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Biomedicines
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Fatty Liver Disease: From Mechanisms to Therapeutic Approaches
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Fatty Liver Disease: From Mechanisms to Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Endocrinology and Metabolism Research".

Deadline for manuscript submissions: closed (28 February 2025) | Viewed by 4875

Special Issue Editor

Dr. Mirela Baus Lončar

E-Mail Website
Guest Editor
Institute Ruder Boskovic, Zagreb, Croatia
Interests: trefoil family petides (Tffs); gut-liver-brain axis, animal model of Tff3 deficiency; metabolism

Special Issue Information

Dear Colleagues,

The liver, as the largest organ, participates in food digestion, energy storage and the removal of toxic substances removal from the body, thus having a major impact on the general health of patients. Excessive buildup of fat in the liver is known as fatty liver, which is becoming increasingly common around the world. Mechanistic accumulation of fat can be related to alcohol toxicity, but the majority of cases nowadays are non-alcohol-related, so this form of fatty liver disease has been renamed to Metabolic dysfunction-associated fatty liver disease (MAFLD). This suggests that a plethora of possible mechanisms are involved in the buildup of fat in the liver, with the possible impact of sex hormones on metabolism needing further study. Excessive fat accumulation can go unnoticed until serious liver dysfunction occurs, disrupting organism homeostasis and possibly resulting in extrahepatic organ pathologies. Fatty liver disease coexists with other diseases like diabetes, cardiovascular diseases, and neurodegenerative diseases, and their connection can no longer be overlooked.

Manuscripts that are being accepted for this Special Issue are those that address the mechanisms of fat accumulation, correlation with other diseases, and the possible effects of sex differences. In addition, manuscripts addressing clinical data, possible early detection, and therapies for fatty liver are also welcome.

Dr. Mirela Baus Lončar
Guest Editor

Manuscript Submission Information

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Keywords

  • fatty liver
  • metabolism
  • animal models of disease
  • gut–liver–brain axis
  • therapy

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Published Papers (5 papers)

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Research

Jump to: Review

27 pages, 1983 KiB  
Article
The Effect of Tff3 Deficiency on the Liver of Mice Exposed to a High-Fat Diet
by Iva Bazina, Kate Šešelja, Tatjana Pirman, Anita Horvatić, Andreja Erman, Martina Mihalj and Mirela Baus Lončar
Biomedicines 2025, 13(5), 1024; https://doi.org/10.3390/biomedicines13051024 - 23 Apr 2025
Viewed by 101
Abstract
Background/Objectives: Trefoil factor protein 3 (Tff3) is a small peptide known as an epithelial tissue-protective protein, and it is also identified as a novel participant in complex metabolic processes. In numerous mouse models of obesity, Tff3 has been found to be downregulated in [...] Read more.
Background/Objectives: Trefoil factor protein 3 (Tff3) is a small peptide known as an epithelial tissue-protective protein, and it is also identified as a novel participant in complex metabolic processes. In numerous mouse models of obesity, Tff3 has been found to be downregulated in the liver and its overexpression is associated with an improvement in metabolic parameters. These mouse models with metabolic phenotypes have a multigenic background, with numerous genes contributing to their phenotype. To elucidate the role of Tff3 protein in metabolic events, we developed a mouse model with Tff3 deficiency on a C57Bl6N background without other intrinsic mutations affecting metabolism. Methods: We investigated the effects of a high-fat diet (9 weeks) on the liver of Tff3 protein-deficient mice of both sexes and the corresponding wild type. We investigated the general metabolic status of the animals and analysed the expression of markers of relevant pathophysiological pathways in the liver. Results:Tff3-deficient mice had significantly lower body weight. They also had a comparable total liver fat content but it was distributed in small vesicles, indicating the protective effect of Tff3 deficiency. The results of molecular analysis showed no major gene expression changes in inflammation-, ER- and oxidative stress-, and lipid metabolism-related genes. Tff3−/− males had reduced expression of Il1α and Cxcr7 genes in the liver and no global proteome changes; Tff3-deficient females had decreased expression of Irs2 and Atf4 genes and total proteome comparison showed decreased levels of proteins related to ribosome biosynthesis and the inhibition of acetylation. Conclusions: Our results demonstrate that Tff3 deficiency reduces lipid accumulation in the liver and we set the direction for further studies aimed at uncovering the exact molecular mechanisms in other organs. Furthermore, it emphasises the need to include both sexes in future research, as the observed phenotype differs significantly depending on sex. Full article
(This article belongs to the Special Issue Fatty Liver Disease: From Mechanisms to Therapeutic Approaches)
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11 pages, 1260 KiB  
Article
Hepatokine and Proinflammatory Cytokine Profile in Patients with Carotid Atherosclerosis and Metabolic Dysfunction-Associated Steatotic Liver Disease
by Ana Delfina Cano-Contreras, Maria del Rocio Francisco, Jose Luis Vargas-Basurto, Kevin David González-Gómez, Hector Vivanco-Cid, Karina Guadalupe Hernández-Flores, Peter Grube-Pagola, Federico Bernardo Roesch-Dietlen and Jose Maria Remes-Troche
Biomedicines 2025, 13(4), 978; https://doi.org/10.3390/biomedicines13040978 - 16 Apr 2025
Viewed by 213
Abstract
Background and Aims: Hepatokines have a regulatory function in adipose tissue inflammation, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular diseases, and atherosclerosis. Our aim was to evaluate the profile of proinflammatory cytokines and hepatokines in patients with MASLD and carotid atherosclerosis (CA). Methods: [...] Read more.
Background and Aims: Hepatokines have a regulatory function in adipose tissue inflammation, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular diseases, and atherosclerosis. Our aim was to evaluate the profile of proinflammatory cytokines and hepatokines in patients with MASLD and carotid atherosclerosis (CA). Methods: A prospective and basic research study was conducted on patients with MASLD. Clinical data were collected from a detailed medical history. Liver stiffness was measured using transient elastography, and carotid Doppler ultrasound was performed. Levels of basic biochemical parameters, systemic inflammation markers (TNF-α, IL-6, IL-10, IL-18), and hepatokines (FGF21, ANGPTL4, fetuin-A) were determined. The results were analyzed with SPSS v22.0 software. Results: Sixty-seven patients with MASLD were included, 72.1% were women, and the mean patient age was 53.9 + 11.3 years. Atherosclerosis was found in 11 patients (16.2%), and carotid intima–media thickness (CIMT) was altered in the right carotid of 13 patients (19.1%), in the left carotid of 19 (27.9%), and bilaterally in 7 (10.3%). Greater age (p = 0.001) and high blood pressure (p = 0.028) were correlated with atherosclerosis. There were no differences in systemic inflammation markers, and the hepatokines FGF21 and fetuin-A tended to increase in the presence of CIMT and CA alterations, regardless of fibrosis. Conclusions: In our population, patients with MASLD had a 16.6% prevalence of CA, and the risk increased with age and a history of high blood pressure. FGF21 tended to increase in patients with MASLD + atherosclerosis, and fetuin-A was correlated with CIMT alterations, suggesting that the combination of these markers could guide us to suspect early endothelial alterations in patients with MASLD. Full article
(This article belongs to the Special Issue Fatty Liver Disease: From Mechanisms to Therapeutic Approaches)
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16 pages, 1196 KiB  
Article
miRNAs and Hematological Markers in Non-Alcoholic Fatty Liver Disease—A New Diagnostic Path?
by Agata Michalak, Małgorzata Guz, Joanna Kozicka, Marek Cybulski, Witold Jeleniewicz, Ilona Telejko, Karolina Szczygieł, Ewa Tywanek and Halina Cichoż-Lach
Biomedicines 2025, 13(1), 230; https://doi.org/10.3390/biomedicines13010230 - 18 Jan 2025
Viewed by 1378
Abstract
Background: Asymptomatic liver steatosis constitutes an emerging issue worldwide. Therefore, we decided to explore relationships between selected types of microRNAs (miRNAs), serological markers of liver fibrosis and hematological parameters in the course of non-alcoholic fatty liver disease (NAFLD). Methods: Two hundred and seven [...] Read more.
Background: Asymptomatic liver steatosis constitutes an emerging issue worldwide. Therefore, we decided to explore relationships between selected types of microRNAs (miRNAs), serological markers of liver fibrosis and hematological parameters in the course of non-alcoholic fatty liver disease (NAFLD). Methods: Two hundred and seven persons were included in the survey: 97 with NAFLD and 110 healthy controls. Serological concentrations of miR-126-3p, miR-197-3p, and miR-1-3p were measured in all participants. Direct indices of liver fibrosis [procollagen I carboxyterminal propeptide (PICP), procollagen III aminoterminal propeptide (PIIINP), platelet-derived growth factor AB (PDGF-AB), transforming growth factor-α (TGF-α) and laminin] together with indirect markers (AAR, APRI, FIB-4 and GPR) were also evaluated. The assessment of hematological parameters concerned: mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), red blood cell distribution width (RDW), MPV to platelet (PLT) ratio (MPR), RDW to PLT ratio (RPR), neutrophil to lymphocyte (LYM) ratio (NLR), PLT to LYM ratio (PLR) and RDW to LYM ratio (RLR). Additionally, the NAFLD fibrosis score and BARD score were applied. Results: The concentration of miR-126-3p and miR-1-3p was higher, and miR-197-3p was lower in the NAFLD group (p < 0.0001). miR-197-3p correlated notably with hematological indices: negatively with PDW (p < 0.05) and positively with PLR (p < 0.05). Conclusions: Significant correlations between miRNA molecules and hematological markers in the course of NAFLD indicate inflammation as a potential background and create new possibilities for a diagnostic approach. Full article
(This article belongs to the Special Issue Fatty Liver Disease: From Mechanisms to Therapeutic Approaches)
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13 pages, 1041 KiB  
Article
Liver Elastography for Liver Fibrosis Stratification: A Comparison of Three Techniques in a Biopsy-Controlled MASLD Cohort
by Antonio Liguori, Giorgio Esposto, Maria Elena Ainora, Irene Mignini, Raffaele Borriello, Linda Galasso, Mattia Paratore, Maria Cristina Giustiniani, Laura Riccardi, Matteo Garcovich, Antonio Gasbarrini, Luca Miele and Maria Assunta Zocco
Biomedicines 2025, 13(1), 138; https://doi.org/10.3390/biomedicines13010138 - 9 Jan 2025
Viewed by 1087
Abstract
Background: The aim of this study was to investigate the accuracy in fibrosis staging of a novel shear wave elastography (SWE) device (S-Shearwave Imaging by Samsung) and a previously validated 2D-SWE by Supersonic Imagine (SSI) in patients with biopsy proven metabolic dysfunction-associated steatotic [...] Read more.
Background: The aim of this study was to investigate the accuracy in fibrosis staging of a novel shear wave elastography (SWE) device (S-Shearwave Imaging by Samsung) and a previously validated 2D-SWE by Supersonic Imagine (SSI) in patients with biopsy proven metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: This prospective study included 75 consecutive patients with MASLD who underwent liver biopsy for suspected MASH. All patients underwent S-Shearwave Imaging by Samsung and 2D-SWE with SSI on the same day of liver biopsy. Fibrosis was histologically assessed using the METAVIR classification system. Agreement between the equipment was assessed with the Pearson coefficient. A receiver operator characteristic curve (ROC) analysis with the Youden index was used to establish thresholds for fibrosis staging. Results: A good correlation was found between S-Shearwave Imaging by Samsung and 2D-SWE with SSI (Pearson’s R = 0.68; p < 0.01). At multivariate regression analysis, S-Shearwave Imaging was associated with advanced fibrosis (≥F3) independently from age, diabetes and platelets (OR 2.94, CI 1.69–5.11, p < 0.01). The fibrosis diagnostic accuracy of both S-Shearwave Imaging and 2D-SWE was good to optimal with AUROCs of 0.81 and 0.70 for significant fibrosis (≥F2), 0.94 and 0.91 for severe fibrosis (≥F3), respectively. The accuracy of S-Shearwave is not significantly different from Fibroscan and Agile3+ (DeLong test p value 0.16 and 0.15, respectively) while is slightly better than 2D-SWE, FIB4 and NFS (DeLong test p value < 0.05). For S-Shearwave Imaging by Samsung, the best cut-off values for diagnosing fibrosis ≥F2, ≥F3 were, respectively, 7.9 kPa (Sens 74.4%, Spec 87.5%) and 8.1 kPa (Sens 95.6%, Spec 78.8%). For 2D-SWE by SSI, the best cut-off values for diagnosing fibrosis ≥F2, ≥F3 were, respectively, 7.2 kPa (Sens 55.8%, Spec 84.4%) and 7.6 kPa (Sens 82.6%, Spec 84.6%). Conclusion: S-Shearwave Imaging is a useful and reliable non-invasive technique for staging liver fibrosis in patients with MASLD. Its diagnostic accuracy is non-inferior to other shear wave elastography techniques (TE and 2D-SWE by SSI). Full article
(This article belongs to the Special Issue Fatty Liver Disease: From Mechanisms to Therapeutic Approaches)
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Review

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43 pages, 1965 KiB  
Review
MASLD: Prevalence, Mechanisms, and Sex-Based Therapies in Postmenopausal Women
by Ilaria Milani, Marianna Chinucci, Frida Leonetti and Danila Capoccia
Biomedicines 2025, 13(4), 855; https://doi.org/10.3390/biomedicines13040855 - 2 Apr 2025
Viewed by 566
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease influenced by genetic, lifestyle, and environmental factors. While MASLD is more prevalent in men, women are at increased risk after menopause, highlighting the critical pathogenetic role of sex hormones. The [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease influenced by genetic, lifestyle, and environmental factors. While MASLD is more prevalent in men, women are at increased risk after menopause, highlighting the critical pathogenetic role of sex hormones. The complex interplay between estrogen deficiency, visceral fat accumulation, metabolic syndrome (MetS), and inflammation accelerates disease progression, increases cardiovascular (CV) risk, and triggers a cycle of worsening adiposity, metabolic dysfunction, and psychological problems, including eating disorders. Weight loss in postmenopausal women can significantly improve both metabolic and psychological outcomes, helping to prevent MASLD and related conditions. This review examines the prevalence of MASLD, its comorbidities (type 2 diabetes T2D, CV, mental disorders), pathogenetic mechanisms, and pharmacological treatment with GLP-1 receptor agonists (GLP1-RAs), with a focus on postmenopausal women. Given the use of GLP1-RAs in the treatment of obesity and T2D in MASLD patients, and the increase in MetS and MASLD after menopause, this review analyzes the potential of a stable GLP-1–estrogen conjugate as a therapeutic approach in this subgroup. By combining the synergistic effects of both hormones, this dual agonist has been shown to increase food intake and food reward suppression, resulting in greater weight loss and improved insulin sensitivity, glucose, and lipid metabolism. Therefore, we hypothesize that this pharmacotherapy may provide more targeted therapeutic benefits than either hormone alone by protecting the liver, β-cells, and overall metabolic health. As these effects are only supported by preclinical data, this review highlights the critical need for future research to evaluate and confirm the mechanisms and efficacy in clinical settings, particularly in postmenopausal women. Full article
(This article belongs to the Special Issue Fatty Liver Disease: From Mechanisms to Therapeutic Approaches)
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