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Genetic and Molecular Mechanisms of Liver Disease

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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 September 2022) | Viewed by 17589

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Special Issue Editors

Dr. Rosellina Mancina

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Guest Editor

Department of Molecular and Clinical Medicine, Göteborgs Universitet, 413 45 Gothenburg, Sweden
Interests: human genetics; molecular biology; liver disease; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); liver cancer; inflammatory bowel diseases (IBD); familial hypercholesterolemia (FH)

Dr. Rocco Spagnuolo

E-Mail Website
Guest Editor

Experimental and Clinical Medicine Department, Magna Graecia University, 88100 Catanzaro, Italy
Interests: inflammatory bowel disease; non alcoholic fatty liver disease; patient reported outcomes; anti-TF-alpha therapy; liver disease; irritable bowel syndrome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Liver disease is a cause of high morbidity and global mortality. It is a complex trait, such that the disease phenotype and its progression are driven by the interactions between environment and genetic background. Despite the different etiologies of liver diseases, ranging from obesity, metabolic disorders, and viral infection to alcohol abuse and cancer, the molecular mechanisms behind the disease onset inexorably lead to the activation of inflammatory mechanisms, leading to fibrosis and liver failure.

Many genome-wide and single-nucleotide association studies have shown that there is a strong genetic component in liver disease onset and progression. However, despite the number of genetic determinants of liver disease identified so far, there is still a missing heritability.

Moreover, although great efforts have been devoted to identifying the molecular mechanisms behind liver disease, a full understanding of these mechanisms is still far from being reached. Many alternatives have been proposed so far, including a role of lipid and phospholipid metabolism, epigenetic modifications, and of gut microbiota alterations.

The complexity and diversity of mechanisms behind liver disease may explain why standard treatments against liver disease are not working so far, highlighting the need to implement precision medicine in this field with tailored treatments based on the specific causative mechanism/gene.

We invite scientists to contribute to this Special Issue both with original research and review articles, with the aim to provide an overview of the currently available knowledge, and of new evidence/findings on the genetic and molecular mechanisms of liver disease.

Dr. Rosellina Mancina
Dr. Rocco Spagnuolo
Guest Editors

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

liver disease
genetic
molecular mechanism
non-alcoholic fatty liver disease (NAFLD)
non-alcoholic Steatohepatitis (NASH)
hepatocellular carcinoma (HCC)
viral hepatitis
liver fibrosis
liver inflammation
alcoholic liver disease (ALD)

Published Papers (5 papers)

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Research

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18 pages, 3793 KiB

Open AccessArticle

Laparoscopic Sleeve Gastrectomy in Patients with Severe Obesity Restores Adaptive Responses Leading to Nonalcoholic Steatohepatitis

by Noemí Cabré, Fedra Luciano-Mateo, Douglas J. Chapski, Gerard Baiges-Gaya, Salvador Fernández-Arroyo, Anna Hernández-Aguilera, Helena Castañé, Elisabet Rodríguez-Tomàs, Marta París, Fàtima Sabench, Daniel Del Castillo, Josep M. del Bas, Mercedes Tomé, Clément Bodineau, Alejandro Sola-García, José López-Miranda, Alejandro Martín-Montalvo, Raúl V. Durán, Thomas M. Vondriska, Manuel Rosa-Garrido, Jordi Camps, Javier A. Menéndez and Jorge Joven Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(14), 7830; https://doi.org/10.3390/ijms23147830 - 15 Jul 2022

Cited by 4 | Viewed by 2092

Abstract

The surgically induced remission of liver disease represents a model to investigate the signalling processes that trigger the development of nonalcoholic steatohepatitis with the aim of identifying novel therapeutic targets. We recruited patients with severe obesity with or without nonalcoholic steatohepatitis and obtained liver and plasma samples before and after laparoscopic sleeve gastrectomy for immunoblotting, immunocytochemical, metabolomic, transcriptomic and epigenetic analyses. Functional studies were performed in HepG2 cells and primary hepatocytes. Surgery was associated with a decrease in the inflammatory response and revealed the role of mitogen-activated protein kinases. Nonalcoholic steatohepatitis was associated with an increased glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy and affected methylation-related epigenomic remodelling enzymes. Hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis. Our results suggest that the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation play a crucial role in the inefficient adaptive responses leading to steatohepatitis in obesity. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Liver Disease)

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Review

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17 pages, 678 KiB

Open AccessReview

Cell Autophagy in NASH and NASH-Related Hepatocellular Carcinoma

by Utibe-Abasi S. Udoh, Pradeep Kumar Rajan, Yuto Nakafuku, Robert Finley and Juan Ramon Sanabria

Int. J. Mol. Sci. 2022, 23(14), 7734; https://doi.org/10.3390/ijms23147734 - 13 Jul 2022

Cited by 17 | Viewed by 3175

Abstract

Autophagy, a cellular self-digestion process, involves the degradation of targeted cell components such as damaged organelles, unfolded proteins, and intracellular pathogens by lysosomes. It is a major quality control system of the cell and plays an important role in cell differentiation, survival, development, and homeostasis. Alterations in the cell autophagic machinery have been implicated in several disease conditions, including neurodegeneration, autoimmunity, cancer, infection, inflammatory diseases, and aging. In non-alcoholic fatty liver disease, including its inflammatory form, non-alcoholic steatohepatitis (NASH), a decrease in cell autophagic activity, has been implicated in the initial development and progression of steatosis to NASH and hepatocellular carcinoma (HCC). We present an overview of autophagy as it occurs in mammalian cells with an insight into the emerging understanding of the role of autophagy in NASH and NASH-related HCC. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Liver Disease)

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17 pages, 745 KiB

Open AccessReview

The Role of Epigenetics in Primary Biliary Cholangitis

by Alessio Gerussi, Elvezia Maria Paraboschi, Claudio Cappadona, Chiara Caime, Eleonora Binatti, Laura Cristoferi, Rosanna Asselta and Pietro Invernizzi

Int. J. Mol. Sci. 2022, 23(9), 4873; https://doi.org/10.3390/ijms23094873 - 28 Apr 2022

Cited by 12 | Viewed by 2963

Abstract

Primary Biliary Cholangitis (PBC) is a rare autoimmune disease of the liver, affecting mostly females. There is evidence that epigenetic changes have a pathogenic role in PBC. Epigenetic modifications are related to methylation of CpG DNA islands, post-translational modifications of histone proteins, and non-coding RNAs. In PBC, there are data showing a dysregulation of all these levels, especially in immune cells. In addition, epigenetics seems to be involved in complex phenomena such as X monosomy or abnormalities in the process of X chromosome inactivation, which have been reported in PBC and appear to influence its sex imbalance and pathogenesis. We review here historical data on epigenetic modifications in PBC, present new data, and discuss possible links among X-chromosome abnormalities at a genetic and epigenetic level, PBC pathogenesis, and PBC sex imbalance. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Liver Disease)

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23 pages, 4318 KiB

Open AccessReview

Phytomedicines to Target Hepatitis B Virus DNA Replication: Current Limitations and Future Approaches

by Rahila Zannat Sadiea, Shahnaj Sultana, Bijan Mohon Chaki, Tasnim Islam, Sharmy Dash, Sharmin Akter, Md Sayeedul Islam, Taheruzzaman Kazi, Abir Nagata, Rocco Spagnuolo, Rosellina Margherita Mancina and Md Golzar Hossain

Int. J. Mol. Sci. 2022, 23(3), 1617; https://doi.org/10.3390/ijms23031617 - 30 Jan 2022

Cited by 2 | Viewed by 3320

Abstract

Hepatitis B virus infection (HBV) is one of the most common causes of hepatitis, and may lead to cirrhosis or hepatocellular carcinoma. According to the World Health Organization (WHO), approximately 296 million people worldwide are carriers of the hepatitis B virus. Various nucleos(t)ide analogs, which specifically suppress viral replication, are the main treatment agents for HBV infection. However, the development of drug-resistant HBV strains due to viral genomic mutations in genes encoding the polymerase protein is a major obstacle to HBV treatment. In addition, adverse effects can occur in patients treated with nucleos(t)ide analogs. Thus, alternative anti-HBV drugs of plant origin are being investigated as they exhibit excellent safety profiles and have few or no side effects. In this study, phytomedicines/phytochemicals exerting significant inhibitory effects on HBV by interfering with its replication were reviewed based on different compound groups. In addition, the chemical structures of these compounds were developed. This will facilitate their commercial synthesis and further investigation of the molecular mechanisms underlying their effects. The limitations of compounds previously screened for their anti-HBV effect, as well as future approaches to anti-HBV research, have also been discussed. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Liver Disease)

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28 pages, 35093 KiB

Open AccessReview

Non-Alcoholic Steatohepatitis (NASH) and Organokines: What Is Now and What Will Be in the Future

by João Paulo Margiotti dos Santos, Mariana Canevari de Maio, Monike Alves Lemes, Lucas Fornari Laurindo, Jesselina Francisco dos Santos Haber, Marcelo Dib Bechara, Pedro Sidnei do Prado, Jr., Eduardo Costa Rauen, Fernando Costa, Barbara Cristina de Abreu Pereira, Uri Adrian Prync Flato, Ricardo de Alvares Goulart, Eduardo Federighi Baisi Chagas and Sandra Maria Barbalho

Int. J. Mol. Sci. 2022, 23(1), 498; https://doi.org/10.3390/ijms23010498 - 2 Jan 2022

Cited by 25 | Viewed by 5065

Abstract

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, and enlargement of the diameter of hepatocytes (ballooning hepatocytes), with or without fibrosis. It affects 20% of patients with non-alcoholic fatty liver disease (NAFLD). Due to liver dysfunction and the numerous metabolic changes that commonly accompany the condition (obesity, insulin resistance, type 2 diabetes, and metabolic syndrome), the secretion of organokines is modified, which may contribute to the pathogenesis or progression of the disease. In this sense, this study aimed to perform a review of the role of organokines in NASH. Thus, by combining descriptors such as NASH, organokines, oxidative stress, inflammation, insulin resistance, and dyslipidemia, a search was carried out in the EMBASE, MEDLINE-PubMed, and Cochrane databases of articles published in the last ten years. Insulin resistance, inflammation and mitochondrial dysfunction, fructose, and intestinal microbiota were factors identified as participating in the genesis and progression of NASH. Changes in the pattern of organokines secretion (adipokines, myokines, hepatokines, and osteokines) directly or indirectly contribute to aggravating the condition or compromise homeostasis. Thus, further studies involving skeletal muscle, adipose, bone, and liver tissue as endocrine organs are essential to better understand the modulation of organokines involved in the pathogenesis of NASH to advance in the treatment of this disease. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Liver Disease)

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