Topic Editors

Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
Translational Liver Research, Department of Medical Cell BioPhysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, 7522 NB Enschede, The Netherlands
Department of Life Sciences, University of Trieste, Trieste, Italy
Liver Cell Biology research group, Vrije Universiteit Brussel, 1090 Brussel, Belgium

Signaling Pathways in Liver Disease

Abstract submission deadline
31 October 2024
Manuscript submission deadline
31 December 2024
Viewed by
36738

Topic Information

Dear Colleagues,

Acute and chronic liver diseases are complex disorders driven by a variety of pathogenic signal transduction processes. These modulate the biology of parenchymal and non-parenchymal liver cells. Most important are cytokine and chemokine networks that orchestrate an inflammatory response leading to the recruitment and activation of distinct leukocyte subsets. Moreover, the different molecular mediators target specific signaling branches that lead to increased formation of extracellular matrix. Simultaneously, different classes of reactive species are formed, resulting in enhanced oxidative- and nitrosative stress, and liver cell damage. Persistent liver damage results in sequential progression from inflammation to fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, there is a great deal of basic and clinical research ongoing, even at the single-cell level, to interrogate core molecular pathways underlying hepatic disease. We cordially invite you to contribute, in the form of original research articles, reviews, or shorter perspective articles, on all aspects related to the theme of “Signaling Pathways in Liver Disease”. Expert articles describing mechanistic, functional, cellular, biochemical, or general aspects of acute and chronic hepatic disease are highly welcome.

Prof. Dr. Ralf Weiskirchen
Dr. Ruchi Bansal
Prof. Dr. Gabriele Grassi
Prof. Dr. Leo A. Van Grunsven
Topic Editors

Keywords

  • cytokine
  • chemokine
  • growth factor, kinases, liver disease
  • fibrosis
  • cirrhosis
  • hepatocellular carcinoma
  • therapy
  • biomarker
  • non-alcoholic fatty liver disease
  • alcohol-associated liver disease

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Cells
cells
6.0 9.0 2012 16.6 Days CHF 2700 Submit
International Journal of Molecular Sciences
ijms
5.6 7.8 2000 16.3 Days CHF 2900 Submit
Journal of Molecular Pathology
jmp
- - 2020 24.9 Days CHF 1000 Submit
Livers
livers
- - 2021 22 Days CHF 1000 Submit
Pathogens
pathogens
3.7 5.1 2012 16.4 Days CHF 2700 Submit
Bioengineering
bioengineering
4.6 4.2 2014 17.7 Days CHF 2700 Submit

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Published Papers (13 papers)

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12 pages, 6950 KiB  
Article
Analysis of the Role of Stellate Cell VCAM-1 in NASH Models in Mice
by Kyoung-Jin Chung, Aigli-Ioanna Legaki, Grigorios Papadopoulos, Bettina Gercken, Janine Gebler, Robert F. Schwabe, Triantafyllos Chavakis and Antonios Chatzigeorgiou
Int. J. Mol. Sci. 2023, 24(5), 4813; https://doi.org/10.3390/ijms24054813 - 02 Mar 2023
Cited by 2 | Viewed by 1779
Abstract
Non-alcoholic fatty liver disease (NAFLD) can progress to non-alcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis. Fibrosis is mediated by hepatic stellate cells (HSC) and their differentiation into activated myofibroblasts; the latter process is also promoted by inflammation. Here we studied the role [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) can progress to non-alcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis. Fibrosis is mediated by hepatic stellate cells (HSC) and their differentiation into activated myofibroblasts; the latter process is also promoted by inflammation. Here we studied the role of the pro-inflammatory adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) in HSCs in NASH. VCAM-1 expression was upregulated in the liver upon NASH induction, and VCAM-1 was found to be present on activated HSCs. We therefore utilized HSC-specific VCAM-1-deficient and appropriate control mice to explore the role of VCAM-1 on HSCs in NASH. However, HSC-specific VCAM-1-deficient mice, as compared to control mice, did not show a difference with regards to steatosis, inflammation and fibrosis in two different models of NASH. Hence, VCAM-1 on HSCs is dispensable for NASH development and progression in mice. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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23 pages, 1687 KiB  
Review
Cellular Senescence in Hepatocellular Carcinoma: The Passenger or the Driver?
by Xiurong Cai, Adrien Guillot and Hanyang Liu
Cells 2023, 12(1), 132; https://doi.org/10.3390/cells12010132 - 29 Dec 2022
Cited by 6 | Viewed by 3428
Abstract
With the high morbidity and mortality, hepatocellular carcinoma (HCC) represents a major yet growing burden for our global community. The relapse-prone nature and drug resistance of HCC are regarded as the consequence of varying intracellular processes and extracellular interplay, which actively participate in [...] Read more.
With the high morbidity and mortality, hepatocellular carcinoma (HCC) represents a major yet growing burden for our global community. The relapse-prone nature and drug resistance of HCC are regarded as the consequence of varying intracellular processes and extracellular interplay, which actively participate in tumor microenvironment remodeling. Amongst them, cellular senescence is regarded as a fail-safe program, leading to double-sword effects of both cell growth inhibition and tissue repair promotion. Particularly, cellular senescence serves a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to carcinogenesis. Given the current challenges in improving the clinical management and outcome of HCC, senescence may exert striking potential in affecting anti-cancer strategies. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies. In this review, we intend to provide an up-to-date understanding of liver cell senescence and its impacts on treatment modalities of HCC. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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26 pages, 18875 KiB  
Article
PNPLA3(I148M) Inhibits Lipolysis by Perilipin-5-Dependent Competition with ATGL
by Hagen Roland Witzel, Inga Maria Gertrud Schwittai, Nils Hartmann, Sebastian Mueller, Jörn M. Schattenberg, Xue-Min Gong, Johannes Backs, Peter Schirmacher, Detlef Schuppan, Wilfried Roth and Beate Katharina Straub
Cells 2023, 12(1), 73; https://doi.org/10.3390/cells12010073 - 24 Dec 2022
Cited by 2 | Viewed by 2834
Abstract
The single nucleotide polymorphism I148M of the lipase patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an unfavorable prognosis in alcoholic and non-alcoholic steatohepatitis (ASH, NASH), with progression to liver cirrhosis and development of hepatocellular carcinoma. In this study, we [...] Read more.
The single nucleotide polymorphism I148M of the lipase patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an unfavorable prognosis in alcoholic and non-alcoholic steatohepatitis (ASH, NASH), with progression to liver cirrhosis and development of hepatocellular carcinoma. In this study, we investigated the mechanistic interaction of PNPLA3 with lipid droplet (LD)-associated proteins of the perilipin family, which serve as gatekeepers for LD degradation. In a collective of 106 NASH, ASH and control liver samples, immunohistochemical analyses revealed increased ballooning, inflammation and fibrosis, as well as an accumulation of PNPLA3–perilipin 5 complexes on larger LDs in patients homo- and heterozygous for PNPLA3(I148M). Co-immunoprecipitation demonstrated an interaction of PNPLA3 with perilipin 5 and the key enzyme of lipolysis, adipose triglyceride lipase (ATGL). Localization studies in cell cultures and human liver showed colocalization of perilipin 5, ATGL and PNPLA3. Moreover, the lipolytic activity of ATGL was negatively regulated by PNPLA3 and perilipin 5, whereas perilipin 1 displaced PNPLA3 from the ATGL complex. Furthermore, ballooned hepatocytes, the hallmark of steatohepatitis, were positive for PNPLA3 and perilipins 2 and 5, but showed decreased perilipin 1 expression with respect to neighboured hepatocytes. In summary, PNPLA3- and ATGL-driven lipolysis is significantly regulated by perilipin 1 and 5 in steatohepatitis. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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15 pages, 2363 KiB  
Article
The Clostridium Metabolite P-Cresol Sulfate Relieves Inflammation of Primary Biliary Cholangitis by Regulating Kupffer Cells
by Hai-Yan Fu, Jia-Min Xu, Xin Ai, Fu-Tao Dang, Xu Tan, Hai-Yan Yu, Juan Feng, Wen-Xia Yang, Hai-Tao Ma, Rong-Fang Tu, Ajay Kumar Gupta, Lagan Kumar Manandhar, Wei-Min Bao and Ying-Mei Tang
Cells 2022, 11(23), 3782; https://doi.org/10.3390/cells11233782 - 26 Nov 2022
Cited by 5 | Viewed by 1627
Abstract
Objective: To study the effect and mechanism of the Clostridium metabolite p-Cresol sulfate (PCS) in primary biliary cholangitis (PBC). Methods: Gas chromatography-mass spectrometry (GC-MS) was used to detect differences in tyrosine, phenylalanine, tryptophan, PCS, and p-Cresyl glucuronide (PCG) between the serum of PBC [...] Read more.
Objective: To study the effect and mechanism of the Clostridium metabolite p-Cresol sulfate (PCS) in primary biliary cholangitis (PBC). Methods: Gas chromatography-mass spectrometry (GC-MS) was used to detect differences in tyrosine, phenylalanine, tryptophan, PCS, and p-Cresyl glucuronide (PCG) between the serum of PBC patients and healthy controls. In vivo experiments, mice were divided into the normal control, PBC group, and PBC tyrosine group. GC-MS was used to detect PCS and PCG. Serum and liver inflammatory factors were compared between groups along with the polarization of liver Kupffer cells. Additionally, PCS was cultured with normal bile duct epithelial cells and Kupffer cells, respectively. PCS-stimulated Kupffer cells were co-cultured with lipopolysaccharide-injured bile duct epithelial cells to detect changes in inflammatory factors. Results: Levels of tyrosine and phenylalanine were increased, but PCS level was reduced in PBC patients, with PCG showing a lower concentration distribution in both groups. PCS in PBC mice was also lower than those in normal control mice. After oral administration of tyrosine feed to PBC mice, PCS increased, liver inflammatory factors were decreased, and anti-inflammatory factors were increased. Furthermore, Kupffer cells in the liver polarized form M1 transitioned to M2. PCS can damage normal bile duct epithelial cells and suppress the immune response of Kupffer cells. But PCS protects bile duct epithelial cells damaged by LPS through Kupffer cells. Conclusions: PCS produced by Clostridium-metabolized tyrosine reduced PBC inflammation, suggesting that intervention by food, or supplementation with PCS might represent an effective clinical strategy for treating PBC. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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14 pages, 17548 KiB  
Article
Oxygen Gradient Induced in Microfluidic Chips Can Be Used as a Model for Liver Zonation
by Shahrouz Ghafoory, Christina Stengl, Stefan Kopany, Mert Mayadag, Nils Mechtel, Brennah Murphy, Sebastian Schattschneider, Niklas Wilhelmi and Stefan Wölfl
Cells 2022, 11(23), 3734; https://doi.org/10.3390/cells11233734 - 23 Nov 2022
Cited by 2 | Viewed by 2177
Abstract
Availability of oxygen plays an important role in tissue organization and cell-type specific metabolism. It is, however, difficult to analyze hypoxia-related adaptations in vitro because of inherent limitations of experimental model systems. In this study, we establish a microfluidic tissue culture protocol to [...] Read more.
Availability of oxygen plays an important role in tissue organization and cell-type specific metabolism. It is, however, difficult to analyze hypoxia-related adaptations in vitro because of inherent limitations of experimental model systems. In this study, we establish a microfluidic tissue culture protocol to generate hypoxic gradients in vitro, mimicking the conditions found in the liver acinus. To accomplish this, four microfluidic chips, each containing two chambers, were serially connected to obtain eight interconnected chambers. HepG2 hepatocytes were uniformly seeded in each chamber and cultivated under a constant media flow of 50 µL/h for 72 h. HepG2 oxygen consumption under flowing media conditions established a normoxia to hypoxia gradient within the chambers, which was confirmed by oxygen sensors located at the inlet and outlet of the connected microfluidic chips. Expression of Hif1α mRNA and protein was used to indicate hypoxic conditions in the cells and albumin mRNA and protein expression served as a marker for liver acinus-like zonation. Oxygen measurements performed over 72 h showed a change from 17.5% to 15.9% of atmospheric oxygen, which corresponded with a 9.2% oxygen reduction in the medium between chamber1 (inlet) and 8 (outlet) in the connected microfluidic chips after 72 h. Analysis of Hif1α expression and nuclear translocation in HepG2 cells additionally confirmed the hypoxic gradient from chamber1 to chamber8. Moreover, albumin mRNA and protein levels were significantly reduced from chamber1 to chamber8, indicating liver acinus zonation along the oxygen gradient. Taken together, microfluidic cultivation in interconnected chambers provides a new model for analyzing cells in a normoxic to hypoxic gradient in vitro. By using a well-characterized cancer cell line as a homogenous hepatocyte population, we also demonstrate that an approximate 10% reduction in oxygen triggers translocation of Hif1α to the nucleus and reduces albumin production. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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11 pages, 3692 KiB  
Review
FYB2 Is a Potential Prognostic Biomarker for Hepatocellular Carcinoma
by Yifan Qu, Xiaozhong Shen, Xinpei Yuan and Bing Lu
Livers 2022, 2(4), 361-371; https://doi.org/10.3390/livers2040027 - 02 Nov 2022
Cited by 1 | Viewed by 1441
Abstract
FYB2 (also known as C1orf168 or ARAP) is an adaptor protein involved in T-cell receptor (TCR)-mediated T-cell activation and adhesion. However, the correlation of FYB2 with prognosis and cancer needs further investigation. In this study, we analyzed the expression levels of FYB2 in [...] Read more.
FYB2 (also known as C1orf168 or ARAP) is an adaptor protein involved in T-cell receptor (TCR)-mediated T-cell activation and adhesion. However, the correlation of FYB2 with prognosis and cancer needs further investigation. In this study, we analyzed the expression levels of FYB2 in hepatocellular carcinoma (LIHC) tumor tissues and correlated it with the pathological stages, survival outcomes, and tumor grades. We found that the expression of FYB2 was significantly downregulated in LIHC. Low FYB2 level leading to weak survival outcomes is linked with advanced tumor grades and elevated pathological stages. Cox regression analysis showed that FYB2 and AJCC-M stages can be used as independent prognostic factors for LIHC. GSEA analysis revealed that FYB2 would be notably correlated with the cellular metabolism-related pathways and particularly involved in the regulation of cancer-related pathways. Single-cell transcriptome analysis revealed that FYB2-positive cells were mainly distributed in hepatocytes, and compared with other cells, the upregulated genes of these cells were mainly enriched in metabolism-related functions. The results of the spatial transcriptome revealed that the expression of FYB2 in the adjacent area was higher than in the tumor area. These results showed that FYB2 is likely to be a new prognostic biomarker in LIHC and would help provide individual treatment decisions for LIHC patients. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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17 pages, 3782 KiB  
Article
ATP7B-Deficient Hepatocytes Reveal the Importance of Protein Misfolding Induced at Low Copper Concentration
by Peggy Charbonnier, Benoît Chovelon, Corinne Ravelet, Tuan Dung Ngo, Mireille Chevallet and Aurélien Deniaud
Cells 2022, 11(21), 3400; https://doi.org/10.3390/cells11213400 - 27 Oct 2022
Cited by 2 | Viewed by 1840
Abstract
Copper is a transition metal essential for human life. Its homeostasis is regulated in the liver, which delivers copper to the whole body and excretes its excess outside the organism in the feces through the bile. These functions are regulated within hepatocytes, and [...] Read more.
Copper is a transition metal essential for human life. Its homeostasis is regulated in the liver, which delivers copper to the whole body and excretes its excess outside the organism in the feces through the bile. These functions are regulated within hepatocytes, and the ATP7B copper transporter is central to making the switch between copper use and excretion. In Wilson disease, the gene coding for ATP7B is mutated, leading to copper overload, firstly, in the liver and the brain. To better understand the role of ATP7B in hepatocytes and to provide a smart tool for the development of novel therapies against Wilson disease, we used the CrispR/Cas9 tool to generate hepatocyte cell lines with the abolished expression of ATP7B. These cell lines revealed that ATP7B plays a major role at low copper concentrations starting in the micromolar range. Moreover, metal stress markers are induced at lower copper concentrations compared to parental cells, while redox stress remains not activated. As shown recently, the main drawback induced by copper exposure is protein unfolding that is drastically exacerbated in ATP7B-deficient cells. Our data enabled us to propose that the zinc finger domain of DNAJ-A1 would serve as a sensor of Cu stress. Therefore, these Wilson-like hepatocytes are of high interest to explore in more detail the role of ATP7B. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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13 pages, 3934 KiB  
Article
Role of Hepatocyte Senescence in the Activation of Hepatic Stellate Cells and Liver Fibrosis Progression
by Pramudi Wijayasiri, Stuart Astbury, Philip Kaye, Fiona Oakley, Graeme J. Alexander, Timothy J. Kendall and Aloysious D. Aravinthan
Cells 2022, 11(14), 2221; https://doi.org/10.3390/cells11142221 - 17 Jul 2022
Cited by 11 | Viewed by 3364
Abstract
Hepatocyte senescence is associated with liver fibrosis. However, the possibility of a direct, causal relation between hepatocyte senescence and hepatic stellate cell (HSC) activation was the subject of this study. Liver biopsy specimens obtained from 50 patients with non-alcoholic fatty liver disease and [...] Read more.
Hepatocyte senescence is associated with liver fibrosis. However, the possibility of a direct, causal relation between hepatocyte senescence and hepatic stellate cell (HSC) activation was the subject of this study. Liver biopsy specimens obtained from 50 patients with non-alcoholic fatty liver disease and a spectrum of liver fibrosis stages were stained for p16, αSMA, and picrosirius red (PSR). Primary human HSCs were cultured in conditioned media derived from senescent or control HepG2 cells. Expression of inflammatory and fibrogenic genes in HSCs cultured in conditioned media were studied using RT-PCR. ELISAs were undertaken to measure factors known to activate HSCs in the conditioned media from senescent and control HepG2 cells and serum samples from healthy volunteers or patients with biopsy-proven cirrhosis. There was a strong association between proportion of senescent hepatocytes and hepatic stellate cell activation. Both proportion of hepatocyte senescence and hepatic stellate cell activation were closely associated with fibrosis stage. Inflammatory and fibrogenic genes were up-regulated significantly in HSCs cultured in conditioned media from senescent HepG2 cells compared with control HepG2 cells. PDGF levels were significantly higher in the conditioned media from senescent hepatocytes than control HepG2-conditioned media, and in serum samples from patients with cirrhosis than healthy volunteers. In conclusion, this ‘proof of concept’ study revealed activation of human HSCs by media from senescent HepG2 cells, indicating direct involvement of factors secreted by senescent hepatocytes in liver fibrosis. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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17 pages, 5970 KiB  
Article
Caveolin-1 Alleviates Acetaminophen—Induced Hepatotoxicity in Alcoholic Fatty Liver Disease by Regulating the Ang II/EGFR/ERK Axis
by Jiao Xin, Tingyu You, Xiangfu Jiang, Dongdong Fu, Jiarong Wang, Wei Jiang, Xiaowen Feng, Jiagen Wen, Yan Huang and Chengmu Hu
Int. J. Mol. Sci. 2022, 23(14), 7587; https://doi.org/10.3390/ijms23147587 - 08 Jul 2022
Cited by 5 | Viewed by 2178
Abstract
Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased [...] Read more.
Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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22 pages, 10627 KiB  
Review
Pituitary Tumor-Transforming Gene 1/Delta like Non-Canonical Notch Ligand 1 Signaling in Chronic Liver Diseases
by Meritxell Perramón and Wladimiro Jiménez
Int. J. Mol. Sci. 2022, 23(13), 6897; https://doi.org/10.3390/ijms23136897 - 21 Jun 2022
Cited by 5 | Viewed by 3233
Abstract
The management of chronic liver diseases (CLDs) remains a challenge, and identifying effective treatments is a major unmet medical need. In the current review we focus on the pituitary tumor transforming gene (PTTG1)/delta like non-canonical notch ligand 1 (DLK1) axis as a potential [...] Read more.
The management of chronic liver diseases (CLDs) remains a challenge, and identifying effective treatments is a major unmet medical need. In the current review we focus on the pituitary tumor transforming gene (PTTG1)/delta like non-canonical notch ligand 1 (DLK1) axis as a potential therapeutic target to attenuate the progression of these pathological conditions. PTTG1 is a proto-oncogene involved in proliferation and metabolism. PTTG1 expression has been related to inflammation, angiogenesis, and fibrogenesis in cancer and experimental fibrosis. On the other hand, DLK1 has been identified as one of the most abundantly expressed PTTG1 targets in adipose tissue and has shown to contribute to hepatic fibrosis by promoting the activation of hepatic stellate cells. Here, we extensively analyze the increasing amount of information pointing to the PTTG1/DLK1 signaling pathway as an important player in the regulation of these disturbances. These data prompted us to hypothesize that activation of the PTTG1/DLK1 axis is a key factor upregulating the tissue remodeling mechanisms characteristic of CLDs. Therefore, disruption of this signaling pathway could be useful in the therapeutic management of CLDs. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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17 pages, 6265 KiB  
Article
Exercise Affects the Formation and Recovery of Alcoholic Liver Disease through the IL-6–p47phox Oxidative–Stress Axis
by Wei Cui, Xiang Li, Weiyue Xue, Huiting Wei, Gang Zhou, Ye Qiu and Di Cui
Cells 2022, 11(8), 1305; https://doi.org/10.3390/cells11081305 - 12 Apr 2022
Cited by 4 | Viewed by 2116
Abstract
(1) Background: To explore the effect of exercise on the formation and recovery of alcoholic liver disease (ALD) and whether the IL-6–p47phox oxidative–stress axis is involved in that process. (2) Methods: Firstly, 23 six-week-old male C57BL/6J mice were randomly divided into the [...] Read more.
(1) Background: To explore the effect of exercise on the formation and recovery of alcoholic liver disease (ALD) and whether the IL-6–p47phox oxidative–stress axis is involved in that process. (2) Methods: Firstly, 23 six-week-old male C57BL/6J mice were randomly divided into the Con group, ALD group, ALD + NOXI group, ALD + Ex group, and ALD + Ex + NOXI group. The Liber–DeCarli alcoholic liquid diet was used for 6 weeks to establish the ALD mice model, and the Con group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet, and exercise intervention was started after the ALD model establishment and lasted for another 6 weeks, with or without administration of the NOX inhibitor apocynin by intraperitoneal injection on every exercise training day. Secondly, 28 mice were randomly divided into the Sed group, Eth group, Eth + Ex group and Eth + Ex + NOXI group. The Sed group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet and exercise intervention was started synchronously combined with or without administration of intraperitoneal apocynin injections on every exercise training day for 5 weeks. After each individual experiment was accomplished, physiological assessment and biochemical analysis of blood and tissue samples were examined. (3) Results: The levels of TG in serum and IL-6 protein content in liver tissue in the ALD group were significantly increased compared to the Con group (p < 0.05); compared with ALD, p47phox expression in muscle was increased significantly in the ALD + NOXI group (p < 0.05), and TG in serum decreased in the ALD + Ex group (p < 0.05). TG in serum, AST/ALT ratio, and IL-6 content in both liver and muscle decreased (p < 0.05) in the ALD + Ex + NOXI group with MDA in muscle significantly increased (p < 0.01). The AST/ALT ratio, TG in serum, SOD in liver, and p47phox in both liver and muscle in the ALD + Ex + NOXI group were significantly decreased compared with the ALD + NOXI group (p < 0.01). Compared with the ALD + Ex group, the liver index and HDL-C levels in serum were decreased (p < 0.05) in the ALD + Ex + NOXI group. The degree of hepatocyte steatosis and inflammatory infiltration were ameliorated after exercise intervention. In the Eth group, the relative epididymal fat content, HDL-C level, and AST/ALT ratio were significantly decreased, and TG and gp91phox in liver were significantly higher than in the Sed group (p < 0.05, p < 0.01). Compared with the Eth group, the AST/ALT ratio, MDA in the liver, and NOX4 and p47phox protein expression in the liver were significantly increased, and body weight decreased significantly in the Eth + Ex group (p < 0.05, p < 0.01), as did TG in the liver and MDA in muscle. In the th + Ex + NOXI group, gp91phox expression in the liver and body weight were significantly decreased (p < 0.05, p < 0.01). In the Eth + Ex + NOXI group, the ratio of AST/ALT and MDA in muscle were increased when compared with the Eth + Ex group, and the protein expression of gp91phox and p47phox were much lower (p < 0.01). (4) Conclusions: 6 weeks of exercise intervention during the recovery phase of ALD ameliorates hepatocyte damage and dyslipidemia through the IL-6–p47phox oxidative–stress axis, and applying a NOX inhibitor in combination could optimize this. However, drinking alcohol during exercise exacerbates dyslipidemia and oxidative stress, with hepatocyte IL-6–p47phox downregulated. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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16 pages, 5399 KiB  
Article
Modulation of the Bile Acid Enterohepatic Cycle by Intestinal Microbiota Alleviates Alcohol Liver Disease
by Dragos Ciocan, Madeleine Spatz, Nicolas Trainel, Kévin Hardonnière, Séverine Domenichini, Françoise Mercier-Nomé, Aurore Desmons, Lydie Humbert, Sylvère Durand, Guido Kroemer, Antonin Lamazière, Cindy Hugot, Gabriel Perlemuter and Anne-Marie Cassard
Cells 2022, 11(6), 968; https://doi.org/10.3390/cells11060968 - 11 Mar 2022
Cited by 16 | Viewed by 3265
Abstract
Reshaping the intestinal microbiota by the ingestion of fiber, such as pectin, improves alcohol-induced liver lesions in mice by modulating bacterial metabolites, including indoles, as well as bile acids (BAs). In this context, we aimed to elucidate how oral supplementation of pectin affects [...] Read more.
Reshaping the intestinal microbiota by the ingestion of fiber, such as pectin, improves alcohol-induced liver lesions in mice by modulating bacterial metabolites, including indoles, as well as bile acids (BAs). In this context, we aimed to elucidate how oral supplementation of pectin affects BA metabolism in alcohol-challenged mice receiving feces from patients with alcoholic hepatitis. Pectin reduced alcohol liver disease. This beneficial effect correlated with lower BA levels in the plasma and liver but higher levels in the caecum, suggesting that pectin stimulated BA excretion. Pectin modified the overall BA composition, favoring an augmentation in the proportion of hydrophilic forms in the liver, plasma, and gut. This effect was linked to an imbalance between hydrophobic and hydrophilic (less toxic) BAs in the gut. Pectin induced the enrichment of intestinal bacteria harboring genes that encode BA-metabolizing enzymes. The modulation of BA content by pectin inhibited farnesoid X receptor signaling in the ileum and the subsequent upregulation of Cyp7a1 in the liver. Despite an increase in BA synthesis, pectin reduced BA serum levels by promoting their intestinal excretion. In conclusion, pectin alleviates alcohol liver disease by modifying the BA cycle through effects on the intestinal microbiota and enhanced BA excretion. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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16 pages, 1854 KiB  
Review
From Inflammation to Fibrosis: Novel Insights into the Roles of High Mobility Group Protein Box 1 in Schistosome-Induced Liver Damage
by Haoran Zhong, Xiang Gui, Ling Hou, Rongxue Lv and Yamei Jin
Pathogens 2022, 11(3), 289; https://doi.org/10.3390/pathogens11030289 - 24 Feb 2022
Cited by 13 | Viewed by 3621
Abstract
Schistosomiasis is a chronic helminthic disease of both humans and animals and the second most prevalent parasitic disease after malaria. Through a complex migration process, schistosome eggs trapped in the liver can lead to the formation of granulomas and subsequent schistosome-induced liver damage, [...] Read more.
Schistosomiasis is a chronic helminthic disease of both humans and animals and the second most prevalent parasitic disease after malaria. Through a complex migration process, schistosome eggs trapped in the liver can lead to the formation of granulomas and subsequent schistosome-induced liver damage, which results in high mortality and morbidity. Although praziquantel can eliminate mature worms and prevent egg deposition, effective drugs to reverse schistosome-induced liver damage are scarce. High mobility group box 1 (HMGB1) is a multifunctional cytokine contributing to liver injury, inflammation, and immune responses in schistosomiasis by binding to cell-surface Toll-like receptors and receptors for advanced glycation end products. HMGB1 is increased in the serum of patients with schistosomiasis and enables hepatic stellate cells to adopt a proliferative myofibroblast-like phenotype, which is crucial to schistosome-induced granuloma formation. Inhibition of HMGB1 was found to generate protective responses against fibrotic diseases in animal models. Clinically, HMGB1 presents a potential target for treatment of the chronic sequelae of schistosomiasis. Here, the pivotal role of HMGB1 in granuloma formation and schistosome-induced liver damage, as well the potential of HMGB1 as a therapeutic target, are discussed. Full article
(This article belongs to the Topic Signaling Pathways in Liver Disease)
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