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New Aspects and Mechanisms in Liver Diseases

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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 (31 August 2021) | Viewed by 57354

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Dr. Heather Francis

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Indiana Center for Liver Research, Division of Gastroenterology & Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Interests: cholangiopathies; fibrosis; mast cells; cholangiocytes; ductular reaction; cholangiocarcinoma; inflammation

Special Issue Information

Dear Colleagues,

Liver diseases are complex in nature and hepatic injury can target specific cells or a multitude of hepatic cell types. Due to the complexity of the liver and the limits to understanding the mechanistic pathways during liver damage, in this Special Issue of Cells, we aim to highlight important therapeutic and bench studies targeting novel mechanisms and signaling pathways in hepatic injury. Articles that focus on specific liver diseases, including, but not limited to, cholangiopathies, liver cancer, non-alcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) and alcoholic liver disease/alcoholic steatohepatitis (ALD/ASH) will be welcome. Liver disease is rapidly becoming a worldwide pathology and the number of liver transplantations has increased over the last decade. Furthermore, we welcome articles that describe current model systems including animal studies, in vitro techniques, organoid or spheroid models and xenograft/xenotranslplantation models. While we recognize that human studies are paramount, these modeling systems are necessary to fully understand the complexity of liver disease. This Special Issue will be dedicated to studies focused on new targets for therapeutic interventions and understanding the mechanical cues that regulate both hepatic damage and homeostasis. Contributions should include potential or proven mechanistic pathways demonstrated to play a key role during hepatic injury. We welcome both review articles and original manuscripts that embrace novelty and potential clinical relevance.

Prof. Heather Francis
Guest Editor

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Keywords

cholangiopathies
liver cancer
fibrosis
senescence
ductular reaction
inflammation
bile acids
NAFLD/NASH
ALD/ASH
liver regeneration
transplantation/xenotransplantation
model systems

Published Papers (12 papers)

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Research

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21 pages, 42843 KiB

Open AccessArticle

The Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling

by Romina Mancinelli, Ludovica Ceci, Lindsey Kennedy, Heather Francis, Vik Meadows, Lixian Chen, Guido Carpino, Konstantina Kyritsi, Nan Wu, Tianhao Zhou, Keisaku Sato, Luigi Pannarale, Shannon Glaser, Sanjukta Chakraborty, Gianfranco Alpini, Eugenio Gaudio, Paolo Onori and Antonio Franchitto

Cells 2022, 11(9), 1591; https://doi.org/10.3390/cells11091591 - 09 May 2022

Cited by 6 | Viewed by 2759

Abstract

Background & aims: Cholangiocytes are the target cells of liver diseases that are characterized by biliary senescence (evidenced by enhanced levels of senescence-associated secretory phenotype, SASP, e.g., TGF-β1), and liver inflammation and fibrosis accompanied by altered bile acid (BA) homeostasis. Taurocholic acid (TC) stimulates biliary hyperplasia by activation of 3′,5′-cyclic cyclic adenosine monophosphate (cAMP) signaling, thereby preventing biliary damage (caused by cholinergic/adrenergic denervation) through enhanced liver angiogenesis. Also: (i) α-calcitonin gene-related peptide (α-CGRP, which activates the calcitonin receptor-like receptor, CRLR), stimulates biliary proliferation/senescence and liver fibrosis by enhanced biliary secretion of SASPs; and (ii) knock-out of α-CGRP reduces these phenotypes by decreased cAMP levels in cholestatic models. We aimed to demonstrate that TC effects on liver phenotypes are dependent on changes in the α-CGRP/CALCRL/cAMP/PKA/ERK1/2/TGF-β1/VEGF axis. Methods: Wild-type and α-CGRP^−/− mice were fed with a control (BAC) or TC diet for 1 or 2 wk. We measured: (i) CGRP levels by both ELISA kits in serum and by qPCR in isolated cholangiocytes (CALCA gene for α-CGRP); (ii) CALCRL immunoreactivity by immunohistochemistry (IHC) in liver sections; (iii) liver histology, intrahepatic biliary mass, biliary senescence (by β-GAL staining and double immunofluorescence (IF) for p16/CK19), and liver fibrosis (by Red Sirius staining and double IF for collagen/CK19 in liver sections), as well as by qPCR for senescence markers in isolated cholangiocytes; and (iv) phosphorylation of PKA/ERK1/2, immunoreactivity of TGF-β1/TGF- βRI and angiogenic factors by IHC/immunofluorescence in liver sections and qPCR in isolated cholangiocytes. We measured changes in BA composition in total liver by liquid chromatography/mass spectrometry. Results: TC feeding increased CALCA expression, biliary damage, and liver inflammation and fibrosis, as well as phenotypes that were associated with enhanced immunoreactivity of the PKA/ERK1/2/TGF-β1/TGF-βRI/VEGF axis compared to BAC-fed mice and phenotypes that were reversed in α-CGRP^−/− mice fed TC coupled with changes in hepatic BA composition. Conclusion: Modulation of the TC/ α-CGRP/CALCRL/PKA/ERK1/2/TGF-β1/VEGF axis may be important in the management of cholangiopathies characterized by BA accumulation. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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25 pages, 44134 KiB

Open AccessArticle

Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma

by Sukanya Roy, Subhashree Kumaravel, Priyanka Banerjee, Tori K. White, April O’Brien, Catherine Seelig, Rahul Chauhan, Burcin Ekser, Kayla J. Bayless, Gianfranco Alpini, Shannon S. Glaser and Sanjukta Chakraborty

Cells 2021, 10(11), 3093; https://doi.org/10.3390/cells10113093 - 09 Nov 2021

Cited by 13 | Viewed by 3310

Abstract

Cholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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17 pages, 3352 KiB

Open AccessArticle

Oxysterol 7-α Hydroxylase (CYP7B1) Attenuates Metabolic-Associated Fatty Liver Disease in Mice at Thermoneutrality

by Ioannis Evangelakos, Dorothee Schwinge, Anna Worthmann, Clara John, Niklas Roeder, Paul Pertzborn, Janina Behrens, Christoph Schramm, Ludger Scheja and Joerg Heeren

Cells 2021, 10(10), 2656; https://doi.org/10.3390/cells10102656 - 05 Oct 2021

Cited by 9 | Viewed by 3317

Abstract

Ambient temperature is an important determinant of both the alternative bile acid synthesis pathway controlled by oxysterol 7-α hydroxylase (CYP7B1) and the progression of metabolic-associated fatty liver disease (MAFLD). Here, we investigated whether CYP7B1 is involved in the etiology of MAFLD under conditions of low and high energy expenditure. For this, Cyp7b1^−/− and wild type (WT) mice were fed a choline-deficient high-fat diet and housed either at 30 °C (thermoneutrality) or at 22 °C (mild cold). To study disease phenotype and underlying mechanisms, plasma and organ samples were analyzed to determine metabolic parameters, immune cell infiltration by immunohistology and flow cytometry, lipid species including hydroxycholesterols, bile acids and structural lipids. In WT and Cyp7b1^−/− mice, thermoneutral housing promoted MAFLD, an effect that was more pronounced in CYP7B1-deficient mice. In these mice, we found higher plasma alanine aminotransferase activity, hyperlipidemia, hepatic accumulation of potentially harmful lipid species, aggravated liver fibrosis, increased inflammation and immune cell infiltration. Bile acids and hydroxycholesterols did not correlate with aggravated MAFLD in Cyp7b1^−/− mice housed at thermoneutrality. Notably, an up-regulation of lipoprotein receptors was detected at 22 °C but not at 30 °C in livers of Cyp7b1^−/− mice, suggesting that accelerated metabolism of lipoproteins carrying lipotoxic molecules counteracts MAFLD progression. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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18 pages, 3816 KiB

Open AccessFeature PaperArticle

Heterogeneity of Hepatic Stellate Cells in Fibrogenesis of the Liver: Insights from Single-Cell Transcriptomic Analysis in Liver Injury

by Wenjun Zhang, Simon J. Conway, Ying Liu, Paige Snider, Hanying Chen, Hongyu Gao, Yunlong Liu, Kadir Isidan, Kevin J. Lopez, Gonzalo Campana, Ping Li, Burcin Ekser, Heather Francis, Weinian Shou and Chandrashekhar Kubal

Cells 2021, 10(8), 2129; https://doi.org/10.3390/cells10082129 - 19 Aug 2021

Cited by 19 | Viewed by 5469

Abstract

Background & Aims: Liver fibrosis is a pathological healing process resulting from hepatic stellate cell (HSC) activation and the generation of myofibroblasts from activated HSCs. The precise underlying mechanisms of liver fibrogenesis are still largely vague due to lack of understanding the functional heterogeneity of activated HSCs during liver injury. Approach and Results: In this study, to define the mechanism of HSC activation, we performed the transcriptomic analysis at single-cell resolution (scRNA-seq) on HSCs in mice treated with carbon tetrachloride (CCl₄). By employing LRAT-Cre:Rosa26^mT/mG mice, we were able to isolate an activated GFP-positive HSC lineage derived cell population by fluorescence-activated cell sorter (FACS). A total of 8 HSC subpopulations were identified based on an unsupervised analysis. Each HSC cluster displayed a unique transcriptomic profile, despite all clusters expressing common mouse HSC marker genes. We demonstrated that one of the HSC subpopulations expressed high levels of mitosis regulatory genes, velocity, and monocle analysis indicated that these HSCs are at transitioning and proliferating phases at the beginning of HSCs activation and will eventually give rise to several other HSC subtypes. We also demonstrated cell clusters representing HSC-derived mature myofibroblast populations that express myofibroblasts hallmark genes with unique contractile properties. Most importantly, we found a novel HSC cluster that is likely to be critical in liver regeneration, immune reaction, and vascular remodeling, in which the unique profiles of genes such as Rgs5, Angptl6, and Meg3 are highly expressed. Lastly, we demonstrated that the heterogeneity of HSCs in the injured mouse livers is closely similar to that of cirrhotic human livers. Conclusions: Collectively, our scRNA-seq data provided insight into the landscape of activated HSC populations and the dynamic transitional pathway from HSC to myofibroblasts in response to liver injury. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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11 pages, 4456 KiB

Open AccessArticle

Colesevelam Reduces Ethanol-Induced Liver Steatosis in Humanized Gnotobiotic Mice

by Noemí Cabré, Yi Duan, Cristina Llorente, Mary Conrad, Patrick Stern, Dennis Yamashita and Bernd Schnabl

Cells 2021, 10(6), 1496; https://doi.org/10.3390/cells10061496 - 14 Jun 2021

Cited by 6 | Viewed by 2342

Abstract

Alcohol-related liver disease is associated with intestinal dysbiosis. Functional changes in the microbiota affect bile acid metabolism and result in elevated serum bile acids in patients with alcohol-related liver disease. The aim of this study was to identify the potential role of the bile acid sequestrant colesevelam in a humanized mouse model of ethanol-induced liver disease. We colonized germ-free (GF) C57BL/6 mice with feces from patients with alcoholic hepatitis and subjected humanized mice to the chronic–binge ethanol feeding model. Ethanol-fed gnotobiotic mice treated with colesevelam showed reduced hepatic levels of triglycerides and cholesterol, but liver injury and inflammation were not decreased as compared with non-treated mice. Colesevelam reduced hepatic cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1) protein expression, although serum bile acids were not lowered. In conclusion, our findings indicate that colesevelam treatment mitigates ethanol-induced liver steatosis in mice. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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Review

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18 pages, 1180 KiB

Open AccessEditor’s ChoiceReview

Key Signaling in Alcohol-Associated Liver Disease: The Role of Bile Acids

by Grayson W. Way, Kaitlyn G. Jackson, Shreya R. Muscu and Huiping Zhou

Cells 2022, 11(8), 1374; https://doi.org/10.3390/cells11081374 - 18 Apr 2022

Cited by 11 | Viewed by 14935

Abstract

Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead to the development of hepatocellular carcinoma (HCC). ALD continues to be a significant health burden and is now the main cause of liver transplantations in the United States. ALD leads to biological, microbial, physical, metabolic, and inflammatory changes in patients that vary depending on disease severity. ALD deaths have been increasing in recent years and are projected to continue to increase. Current treatment centers focus on abstinence and symptom management, with little in the way of resolving disease progression. Due to the metabolic disruption and gut dysbiosis in ALD, bile acid (BA) signaling and metabolism are also notably affected and play a prominent role in disease progression in ALD, as well as other liver disease states, such as non-alcoholic fatty liver disease (NAFLD). In this review, we summarize the recent advances in the understanding of the mechanisms by which alcohol consumption induces hepatic injury and the role of BA-mediated signaling in the pathogenesis of ALD. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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21 pages, 1054 KiB

Open AccessReview

Recent Advances in Adipose Tissue Dysfunction and Its Role in the Pathogenesis of Non-Alcoholic Fatty Liver Disease

by Xiaoxiao Wang, Huiying Rao, Feng Liu, Lai Wei, Honggui Li and Chaodong Wu

Cells 2021, 10(12), 3300; https://doi.org/10.3390/cells10123300 - 25 Nov 2021

Cited by 23 | Viewed by 3288

Abstract

Obesity is a serious ongoing health problem that significantly increases the incidence of nonalcoholic fatty liver disease (NAFLD). During obesity, adipose tissue dysfunction is obvious and characterized by increased fat deposition (adiposity) and chronic low-grade inflammation. The latter has been implicated to critically promote the development and progression of NAFLD, whose advanced form non-alcoholic steatohepatitis (NASH) is considered one of the most common causes of terminal liver diseases. This review summarizes the current knowledge on obesity-related adipose dysfunction and its roles in the pathogenesis of hepatic steatosis and inflammation, as well as liver fibrosis. A better understanding of the crosstalk between adipose tissue and liver under obesity is essential for the development of new and improved preventive and/or therapeutic approaches for managing NAFLD. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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20 pages, 1268 KiB

Open AccessReview

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases

by Claudio Pinto, Elisabetta Ninfole, Antonio Benedetti, Marco Marzioni and Luca Maroni

Cells 2021, 10(10), 2772; https://doi.org/10.3390/cells10102772 - 16 Oct 2021

Cited by 4 | Viewed by 3335

Abstract

Autophagy is a “housekeeping” lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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20 pages, 2365 KiB

Open AccessReview

The TGF-β/NADPH Oxidases Axis in the Regulation of Liver Cell Biology in Health and Disease

by Macarena Herranz-Itúrbide, Irene Peñuelas-Haro, Rut Espinosa-Sotelo, Esther Bertran and Isabel Fabregat

Cells 2021, 10(9), 2312; https://doi.org/10.3390/cells10092312 - 03 Sep 2021

Cited by 15 | Viewed by 4634

Abstract

The Transforming Growth Factor-beta (TGF-β) pathway plays essential roles in liver development and homeostasis and become a relevant factor involved in different liver pathologies, particularly fibrosis and cancer. The family of NADPH oxidases (NOXs) has emerged in recent years as targets of the TGF-β pathway mediating many of its effects on hepatocytes, stellate cells and macrophages. This review focuses on how the axis TGF-β/NOXs may regulate the biology of different liver cells and how this influences physiological situations, such as liver regeneration, and pathological circumstances, such as liver fibrosis and cancer. Finally, we discuss whether NOX inhibitors may be considered as potential therapeutic tools in liver diseases. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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19 pages, 2826 KiB

Open AccessReview

Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease

by Tianhao Zhou, Debjyoti Kundu, Jonathan Robles-Linares, Vik Meadows, Keisaku Sato, Leonardo Baiocchi, Burcin Ekser, Shannon Glaser, Gianfranco Alpini, Heather Francis and Lindsey Kennedy

Cells 2021, 10(8), 2072; https://doi.org/10.3390/cells10082072 - 12 Aug 2021

Cited by 12 | Viewed by 5329

Abstract

Fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), are global health disparities, particularly in the United States, as a result of cultural eating habits and lifestyle. Pathological studies on NAFLD have been mostly focused on hepatocytes and other inflammatory cell types; however, the impact of other biliary epithelial cells (i.e., cholangiocytes) in the promotion of NAFLD is growing. This review article will discuss how cholestatic injury and cholangiocyte activity/ductular reaction influence NAFLD progression. Furthermore, this review will provide informative details regarding the fundamental properties of cholangiocytes and bile acid signaling that can influence NAFLD. Lastly, studies relating to the pathogenesis of NAFLD, cholangiopathies, and ductular reaction will be analyzed to help gain insight for potential therapies. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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15 pages, 1108 KiB

Open AccessReview

Circular RNA as An Epigenetic Regulator in Chronic Liver Diseases

by Xianhui Zeng, Xianglei Yuan, Qiuyu Cai, Chengwei Tang and Jinhang Gao

Cells 2021, 10(8), 1945; https://doi.org/10.3390/cells10081945 - 30 Jul 2021

Cited by 37 | Viewed by 3896

Abstract

Circular RNA (circRNA) is a type of non-coding RNA characterized by a covalently closed continuous loop. CircRNA is generated by pre-mRNA through back-splicing and is probably cleared up by extracellular vesicles. CircRNAs play a pivotal role in the epigenetic regulation of gene expression at transcriptional and post-transcriptional levels. Recently, circRNAs have been demonstrated to be involved in the regulation of liver homeostasis and diseases. However, the epigenetic role and underlying mechanisms of circRNAs in chronic liver diseases remain unclear. This review discussed the role of circRNAs in non-neoplastic chronic liver diseases, including alcoholic liver disease (ALD), metabolic-associated fatty liver disease (MAFLD), viral hepatitis, liver injury and regeneration, liver cirrhosis, and autoimmune liver disease. The review also highlighted that further efforts are urgently needed to develop circRNAs as novel diagnostics and therapeutics for chronic liver diseases. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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14 pages, 947 KiB

Open AccessReview

Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?

by Leonardo Baiocchi, Ilaria Lenci, Martina Milana, Lindsey Kennedy, Keisaku Sato, Wenjun Zhang, Burcin Ekser, Ludovica Ceci, Vik Meadows, Shannon Glaser, Gianfranco Alpini and Heather Francis

Cells 2021, 10(7), 1692; https://doi.org/10.3390/cells10071692 - 04 Jul 2021

Cited by 7 | Viewed by 3190

Abstract

Cholangiocarcinoma is a lethal disease with scarce response to current systemic therapy. The rare occurrence and large heterogeneity of this cancer, together with poor knowledge of its molecular mechanisms, are elements contributing to the difficulties in finding an appropriate cure. Cholangiocytes (and their cellular precursors) are considered the liver component giving rise to cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli employing the cAMP/PKA system for the translation of messages in the intracellular space. For instance, in physiological conditions, stimulation of the secretin receptor determines an increase of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes’ injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific pieces of evidence link cAMP signaling system to cholangiocytes’ proliferation, the possible changes of this pathway during cancer growth also seem relevant. In this review, we summarize the current findings regarding the cAMP pathway and its role in biliary normal and neoplastic cell proliferation. Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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