonntag and Christian Liedtke

Int. J. Mol. Sci. 2020, 21(9), 3267; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093267 - 5 May 2020

Cited by 8 | Viewed by 3238

Abstract

Liver fibrosis is a wound healing process in response to chronic liver injury, which is characterized by the accumulation of extracellular collagen produced by Hepatic Stellate Cells (HSCs). This process involves cell cycle re-entry and proliferation of normally quiescent HSCs controlled by cyclins and associated cyclin-dependent kinases (Cdks). Cdk2 mediates the entry and progression through S-phase in complex with E-and A-type cyclins. We have demonstrated that cyclin E1 is essential for liver fibrogenesis in mice, but it is not known if this is dependent on Cdk2 or related Cdks. Here, we aimed to evaluate the benefit of the pan-Cdk inhibitor CR8 for treatment of liver fibrosis in vitro. CR8-treatment reduced proliferation and survival in immortalized HSC lines and in addition attenuated pro-fibrotic properties in primary murine HSCs. Importantly, primary murine hepatocytes were much more tolerant against the cytotoxic and anti-proliferative effects of CR8. We identified CR8 dosages mediating anti-fibrotic effects in primary HSCs without affecting cell cycle activity and survival in primary hepatocytes. In conclusion, the pharmacological pan-Cdk inhibitor CR8 restricts the pro-fibrotic properties of HSCs, while preserving proliferation and viability of hepatocytes at least in vitro. Therefore, CR8 and related drugs might be beneficial for the treatment of liver fibrosis. Full article

(This article belongs to the Special Issue Pathophysiology of Liver Fibrosis and Its Therapies)

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8 pages, 682 KiB

Open AccessCommunication

The Bile Acid-Phospholipid Conjugate Ursodeoxycholyl-Lysophosphatidylethanolamide (UDCA-LPE) Disintegrates the Lipid Backbone of Raft Plasma Membrane Domains by the Removal of the Membrane Phospholipase A2

by Wolfgang Stremmel, Simone Staffer, Gert Fricker and Ralf Weiskirchen

Int. J. Mol. Sci. 2019, 20(22), 5631; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225631 - 11 Nov 2019

Cited by 2 | Viewed by 3058

Abstract

The bile acid-phospholipid conjugate ursodeoxycholyl-lysophosphatidylethanolamide (UDCA-LPE) was shown to have anti-inflammatory, antisteatotic, and antifibrotic properties, rendering it as a drug targeting non-alcoholic steatohepatitis (NASH). On a molecular level, it disrupted the heterotetrameric fatty acid uptake complex localized in detergent-resistant membrane domains of the plasma membrane (DRM-PM). However, its mode of action was unclear. Methodologically, UDCA-LPE was incubated with the liver tumor cell line HepG2 as well as their isolated DRM-PM and all other cellular membranes (non-DRM). The membrane cholesterol and phospholipids were quantified as well as the DRM-PM protein composition by Western blotting. The results show a loss of DRM-PM by UDCA-LPE (50 µM) with a 63.13 ± 7.14% reduction of phospholipids and an 81.94 ± 8.30% reduction of cholesterol in relation to mg total protein. The ratio of phospholipids to cholesterol changed from 2:1 to 4:1, resembling those of non-DRM fractions. Among the members of the fatty acid uptake complex, the calcium-independent membrane phospholipase A2 (iPLA₂β) abandoned DRM-PM most rapidly. As a consequence, the other members of this transport system disappeared as well as the DRM-PM anchored fibrosis regulating proteins integrin β-1 and lysophospholipid receptor 1 (LPAR-1). It is concluded that UDCA-LPE executes its action by iPLA₂β removal from DRM-PM and consequent dissolution of the raft lipid platform. Full article

(This article belongs to the Special Issue Pathophysiology of Liver Fibrosis and Its Therapies)

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Review

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18 pages, 1790 KiB

Open AccessReview

Extracellular Vesicles: A Therapeutic Option for Liver Fibrosis

by Stefania Bruno, Giulia Chiabotto and Giovanni Camussi

Int. J. Mol. Sci. 2020, 21(12), 4255; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124255 - 15 Jun 2020

Cited by 34 | Viewed by 4283

Abstract

Extracellular vesicles (EVs) are a heterogeneous population of small membrane vesicles released by all types of cells in both physiological and pathological conditions. EVs shuttle different types of molecules and are able to modify the behavior of target cells by various mechanisms of action. In this review, we have summarized the papers present in the literature, to our acknowledge, that reported the EV effects on liver diseases. EVs purified from serum, stem cells, and hepatocytes were investigated in different experimental in vivo models of liver injury and in particular of liver fibrosis. Despite the different EV origin and the different types of injury (toxic, ischemic, diet induced, and so on), EVs showed an anti-fibrotic effect. In particular, EVs had the capacities to inhibit activation of hepatic stellate cells, one of the major players of liver fibrosis development; to reduce inflammation and apoptosis; to counteract the oxidative stress; and to increase hepatocyte proliferation, contributing to reducing fibrosis and ameliorating liver function and morphology. Full article

(This article belongs to the Special Issue Pathophysiology of Liver Fibrosis and Its Therapies)

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25 pages, 920 KiB

Open AccessReview

Reclassifying Hepatic Cell Death during Liver Damage: Ferroptosis—A Novel Form of Non-Apoptotic Cell Death?

by Ricardo U. Macías-Rodríguez, María Eugenia Inzaugarat, Astrid Ruiz-Margáin, Leonard J. Nelson, Christian Trautwein and Francisco Javier Cubero

Int. J. Mol. Sci. 2020, 21(5), 1651; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051651 - 28 Feb 2020

Cited by 68 | Viewed by 9249

Abstract

Ferroptosis has emerged as a new type of cell death in different pathological conditions, including neurological and kidney diseases and, especially, in different types of cancer. The hallmark of this regulated cell death is the presence of iron-driven lipid peroxidation; the activation of key genes related to this process such as glutathione peroxidase-4 (gpx4), acyl-CoA synthetase long-chain family member-4 (acsl4), carbonyl reductase [NADPH] 3 (cbr3), and prostaglandin peroxidase synthase-2 (ptgs2); and morphological changes including shrunken and electron-dense mitochondria. Iron overload in the liver has long been recognized as both a major trigger of liver damage in different diseases, and it is also associated with liver fibrosis. New evidence suggests that ferroptosis might be a novel type of non-apoptotic cell death in several liver diseases including non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), drug-induced liver injury (DILI), viral hepatitis, and hemochromatosis. The interaction between iron-related lipid peroxidation, cellular stress signals, and antioxidant systems plays a pivotal role in the development of this novel type of cell death. In addition, integrated responses from lipidic mediators together with free iron from iron-containing enzymes are essential to understanding this process. The presence of ferroptosis and the exact mechanisms leading to this non-apoptotic type of cell death in the liver remain scarcely elucidated. Recognizing ferroptosis as a novel type of cell death in the liver could lead to the understanding of the complex interaction between different types of cell death, their role in progression of liver fibrosis, the development of new biomarkers, as well as the use of modulators of ferroptosis, allowing improved theranostic approaches in the clinic. Full article

(This article belongs to the Special Issue Pathophysiology of Liver Fibrosis and Its Therapies)

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