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Pathophysiology of Chronic Liver Disease Development
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Pathophysiology of Chronic Liver Disease Development

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 2021) | Viewed by 34751

Special Issue Editor

Dr. Pavel Strnad

E-Mail Website
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,

Chronic liver injury results in hepatocellular death, influx of inflammatory cells, and the activation of multiple signaling pathways. In addition, it leads to the activation of stellate cells and to the progressive deposition of the extracellular matrix, termed as fibrogenesis. Alcoholic and non-alcoholic liver diseases 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 in order 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 not completely understood. This upcoming Special Issue of IJMS aims to reflect the diversity of this complex process and to bring together biologists, immunologists, physician scientists, 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 chronic liver disease development, 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 (8 papers)

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Editorial

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3 pages, 185 KiB  
Editorial
Pathophysiology of Chronic Liver Disease Development
by Malin Fromme and Pavel Strnad
Int. J. Mol. Sci. 2022, 23(6), 3385; https://doi.org/10.3390/ijms23063385 - 21 Mar 2022
Cited by 2 | Viewed by 3801
Abstract
Chronic liver disease is a major public threat and the second leading cause of loss of working life years in Europe [...] Full article
(This article belongs to the Special Issue Pathophysiology of Chronic Liver Disease Development)

Research

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13 pages, 1327 KiB  
Article
Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk
by Zuzana Rabekova, Sona Frankova, Milan Jirsa, Magdalena Neroldova, Mariia Lunova, Ondrej Fabian, Martin Kveton, David Varys, Klara Chmelova, Vera Adamkova, Jaroslav A. Hubacek, Julius Spicak, Dusan Merta and Jan Sperl
Int. J. Mol. Sci. 2021, 22(19), 10560; https://doi.org/10.3390/ijms221910560 - 29 Sep 2021
Cited by 8 | Viewed by 2134
Abstract
Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of [...] Read more.
Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). The MS genotype frequency was comparable in controls (32/119 vs. 101/3240, p = 0.84). MZ and MS heterozygotes had lower serum AAT level than MM homozygotes (medians: 0.90 g/L; 1.40 g/L and 1.67 g/L; p < 0.001 for both). There were significantly fewer patients with HCC in the cirrhosis group among MZ and MS heterozygotes than in MM homozygotes (5/55 and 1/32 respectively, vs. 243/1022, p < 0.01 for both). The risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (OR 0.3202; 95% CI 0.1361–0.7719 and OR 0.1522; 95% CI 0.02941–0.7882, respectively). Multivariate analysis of HCC risk factors identified MZ or MS genotype carriage as a protective factor, whereas age, male sex, BMI and viral aetiology of cirrhosis increased HCC risk. Full article
(This article belongs to the Special Issue Pathophysiology of Chronic Liver Disease Development)
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16 pages, 4091 KiB  
Article
Expression of Interferons Lambda 3 and 4 Induces Identical Response in Human Liver Cell Lines Depending Exclusively on Canonical Signaling
by Mariia Lunova, Jan Kubovciak, Barbora Smolková, Mariia Uzhytchak, Kyra Michalova, Alexandr Dejneka, Pavel Strnad, Oleg Lunov and Milan Jirsa
Int. J. Mol. Sci. 2021, 22(5), 2560; https://doi.org/10.3390/ijms22052560 - 04 Mar 2021
Cited by 5 | Viewed by 3022
Abstract
Lambda interferons mediate antiviral immunity by inducing interferon-stimulated genes (ISGs) in epithelial tissues. A common variant rs368234815TT/∆G creating functional gene from an IFNL4 pseudogene is associated with the expression of major ISGs in the liver but impaired clearance of hepatitis C. To explain [...] Read more.
Lambda interferons mediate antiviral immunity by inducing interferon-stimulated genes (ISGs) in epithelial tissues. A common variant rs368234815TT/∆G creating functional gene from an IFNL4 pseudogene is associated with the expression of major ISGs in the liver but impaired clearance of hepatitis C. To explain this, we compared Halo-tagged and non-tagged IFNL3 and IFNL4 signaling in liver-derived cell lines. Transfection with non-tagged IFNL3, non-tagged IFNL4 and Halo-tagged IFNL4 led to a similar degree of JAK-STAT activation and ISG induction; however, the response to transfection with Halo-tagged IFNL3 was lower and delayed. Transfection with non-tagged IFNL3 or IFNL4 induced no transcriptome change in the cells lacking either IL10R2 or IFNLR1 receptor subunits. Cytosolic overexpression of signal peptide-lacking IFNL3 or IFNL4 in wild type cells did not interfere with JAK-STAT signaling triggered by interferons in the medium. Finally, expression profile changes induced by transfection with non-tagged IFNL3 and IFNL4 were highly similar. These data do not support the hypothesis about IFNL4-specific non-canonical signaling and point out that functional studies conducted with tagged interferons should be interpreted with caution. Full article
(This article belongs to the Special Issue Pathophysiology of Chronic Liver Disease Development)
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14 pages, 2274 KiB  
Article
IL-18 But Not IL-1 Signaling Is Pivotal for the Initiation of Liver Injury in Murine Non-Alcoholic Fatty Liver Disease
by Simon Hohenester, Veronika Kanitz, Tobias Schiergens, Claudia Einer, Jutta Nagel, Ralf Wimmer, Florian P. Reiter, Alexander L. Gerbes, Enrico N. De Toni, Christian Bauer, Lesca Holdt, Doris Mayr, Christian Rust, Max Schnurr, Hans Zischka, Andreas Geier and Gerald Denk
Int. J. Mol. Sci. 2020, 21(22), 8602; https://doi.org/10.3390/ijms21228602 - 14 Nov 2020
Cited by 16 | Viewed by 2962
Abstract
Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life “American lifestyle-induced obesity syndrome” (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r−/−- but not Il-1r−/− mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH. Full article
(This article belongs to the Special Issue Pathophysiology of Chronic Liver Disease Development)
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15 pages, 3755 KiB  
Article
miR-29a Modulates GSK3β/SIRT1-Linked Mitochondrial Proteostatic Stress to Ameliorate Mouse Non-Alcoholic Steatohepatitis
by Ya-Ling Yang, Pei-Wen Wang, Feng-Sheng Wang, Hung-Yu Lin and Ying-Hsien Huang
Int. J. Mol. Sci. 2020, 21(18), 6884; https://doi.org/10.3390/ijms21186884 - 19 Sep 2020
Cited by 27 | Viewed by 3243
Abstract
MicroRNA-29a (miR-29a) has been shown to ameliorate hepatocellular damage, such as in the context of non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), and cholestatic injury. However, the mechanism mediating the hepatoprotective effect of miR-29a in diet-induced NASH remains elusive. In the present study, [...] Read more.
MicroRNA-29a (miR-29a) has been shown to ameliorate hepatocellular damage, such as in the context of non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), and cholestatic injury. However, the mechanism mediating the hepatoprotective effect of miR-29a in diet-induced NASH remains elusive. In the present study, C57BL/6 mice of wild-type (WT) or miR-29a overexpression were fed with methionine–choline sufficient (MCS) or methionine–choline-deficient (MCD) diet for four weeks. The C57BL/6 mice harboring miR-29a overexpression presented reduced plasma AST, hepatic CD36, steatosis, and fibrosis induced by MCD. The TargetScan Release7.2-based bioinformatic analysis, KEGG pathway analysis, and luciferase reporter assay confirmed that miR-29a targets 3′UTR of glycogen synthase kinase 3 beta (Gsk3b) mRNA in the HepG2 hepatocyte cell line. Furthermore, miR-29a overexpression in the MCD-fed group resulted in inhibition of Gsk3b mRNA and GSK3β protein levels in the liver. GSK3β was notably expressed jointly with the extent of aggregated protein, which was then identified to be associated with mitochondrial unfolded protein response (UPRmt), but not with endoplasmic reticulum UPR (UPRER). Additionally, in silico analysis of protein–protein interaction, in vivo, and in vitro correlation analyses of protein expression demonstrated that GSK3β closely associated with sirtuin 1(SIRT1). Finally, the implication of SIRT1-mediated mitochondrial biogenesis in the perturbation of proteostasis was observed. We herein provide novel insight into a hepatoprotective pathway, whereby miR-29a inhibits GSK3β to repress SIRT1-mediated mitochondrial biogenesis, leading to alleviation of mitochondrial proteostatic stress and UPRmt in the context of NASH. miR-29a, GSK3β, and SIRT1 could thus serve as possible therapeutic targets to improve the treatment of NAFLD/NASH. Full article
(This article belongs to the Special Issue Pathophysiology of Chronic Liver Disease Development)
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Review

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21 pages, 736 KiB  
Review
Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA
by Tomoko Tadokoro, Asahiro Morishita and Tsutomu Masaki
Int. J. Mol. Sci. 2021, 22(15), 8139; https://doi.org/10.3390/ijms22158139 - 29 Jul 2021
Cited by 39 | Viewed by 5195
Abstract
Remarkable progress has been made in the treatment and control of hepatitis B and C viral infections. However, fundamental treatments for diseases in which liver fibrosis is a key factor, such as cirrhosis, alcoholic/nonalcoholic steatohepatitis, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing [...] Read more.
Remarkable progress has been made in the treatment and control of hepatitis B and C viral infections. However, fundamental treatments for diseases in which liver fibrosis is a key factor, such as cirrhosis, alcoholic/nonalcoholic steatohepatitis, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, are still under development and remain an unmet medical need. To solve this problem, it is essential to elucidate the pathogenesis of liver fibrosis in detail from a molecular and cellular perspective and to develop targeted therapeutic agents based on this information. Recently, microRNAs (miRNAs), functional RNAs of 22 nucleotides, have been shown to be involved in the pathogenesis of liver fibrosis. In addition, extracellular vesicles called “exosomes” have been attracting attention, and research is being conducted to establish noninvasive and extremely sensitive biomarkers using miRNAs in exosomes. In this review, we summarize miRNAs directly involved in liver fibrosis, miRNAs associated with diseases leading to liver fibrosis, and miRNAs related to complications of cirrhosis. We will also discuss the efficacy of each miRNA as a biomarker of liver fibrosis and pathology, and its potential application as a therapeutic agent. Full article
(This article belongs to the Special Issue Pathophysiology of Chronic Liver Disease Development)
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27 pages, 344 KiB  
Review
Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives
by Szu-Yi Liu, I-Ting Tsai and Yin-Chou Hsu
Int. J. Mol. Sci. 2021, 22(10), 5170; https://doi.org/10.3390/ijms22105170 - 13 May 2021
Cited by 53 | Viewed by 7209
Abstract
Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount [...] Read more.
Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount and duration of alcohol usage; however, it is also influenced by genetic, epigenetic, and environmental factors. The definite diagnosis of ALD is based on a liver biopsy, although several non-invasive diagnostic tools and serum biomarkers have emerging roles in the early detection of ALD. While alcohol abstinence and nutritional support remain the cornerstone of ALD treatment, growing evidence has revealed that the therapeutic agents that target oxidative stress or gut-liver axis, inflammatory response inhibition, and liver regeneration enhancement also play a role in ALD management. Furthermore, microRNAs modulation and mesenchymal stem cell-based therapy have emerging potential as ALD therapeutic options. This review summarizes the updated understanding of the pathophysiology, diagnosis, and novel therapeutic approaches for ALD. Full article
(This article belongs to the Special Issue Pathophysiology of Chronic Liver Disease Development)
17 pages, 1122 KiB  
Review
From Liver Cirrhosis to Cancer: The Role of Micro-RNAs in Hepatocarcinogenesis
by Raphael Mohr, Burcin Özdirik, Joeri Lambrecht, Münevver Demir, Johannes Eschrich, Lukas Geisler, Teresa Hellberg, Sven H. Loosen, Tom Luedde, Frank Tacke, Linda Hammerich and Christoph Roderburg
Int. J. Mol. Sci. 2021, 22(3), 1492; https://doi.org/10.3390/ijms22031492 - 02 Feb 2021
Cited by 17 | Viewed by 5078
Abstract
In almost all cases, hepatocellular carcinoma (HCC) develops as the endpoint of a sequence that starts with chronic liver injury, progresses to liver cirrhosis, and finally, over years and decades, results in liver cancer. Recently, the role of non-coding RNA such as microRNA [...] Read more.
In almost all cases, hepatocellular carcinoma (HCC) develops as the endpoint of a sequence that starts with chronic liver injury, progresses to liver cirrhosis, and finally, over years and decades, results in liver cancer. Recently, the role of non-coding RNA such as microRNA (miRNA) has been demonstrated in the context of chronic liver diseases and HCC. Moreover, data from a phase II trial suggested a potential role of microRNAs as therapeutics in hepatitis-C-virus infection, representing a significant risk factor for development of liver cirrhosis and HCC. Despite progress in the clinical management of chronic liver diseases, pharmacological treatment options for patients with liver cirrhosis and/or advanced HCC are still limited. With their potential to regulate whole networks of genes, miRNA might be used as novel therapeutics in these patients but could also serve as biomarkers for improved patient stratification. In this review, we discuss available data on the role of miRNA in the transition from liver cirrhosis to HCC. We highlight opportunities for clinical translation and discuss open issues applicable to future developments. Full article
(This article belongs to the Special Issue Pathophysiology of Chronic Liver Disease Development)
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