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Current Understanding of Cellular Changes in Liver Pathophysiology
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Current Understanding of Cellular Changes in Liver Pathophysiology

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Cell Biology".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 6922

Special Issue Editors

Dr. Paul G. Thomes

E-Mail Website
Guest Editor
College of Veterinary Medicine, Auburn University, 218 Greene Hall, Auburn, AL 36849, USA
Interests: cellular and molecular mechanisms behind alcohol-induced organ dysfunction and loss of homeostasis
Dr. Nabil Eid

E-Mail Website
Co-Guest Editor
Anatomy Department, School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia
Interests: fasting; nutrition; health
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

The liver plays vital roles in maintaining the body’s metabolic homeostasis. This includes the synthesis and secretion of nearly all plasma proteins, the metabolism of nutrients, lipids, toxins, and xenobiotics, and the provision of glucose in times of nutrient deprivation. The liver also recycles obsolete macromolecules by degrading and then resynthesizing both intracellular as well as extracellular (circulating) species. These varied liver functions are carried out by distinct liver cell types, including hepatocytes, cholangiocytes, sinusoidal endothelial cells, and stellate cells. Genetic abnormalities, aging, overnutrition, infection, and hepatotoxins all induce a wide range of changes in liver cells. Many of these cause oxidant stress, cell death, and/or an abnormal cell phenotype, each of which causes loss of cellular homeostasis, metabolic dysregulation, and acute or chronic liver disease. Importantly, persistent (chronic) insults to the liver further potentiate the progression of liver disease, eventually resulting in its failure. Our understanding of the cellular and molecular changes that contribute to the development of liver pathophysiology has progressed significantly. However, we need to identify the key changes in liver cell function that trigger pathogenesis before it progresses to overt liver disease. Identifying these cellular changes is the first step in recognizing intracellular targets that respond to treatment. This Special Issue will highlight current understanding as well as previously unaddressed liver cell changes in normal and diseased states.

This Special Issue entitled “Current Understanding of Cellular Changes in Liver Pathophysiology” will highlight current development in hepatic cell biology research.  We will consider reviews and experimental articles. We look forward to your contribution.

Dr. Paul G. Thomes
Dr. Nabil Eid
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. Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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 cell
  • metabolism
  • organelle
  • trafficking
  • injury
  • regeneration
  • organ damage

Published Papers (4 papers)

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Research

14 pages, 4886 KiB  
Article
Multi-Probe RFA vs. Single-Probe MWA in an Ex Vivo Bovine Liver Model: Comparison of Volume and Shape of Coagulation Zones
by Gregor Laimer, Michael Bauer, Yannick Scharll, Peter Schullian and Reto Bale
Biology 2023, 12(8), 1103; https://doi.org/10.3390/biology12081103 - 08 Aug 2023
Viewed by 749
Abstract
Objectives: To compare the volumes and shapes of the coagulation zone (CZ) of a multi-probe RFA system (three RFA electrodes) and a single-probe MWA system from the same vendor in an ex vivo bovine liver model. Material & Methods: A total of 48 [...] Read more.
Objectives: To compare the volumes and shapes of the coagulation zone (CZ) of a multi-probe RFA system (three RFA electrodes) and a single-probe MWA system from the same vendor in an ex vivo bovine liver model. Material & Methods: A total of 48 CZs were obtained in bovine liver specimens with three different ablation system configurations (single-probe MWA vs. multi-probe RFA with 20 mm inter-probe distance [confluent CZ] vs. multi-probe RFA with 50 mm inter-probe distance [three individual CZs]) at 4, 6, 8, and 10 min ablation time using a fixed ablation protocol. Ablation diameters were measured and ellipticity indices (EIs) and volumes calculated. Calculations for all systems/configurations were compared. Results: Volumes and diameters increased with ablation time for all configurations. At 4 and 6 min ablation time volumes obtained with the RFA 50 mm setup, and at 8 and 10 min with the RFA 20 mm setup were the largest at 26.5 ± 4.1 mL, 38.1 ± 5.8 mL, 46.3 ± 4.9 mL, 48.4 ± 7.3 mL, respectively. The single-probe MWA could not reach the volumes of the RFA setups for any of the ablation times evaluated. EI were very similar and almost round for RFA 20 mm and single-probe MWA, and differed significantly to the more ovoid ones for the RFA 50 mm configuration. Conclusions: The multi-probe RFA system employing three electrodes achieved significantly larger ablation volumes in both configurations (confluent CZ and three individual CZs) per time as compared with a single-probe MWA system in this ex vivo bovine liver model. Full article
(This article belongs to the Special Issue Current Understanding of Cellular Changes in Liver Pathophysiology)
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21 pages, 3475 KiB  
Article
Multiomics Approach Captures Hepatic Metabolic Network Altered by Chronic Ethanol Administration
by Isin Tuna Sakallioglu, Bridget Tripp, Jacy Kubik, Carol A. Casey, Paul Thomes and Robert Powers
Biology 2023, 12(1), 28; https://doi.org/10.3390/biology12010028 - 23 Dec 2022
Cited by 2 | Viewed by 1572
Abstract
Using a multiplatform and multiomics approach, we identified metabolites, lipids, proteins, and metabolic pathways that were altered in the liver after chronic ethanol administration. A functional enrichment analysis of the multiomics dataset revealed that rats treated with ethanol experienced an increase in hepatic [...] Read more.
Using a multiplatform and multiomics approach, we identified metabolites, lipids, proteins, and metabolic pathways that were altered in the liver after chronic ethanol administration. A functional enrichment analysis of the multiomics dataset revealed that rats treated with ethanol experienced an increase in hepatic fatty acyl content, which is consistent with an initial development of steatosis. The nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography–mass spectrometry (LC-MS) metabolomics data revealed that the chronic ethanol exposure selectively modified toxic substances such as an increase in glucuronidation tyramine and benzoyl; and a depletion in cholesterol-conjugated glucuronides. Similarly, the lipidomics results revealed that ethanol decreased diacylglycerol, and increased triacylglycerol, sterol, and cholesterol biosynthesis. An integrated metabolomics and lipidomics pathway analysis showed that the accumulation of hepatic lipids occurred by ethanol modulation of the upstream lipid regulatory pathways, specifically glycolysis and glucuronides pathways. A proteomics analysis of lipid droplets isolated from control EtOH-fed rats and a subsequent functional enrichment analysis revealed that the proteomics data corroborated the metabolomic and lipidomic findings that chronic ethanol administration altered the glucuronidation pathway. Full article
(This article belongs to the Special Issue Current Understanding of Cellular Changes in Liver Pathophysiology)
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16 pages, 2937 KiB  
Article
Role of AMPK-SREBP Signaling in Regulating Fatty Acid Binding-4 (FABP4) Expression following Ethanol Metabolism
by Neha Attal, Emilio Marrero, Kyle J. Thompson and Iain H. McKillop
Biology 2022, 11(11), 1613; https://doi.org/10.3390/biology11111613 - 04 Nov 2022
Cited by 3 | Viewed by 1598
Abstract
Fatty acid binding protein-4 (FABP4) is not normally expressed in the liver but is induced in alcohol-dependent liver disease (ALD)). This study sought to identify mechanisms whereby ethanol (EtOH) metabolism alters triglyceride accumulation and FABP4 production. Human hepatoma cells which were [...] Read more.
Fatty acid binding protein-4 (FABP4) is not normally expressed in the liver but is induced in alcohol-dependent liver disease (ALD)). This study sought to identify mechanisms whereby ethanol (EtOH) metabolism alters triglyceride accumulation and FABP4 production. Human hepatoma cells which were stably transfected to express alcohol dehydrogenase (ADH) or cytochrome P4502E1 (CYP2E1) were exposed to EtOH in the absence/presence of inhibitors of ADH (4-methylpyrazole) or CYP2E1 (chlormethiazole). Cells were analyzed for free fatty acid (FFA) content and FABP4 mRNA, then culture medium assayed for FABP4 levels. Cell lysates were analyzed for AMP-activated protein kinase-α (AMPKα), Acetyl-CoA carboxylase (ACC), sterol regulatory element binding protein-1c (SREBP-1c), and Lipin-1β activity and localization in the absence/presence of EtOH and pharmacological inhibitors. CYP2E1-EtOH metabolism led to increased FABP4 mRNA/protein expression and FFA accumulation. Analysis of signaling pathway activity revealed decreased AMPKα activation and increased nuclear-SREBP-1c localization following CYP2E1-EtOH metabolism. The role of AMPKα-SREBP-1c in regulating CYP2E1-EtOH-dependent FFA accumulation and increased FABP4 was confirmed using pharmacological inhibitors and over-expression of AMPKα. Inhibition of ACC or Lipin-1β failed to prevent FFA accumulation or changes in FABP4 mRNA expression or protein secretion. These data suggest that CYP2E1-EtOH metabolism inhibits AMPKα phosphorylation to stimulate FFA accumulation and FABP4 protein secretion via an SREBP-1c dependent mechanism. Full article
(This article belongs to the Special Issue Current Understanding of Cellular Changes in Liver Pathophysiology)
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25 pages, 7710 KiB  
Article
Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell Activation
by Moses New-Aaron, Raghubendra Singh Dagur, Siva Sankar Koganti, Murali Ganesan, Weimin Wang, Edward Makarov, Mojisola Ogunnaike, Kusum K. Kharbanda, Larisa Y. Poluektova and Natalia A. Osna
Biology 2022, 11(7), 1059; https://doi.org/10.3390/biology11071059 - 14 Jul 2022
Cited by 5 | Viewed by 2171
Abstract
Recently, we found that both HIV and acetaldehyde, an alcohol metabolite, induce hepatocyte apoptosis, resulting in the release of large extracellular vesicles called apoptotic bodies (ABs). The engulfment of these hepatocyte ABs by hepatic stellate cells (HSC) leads to their profibrotic activation. This [...] Read more.
Recently, we found that both HIV and acetaldehyde, an alcohol metabolite, induce hepatocyte apoptosis, resulting in the release of large extracellular vesicles called apoptotic bodies (ABs). The engulfment of these hepatocyte ABs by hepatic stellate cells (HSC) leads to their profibrotic activation. This study aims to establish the mechanisms of HSC activation after engulfment of ABs from acetaldehyde and HIV-exposed hepatocytes (ABAGS+HIV). In vitro experiments were performed on Huh7.5-CYP (RLW) cells to generate hepatocyte ABs and LX2 cells were used as HSC. To generate ABs, RLW cells were pretreated for 24 h with acetaldehyde, then exposed overnight to HIV1ADA and to acetaldehyde for 96 h. Thereafter, ABs were isolated from cell suspension by a differential centrifugation method and incubated with LX2 cells (3:1 ratio) for profibrotic genes and protein analyses. We found that HSC internalized ABs via the tyrosine kinase receptor, Axl. While the HIV gag RNA/HIV proteins accumulated in ABs elicited no productive infection in LX2 and immune cells, they triggered ROS and IL6 generation, which, in turn, activated profibrotic genes via the JNK-ERK1/2 and JAK-STAT3 pathways. Similarly, ongoing profibrotic activation was observed in immunodeficient NSG mice fed ethanol and injected with HIV-derived RLW ABs. We conclude that HSC activation by hepatocyte ABAGS+HIV engulfment is mediated by ROS-dependent JNK-ERK1/2 and IL6 triggering of JAK-STAT3 pathways. This can partially explain the mechanisms of liver fibrosis development frequently observed among alcohol abusing PLWH. Full article
(This article belongs to the Special Issue Current Understanding of Cellular Changes in Liver Pathophysiology)
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