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Cells
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Cellular and Molecular Mechanisms of Liver Diseases
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Cellular and Molecular Mechanisms of Liver Diseases

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

Deadline for manuscript submissions: 31 May 2026 | Viewed by 9737

Special Issue Editor

Dr. Jieyun Jiang

E-Mail Website
Guest Editor
Department of Radiation Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
Interests: liver cancer; fatty liver diseases; role of obesity in cancers; cancer biology; pharmacology

Special Issue Information

Dear Colleagues,

The liver is the largest internal organ and gland in the human body. It performs many vital functions to keep the body pure from toxins and harmful substances; thus, it is considered a central organ for metabolic homeostasis. Liver diseases account for two million deaths annually. The major risk factors include prolonged excessive alcohol consumption, chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, autoimmune hepatitis, drug-induced liver injury, diabetes mellitus, obesity, and other metabolic diseases.

Liver injury induced by these risk factors is often reversible at early stages since normally quiescent hepatocytes can proliferate and restore normal liver mass and functions. However, persistent injury increases cellular damage, oxidative stress, and inflammation, which can lead to liver fibrosis, progress to cirrhosis, and may ultimately result in liver cancer. In addition, genetic and epigenetic alterations are involved in the development and progression of liver diseases.

This Special Issue will publish original articles and review articles in basic, translational research concerning Cellular and Molecular Mechanisms of all aspects of liver diseases.

Dr. Jieyun Jiang
Guest Editor

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 250 words) can be sent to the Editorial Office for assessment.

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. Cells is an international peer-reviewed open access semimonthly 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
  • alcoholic liver disease (ALD)
  • viral hepatitis
  • metabolic associated steatotic liver disease (MASLD)
  • autoimmune hepatitis
  • drug-induced liver injury
  • liver fibrosis and cirrhosis
  • liver cancer
  • cellular and molecular mechanisms

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Published Papers (4 papers)

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Research

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29 pages, 6095 KB  
Article
Comprehensive Cytogenetic and Genomic Profiling of the Murine AML12 (Alpha Mouse Liver 12) Hepatocyte Cell Line
by Darine Y. Asar, Stefanie Kankel, Diandra T. Keller, Katharina S. Hardt, Sarah K. Schröder-Lange, Eva M. Buhl, Thomas Liehr and Ralf Weiskirchen
Cells 2026, 15(5), 390; https://doi.org/10.3390/cells15050390 - 24 Feb 2026
Viewed by 1057
Abstract
The murine Alpha Mouse Liver 12 (AML12) cell line, established over four decades ago, is one of the most commonly used non-transformed hepatocyte models in basic and pre-clinical liver research. Despite its widespread use, a comprehensive and current molecular characterization has been lacking. [...] Read more.
The murine Alpha Mouse Liver 12 (AML12) cell line, established over four decades ago, is one of the most commonly used non-transformed hepatocyte models in basic and pre-clinical liver research. Despite its widespread use, a comprehensive and current molecular characterization has been lacking. In this study, we combined cytogenetics with high-resolution genomic technologies to establish a detailed genetic reference profile of AML12. Inverted DAPI banding and multicolor fluorescence in situ hybridization (m-FISH) revealed a complex yet stable, near-tetraploid karyotype featuring double X-chromosome deletions [del(X)(A3)×2], a recurrent derivative chromosome der(3)t(2;3)(A2;H4), biallelic deletions of 17D1, two dicentric chromosomes dic(X;17), and multiple whole-chromosome gains (e.g., +1, +6, +15, +19×4) and losses (e.g., −4, −12, −16, −18). Multicolor banding (mcb) further pinpointed cryptic inversions on chromosomes 7 and 11. Copy number imbalances were visualized as in silico array comparative genomic hybridization (aCGH)-style profiles inferred from these metaphase-based assays, and no independent array- or sequencing-based copy number variation (CNV) experiment was performed in this study. Short tandem repeat (STR) profiling created a unique 16-locus authentication barcode that unambiguously distinguishes AML12 from other murine cell lines in public databases. Bulk RNA sequencing (RNA-seq) further demonstrated a transcriptional profile in AML12 cells that is indicative of hepatocyte origin while also revealing partial de-differentiation and reduced expression of selected urea cycle, gluconeogenic, and xenobiotic-metabolizing transcripts, consistent with limited mature hepatocyte functions. These functional inferences are likely based on gene expression patterns rather than on direct physiological assays. In summary, our study provides (i) the first integrated cytogenetic, STR, and next-generation sequencing dataset for AML12, (ii) a practical authentication panel for routine laboratory use, and (iii) reference information that will enhance the interpretation, reproducibility, and translational relevance of future studies using this versatile hepatocyte model. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Liver Diseases)
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20 pages, 3065 KB  
Article
CES1 Increases Hepatic Triacylglycerol Synthesis Through Activation of PPARγ, LXR and SREBP1c
by Rajakumar Selvaraj, Jihong Lian, Russell Watts, Randal Nelson, Michael F. Saikali, Carolyn L. Cummins and Richard Lehner
Cells 2025, 14(19), 1548; https://doi.org/10.3390/cells14191548 - 3 Oct 2025
Cited by 2 | Viewed by 1931
Abstract
Increased hepatic triacylglycerol (TG) storage in lipid droplets (LDs) is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Human carboxylesterase 1 (CES1) regulates TG storage and secretion in hepatocytes, but the mechanism remains to be elucidated. We [...] Read more.
Increased hepatic triacylglycerol (TG) storage in lipid droplets (LDs) is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Human carboxylesterase 1 (CES1) regulates TG storage and secretion in hepatocytes, but the mechanism remains to be elucidated. We performed studies in rat hepatoma McArdle RH7777 cells stably transfected with CES1 cDNA and in Ces1d-deficient mice using a variety of biochemical, pharmacological and cell biology approaches including the assessment of gene expression, confocal immunofluorescence microscopy, lipid synthesis measurements and quantitative mass spectrometry. CES1-expressing cells accrued more TG compared to cells lacking CES1 when incubated with oleic acid. CES1 increased the expression of Srebf1c, Nr1h3 and Nr1h2 encoding transcription factors (SREBP1c and LXRα and LXRβ, respectively) that regulate the expression of lipogenic genes. Additionally, CES1 increased the expression of Acsl1 encoding an enzyme catalyzing fatty acid activation and the expression of Dgat1 and Dgat2 encoding enzymes catalyzing TG synthesis. Treatment of CES1-expressing cells with PPARγ antagonist (GW9662), LXR antagonist (GSK2033) or CYP27A1 inhibitor Felodipine prevented CES1-mediated fatty acid esterification into TG. Ces1d-deficient mice fed high-fat diet (HFD) presented with decreased expression of Nr1h3, Nr1h2, Srebf1c and reduced hepatic TG content. Felodipine and GSK2033 treatment eliminated the differential effects on TG concentration between wild-type and Ces1d-deficient hepatocytes. The results suggest that CES1/Ces1d activates PPARγ, LXR and SREBP1c pathways, thereby increasing TG synthesis and LD storage by augmenting fatty acid esterification. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Liver Diseases)
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22 pages, 5739 KB  
Article
Development and Validation of AAV-Mediated Liver, Liver-VAT, and Liver-Brain SORT and Therapeutic Regulation of FASN in Hepatic De Novo Lipogenesis
by Ratulananda Bhadury, Mohammad Athar, Pooja Mishra, Chayanika Gogoi, Shubham Sharma and Devram S. Ghorpade
Cells 2025, 14(5), 372; https://doi.org/10.3390/cells14050372 - 4 Mar 2025
Viewed by 4838
Abstract
Hepatic lipogenesis combined with elevated endoplasmic reticulum (ER) stress is central to non-alcoholic steatohepatitis (NASH). However, the therapeutic targeting of key molecules is considerably less accomplished. Adeno-associated virus (AAV)-mediated gene therapies offer a new solution for various human ailments. Comprehensive bio-functional validation studies [...] Read more.
Hepatic lipogenesis combined with elevated endoplasmic reticulum (ER) stress is central to non-alcoholic steatohepatitis (NASH). However, the therapeutic targeting of key molecules is considerably less accomplished. Adeno-associated virus (AAV)-mediated gene therapies offer a new solution for various human ailments. Comprehensive bio-functional validation studies are essential to assess the impact of AAVs in the target organ for developing both preclinical and clinical gene therapy programs. Here, we have established a robust and efficient protocol for high-titer AAV production to enable detailed Selective ORgan Targeting (SORT) of AAV1, 5, 7, and 8 in vivo. Our results for in vivo SORT showed single organ (liver) targeting by AAV8, no organ targeting by AAV1, and dual organ transduction (liver-brain and liver-VAT) by AAV5 and AAV7. Using a human dataset and preclinical murine models of NASH, we identified an inverse correlation between ER stress-triggered CRELD2 and the de novo lipogenesis driver FASN. Furthermore, liver-specific silencing of CRELD2 via AAV8-shCreld2 strongly supports the contribution of CRELD2 to de novo lipogenesis through FASN regulation. Thus, our study demonstrates a robust method for producing clinically translatable AAVs that could be readily adapted for liver and/or liver-VAT or liver-brain targeted gene therapy. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Liver Diseases)
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Review

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13 pages, 1392 KB  
Review
MYO5B Deficiency-Associated Cholestasis and the Role of the Bile Salt Export Pump
by Zhe Zhou and Sven C. D. van IJzendoorn
Cells 2026, 15(1), 92; https://doi.org/10.3390/cells15010092 - 5 Jan 2026
Viewed by 719
Abstract
Variants of the MYO5B gene, which encodes the molecular motor protein myosin-Vb, have gained prominence as a causative factor in familial intrahepatic cholestasis (FIC). Understanding the disease mechanism is pivotal for therapy development and clinical decision-making. The prevailing theory for the mechanism underlying [...] Read more.
Variants of the MYO5B gene, which encodes the molecular motor protein myosin-Vb, have gained prominence as a causative factor in familial intrahepatic cholestasis (FIC). Understanding the disease mechanism is pivotal for therapy development and clinical decision-making. The prevailing theory for the mechanism underlying MYO5B-associated cholestasis implicates faulty trafficking of the ABCB11-encoded bile salt export pump (BSEP) in hepatocytes due to dysfunctional myosin-Vb. This is supported by cell and mouse studies. However, while BSEP localization was abnormal in some patients’ liver biopsies, BSEP appeared normally localized in others, raising questions with regard to the role of BSEP in MYO5B-associated FIC. We present a focused systematic narrative review of all cases of MYO5B variant-associated isolated FIC reported in the MEDLINE database. We assembled a comprehensive patient dataset and assessed clinical features of MYO5B-associated FIC, their relationship with MYO5B genotype, the clinical value and significance of BSEP abnormalities, and the relationship of MYO5B-associated FIC to ABCB11 variant-associated FIC. Our review revealed that aberrant BSEP localization correlated with the absence of one MYO5B allele carrying a truncating nonsense or frameshift variant. Notably, biochemical and clinical parameters including treatment outcome were indistinguishable between patients presenting with normal and aberrant BSEP localization. Further, myosin-Vb and BSEP deficiency-associated FIC patient cohorts showed distinct biochemical and clinical phenotypes, indicating different underlying mechanisms. This suggests that whether or not BSEP localization was abnormal depended on the MYO5B genotype without a predictable effect on clinical parameters and treatment response. Treatment decisions should be guided by clinical parameters rather than by genotype or immunohistochemistry findings. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Liver Diseases)
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