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Cellular and Molecular Mechanisms Governing Liver Pathophysiology

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

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 43997

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Dr. Jérôme Eeckhoute

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INSERM U1011, Faculté de Médecine de Lille-Pôle Recherche, Université de Lille, Boulevard du Professeur Leclerc, Bâtiment J&K, CEDEX, 59045 Lille, France
Interests: functional genomics; transcriptional regulation; regulatory elements; transcriptomics; cell identity; liver pathophysiology
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Dear Colleagues,

Liver functions are finely tuned by environmental stimuli, which translate into adaptative cellular behaviors partly through modulation of their transcriptome. While these mechanisms have historically been studied in detailed in hepatocytes, current efforts also aim to better define how the activities of additional liver cell-types are controlled. Indeed, cells of the non-parenchymal fraction and their inter-cellular cross-talks with hepatocytes are increasingly being defined as central components in healthy and injured liver. In this context, liver physiological activities, regenerative capacity, and alterations in acute or chronic conditions are driven by coordinated molecular changes in the different liver cell-types. These mechanisms are now investigated at (multi-)omics levels, allowing us to obtain novel insights into the molecular control of liver cells’ activities.

The purpose of this Special Issue is to highlight recent findings that shed light on how the functions of hepatocytes and non-parenchymal cells are controlled at the molecular level to trigger adaptative or maladaptive responses in liver pathophysiology. We welcome the submission of both original research articles and reviews.

Dr. Jérôme Eeckhoute
Guest Editor

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Keywords

functional genomics
transcriptional regulation
cell identity
cell plasticity
single-cell omics
cellular dialogues
hepatocytes
non-parenchymal cells
liver pathophysiology

Related Special Issue

Novel Advances in Cellular and Molecular Mechanisms Governing Liver Pathophysiology in Cells (1 article)

Published Papers (10 papers)

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Research

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19 pages, 3469 KiB

Open AccessArticle

Reinfection of Transplanted Livers in HCV- and HCV/HIV-Infected Patients Is Characterized by a Different MicroRNA Expression Profile

by Emiliano Dalla, Michela Bulfoni, Daniela Cesselli, Riccardo Pravisani, Masaaki Hidaka, Susumu Eguchi and Umberto Baccarani

Cells 2022, 11(4), 690; https://doi.org/10.3390/cells11040690 - 16 Feb 2022

Cited by 4 | Viewed by 2058

Abstract

Background: After liver transplantation, HCV/HIV co-infected patients present, compared to the HCV mono-infected ones, increased HCV viral load, rapid progression to liver fibrosis and higher mortality. Liver biopsies (LB), obtained routinely 6 months after transplantation, represent a unique model to assess the early events related to graft re-infection. Here, we used miRNA sequencing of LB obtained from both HCV-and HCV/HIV-infected recipients, to identify transcriptional profiles able to explain the more severe outcome of these latter. Methods: miRNAs of 3 healthy livers, 3 HCV-LB and 3 HCV/HIV-LB were sequenced by Illumina HiSeq2500 platform. The DIANA-miRPath v3.0 webserver and DIANA-microT-CDS algorithm (v5.0) were used to characterize the functions of differentially expressed (DE-) miRNAs, querying the KEGG and Gene Ontology-Biological Process databases. Results: LB obtained from infected patients were characterized, with respect to controls, by a miRNA profile related to viral infection, immune system signaling and DNA damage in HCV-induced carcinogenesis. Instead, HCV-LB and HCV/HIV-LB differed in the expression of miRNAs involved in immunological and apoptotic processes and in extracellular matrix remodeling. Conclusions: liver reinfection processes are associated with early miRNA changes. Further studies are necessary to establish their prognostic role and possible actionability. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Governing Liver Pathophysiology)

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13 pages, 2404 KiB

Open AccessArticle

Steatosis Alters the Activity of Hepatocyte Membrane Transporters in Obese Rats

by Catherine M. Pastor and Valérie Vilgrain

Cells 2021, 10(10), 2733; https://doi.org/10.3390/cells10102733 - 13 Oct 2021

Cited by 4 | Viewed by 1594

Abstract

Fat accumulation (steatosis) in ballooned hepatocytes alters the expression of membrane transporters in Zucker fatty (fa/fa) rats. The aim of the study was to quantify the functions of these transporters and their impact on hepatocyte concentrations using a clinical hepatobiliary contrast agent (Gadobenate dimeglumine, BOPTA) for liver imaging. In isolated and perfused rat livers, we quantified BOPTA accumulation and decay profiles in fa/+ (normal) and fa/fa hepatocytes by placing a gamma counter over livers. Profiles of BOPTA accumulation and decay in hepatocytes were analysed with nonlinear regressions to characterise BOPTA influx and efflux across hepatocyte transporters. At the end of the accumulation period, BOPTA hepatocyte concentrations and influx clearances were not significantly different in fa/+ and fa/fa livers. In contrast, bile clearance was significantly lower in fatty hepatocytes while efflux clearance back to sinusoids compensated the low efflux into canaliculi. The time when BOPTA cellular efflux impacts the accumulation profile of hepatocyte concentrations was slightly delayed (2 min) by steatosis, anticipating a delayed emptying of hepatocytes. The experimental model is useful for quantifying the functions of hepatocyte transporters in liver diseases. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Governing Liver Pathophysiology)

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18 pages, 14777 KiB

Open AccessArticle

Impaired Bile Acid Metabolism and Gut Dysbiosis in Mice Lacking Lysosomal Acid Lipase

by Vinay Sachdev, Madalina Duta-Mare, Melanie Korbelius, Nemanja Vujić, Christina Leopold, Jan Freark de Boer, Silvia Rainer, Peter Fickert, Dagmar Kolb, Folkert Kuipers, Branislav Radovic, Gregor Gorkiewicz and Dagmar Kratky

Cells 2021, 10(10), 2619; https://doi.org/10.3390/cells10102619 - 01 Oct 2021

Cited by 8 | Viewed by 2787

Abstract

Lysosomal acid lipase (LAL) is the sole enzyme known to be responsible for the hydrolysis of cholesteryl esters and triglycerides at an acidic pH in lysosomes, resulting in the release of unesterified cholesterol and free fatty acids. However, the role of LAL in diet-induced adaptations is largely unexplored. In this study, we demonstrate that feeding a Western-type diet to Lal-deficient (LAL-KO) mice triggers metabolic reprogramming that modulates gut-liver cholesterol homeostasis. Induction of ileal fibroblast growth factor 15 (three-fold), absence of hepatic cholesterol 7α-hydroxylase expression, and activation of the ERK phosphorylation cascade results in altered bile acid composition, substantial changes in the gut microbiome, reduced nutrient absorption by 40%, and two-fold increased fecal lipid excretion in LAL-KO mice. These metabolic adaptations lead to impaired bile acid synthesis, lipoprotein uptake, and cholesterol absorption and ultimately to the resistance of LAL-KO mice to diet-induced obesity. Our results indicate that LAL-derived lipolytic products might be important metabolic effectors in the maintenance of whole-body lipid homeostasis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Governing Liver Pathophysiology)

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15 pages, 2041 KiB

Open AccessArticle

Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis

by Biljana Atanasovska, Sander S. Rensen, Glenn Marsman, Ronit Shiri-Sverdlov, Sebo Withoff, Folkert Kuipers, Cisca Wijmenga, Bart van de Sluis and Jingyuan Fu

Cells 2021, 10(8), 1883; https://doi.org/10.3390/cells10081883 - 25 Jul 2021

Cited by 12 | Viewed by 3500

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is characterized by different stages varying from benign fat accumulation to non-alcoholic steatohepatitis (NASH) that may progress to cirrhosis and liver cancer. In recent years, a regulatory role of long non-coding RNAs (lncRNAs) in NAFLD has emerged. Therefore, we aimed to characterize the still poorly understood lncRNA contribution to disease progression. Transcriptome analysis in 60 human liver samples with various degrees of NAFLD/NASH was combined with a functional genomics experiment in an in vitro model where we exposed HepG2 cells to free fatty acids (FFA) to induce steatosis, then stimulated them with tumor necrosis factor alpha (TNFα) to mimic inflammation. Bioinformatics analyses provided a functional prediction of novel lncRNAs. We further functionally characterized the involvement of one novel lncRNA in the nuclear-factor-kappa B (NF-κB) signaling pathway by its silencing in Hepatoma G2 (HepG2) cells. We identified 730 protein-coding genes and 18 lncRNAs that responded to FFA/TNFα and associated with human NASH phenotypes with consistent effect direction, with most being linked to inflammation. One novel intergenic lncRNA, designated lncTNF, was 20-fold up-regulated upon TNFα stimulation in HepG2 cells and positively correlated with lobular inflammation in human liver samples. Silencing lncTNF in HepG2 cells reduced NF-κB activity and suppressed expression of the NF-κB target genes A20 and NFKBIA. The lncTNF we identified in the NF-κB signaling pathway may represent a novel target for controlling liver inflammation. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Governing Liver Pathophysiology)

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13 pages, 5028 KiB

Open AccessArticle

Hepatic Failure in COVID-19: Is Iron Overload the Dangerous Trigger?

by Franca Del Nonno, Roberta Nardacci, Daniele Colombo, Ubaldo Visco-Comandini, Stefania Cicalini, Andrea Antinori, Luisa Marchioni, Gianpiero D’Offizi, Mauro Piacentini and Laura Falasca

Cells 2021, 10(5), 1103; https://doi.org/10.3390/cells10051103 - 04 May 2021

Cited by 15 | Viewed by 9224

Abstract

Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Governing Liver Pathophysiology)

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Review

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22 pages, 2252 KiB

Open AccessReview

The Role of Catecholamines in Pathophysiological Liver Processes

by Elise Lelou, Anne Corlu, Nicolas Nesseler, Claudine Rauch, Yannick Mallédant, Philippe Seguin and Caroline Aninat

Cells 2022, 11(6), 1021; https://doi.org/10.3390/cells11061021 - 17 Mar 2022

Cited by 14 | Viewed by 5228

Abstract

Over the last few years, the number of research publications about the role of catecholamines (epinephrine, norepinephrine, and dopamine) in the development of liver diseases such as liver fibrosis, fatty liver diseases, or liver cancers is constantly increasing. However, the mechanisms involved in these effects are not well understood. In this review, we first recapitulate the way the liver is in contact with catecholamines and consider liver implications in their metabolism. A focus on the expression of the adrenergic and dopaminergic receptors by the liver cells is also discussed. Involvement of catecholamines in physiological (glucose metabolism, lipids metabolism, and liver regeneration) and pathophysiological (impact on drug-metabolizing enzymes expression, liver dysfunction during sepsis, fibrosis development, or liver fatty diseases and liver cancers) processes are then discussed. This review highlights the importance of understanding the mechanisms through which catecholamines influence liver functions in order to draw benefit from the adrenergic and dopaminergic antagonists currently marketed. Indeed, as these molecules are well-known drugs, their use as therapies or adjuvant treatments in several liver diseases could be facilitated. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Governing Liver Pathophysiology)

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18 pages, 1528 KiB

Open AccessFeature PaperReview

Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD

by Trine V. Dam, Nicolaj I. Toft and Lars Grøntved

Cells 2022, 11(5), 870; https://doi.org/10.3390/cells11050870 - 03 Mar 2022

Cited by 1 | Viewed by 3785

Abstract

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly, and unmet treatment can result in the development of hepatitis, fibrosis, and liver failure. There are difficulties involved in diagnosing NAFLD early and for this reason there are challenges involved in its treatment. Furthermore, no drugs are currently approved to alleviate complications, a fact which highlights the need for further insight into disease mechanisms. NAFLD pathogenesis is associated with complex cellular changes, including hepatocyte steatosis, immune cell infiltration, endothelial dysfunction, hepatic stellate cell activation, and epithelial ductular reaction. Many of these cellular changes are controlled by dramatic changes in gene expression orchestrated by the cis-regulatory genome and associated transcription factors. Thus, to understand disease mechanisms, we need extensive insights into the gene regulatory mechanisms associated with tissue remodeling. Mapping cis-regulatory regions genome-wide is a step towards this objective and several current and emerging technologies allow detection of accessible chromatin and specific histone modifications in enriched cell populations of the liver, as well as in single cells. Here, we discuss recent insights into the cis-regulatory genome in NAFLD both at the organ-level and in specific cell populations of the liver. Moreover, we highlight emerging technologies that enable single-cell resolved analysis of the cis-regulatory genome of the liver. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Governing Liver Pathophysiology)

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44 pages, 4935 KiB

Open AccessFeature PaperReview

Beyond the X Factor: Relevance of Sex Hormones in NAFLD Pathophysiology

by Sara Della Torre

Cells 2021, 10(9), 2502; https://doi.org/10.3390/cells10092502 - 21 Sep 2021

Cited by 30 | Viewed by 4009

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, being frequently associated with obesity, unbalanced dietary regimens, and reduced physical activity. Despite their greater adiposity and reduced physical activity, women show a lower risk of developing NAFLD in comparison to men, likely a consequence of a sex-specific regulation of liver metabolism. In the liver, sex differences in the uptake, synthesis, oxidation, deposition, and mobilization of lipids, as well as in the regulation of inflammation, are associated with differences in NAFLD prevalence and progression between men and women. Given the major role of sex hormones in driving hepatic sexual dimorphism, this review will focus on the role of sex hormones and their signaling in the regulation of hepatic metabolism and in the molecular mechanisms triggering NAFLD development and progression. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Governing Liver Pathophysiology)

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20 pages, 1300 KiB

Open AccessReview

Hepatitis E Virus Infection—Immune Responses to an Underestimated Global Threat

by Paul Kupke and Jens M. Werner

Cells 2021, 10(9), 2281; https://doi.org/10.3390/cells10092281 - 02 Sep 2021

Cited by 12 | Viewed by 3644

Abstract

Infection with the hepatitis E virus (HEV) is one of the main ubiquitous causes for developing an acute hepatitis. Moreover, chronification plays a predominant role in immunocompromised patients such as transplant recipients with more frequent severe courses. Unfortunately, besides reduction of immunosuppression and off-label use of ribavirin or pegylated interferon alfa, there is currently no specific anti-viral treatment to prevent disease progression. So far, research on involved immune mechanisms induced by HEV is limited. It is very difficult to collect clinical samples especially from the early phase of infection since this is often asymptomatic. Nevertheless, it is certain that the outcome of HEV-infected patients correlates with the strength of the proceeding immune response. Several lymphoid cells have been identified in contributing either to disease progression or achieving sustained virologic response. In particular, a sufficient immune control by both CD4⁺ and CD8⁺ T cells is necessary to prevent chronic viral replication. Especially the mechanisms underlying fulminant courses are poorly understood. However, liver biopsies indicate the involvement of cytotoxic T cells in liver damage. In this review, we aimed to highlight different parts of the lymphoid immune response against HEV and point out questions that remain unanswered regarding this underestimated global threat. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Governing Liver Pathophysiology)

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20 pages, 1480 KiB

Open AccessReview

Transcription Control of Liver Development

by Evangelia C. Tachmatzidi, Ourania Galanopoulou and Iannis Talianidis

Cells 2021, 10(8), 2026; https://doi.org/10.3390/cells10082026 - 08 Aug 2021

Cited by 17 | Viewed by 6571

Abstract

During liver organogenesis, cellular transcriptional profiles are constantly reshaped by the action of hepatic transcriptional regulators, including FoxA1-3, GATA4/6, HNF1α/β, HNF4α, HNF6, OC-2, C/EBPα/β, Hex, and Prox1. These factors are crucial for the activation of hepatic genes that, in the context of compact chromatin, cannot access their targets. The initial opening of highly condensed chromatin is executed by a special class of transcription factors known as pioneer factors. They bind and destabilize highly condensed chromatin and facilitate access to other “non-pioneer” factors. The association of target genes with pioneer and non-pioneer transcription factors takes place long before gene activation. In this way, the underlying gene regulatory regions are marked for future activation. The process is called “bookmarking”, which confers transcriptional competence on target genes. Developmental bookmarking is accompanied by a dynamic maturation process, which prepares the genomic loci for stable and efficient transcription. Stable hepatic expression profiles are maintained during development and adulthood by the constant availability of the main regulators. This is achieved by a self-sustaining regulatory network that is established by complex cross-regulatory interactions between the major regulators. This network gradually grows during liver development and provides an epigenetic memory mechanism for safeguarding the optimal expression of the regulators. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Governing Liver Pathophysiology)

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