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Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 December 2022) | Viewed by 62904

Special Issue Editors

Dr. Alessandro Mantovani

E-Mail Website
Guest Editor
Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
Interests: NAFLD; diabetes; ceramics; gender disparity in science
Special Issues, Collections and Topics in MDPI journals
Dr. Andrea Dalbeni

E-Mail
Guest Editor
Hypertension and Liver Unit, Section of General Medicine, University of Verona, Verona, Italy
Interests: liver diseases; NAFLD; metabolic syndrome; cardiovascular complication in liver disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nonalcoholic fatty liver disease (NAFLD) is an important health care problem worldwide. It affects 30% of adults in the general population, 70% of patients with type 2 diabetes (T2DM), and all patients with obesity. Importantly, NAFLD is now the second most frequent indication for liver transplantation in the United States. In the last several decades, it has become evident that NAFLD is not only associated with serious liver-related complications, but also with relevant metabolic, cardiovascular, and renal complications. Although the pathogenesis of NAFLD is complex, it was established that NAFLD is strongly linked to insulin resistance, abdominal obesity, and T2DM. Based on this evidence, in 2020, some authors have proposed the change of the terminology from NAFLD to metabolic associated fatty liver disease (MAFLD), as well as an update of the definition of this fatty liver disease. Regardless of terminology used, however, it is clearly evident that NAFLD/MAFLD is a dynamic disease, characterized by many factors that change over time. In this regard, specific phenotypes of NAFLD/MAFLD may be broadly driven by environmental factors, genetic predisposition, or metabolic factors.

This Special Issue of the International Journal of Molecular Sciences will focus on recent developments in the area of NAFLD/MAFLD pathogenesis and treatment, as well as new insights into the mechanisms and therapies for NAFLD/MAFLD. It will cover a selection of recent research topics and current review articles in the field of NAFLD/MAFLD. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Dr. Alessandro Mantovani
Dr. Andrea Dalbeni
Guest Editors

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • nonalcoholic fatty liver disease (NAFLD)
  • metabolic associated fatty liver disease (MAFLD)
  • nonalcoholic steatohepatitis (NASH)
  • fatty liver
  • cardiovascular disease

Published Papers (18 papers)

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Editorial

Jump to: Research, Review

3 pages, 204 KiB  
Editorial
NAFLD/MAFLD: New Evidence
by Alessandro Mantovani and Andrea Dalbeni
Int. J. Mol. Sci. 2023, 24(8), 7241; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087241 - 14 Apr 2023
Cited by 1 | Viewed by 1305
Abstract
The aim of the second edition of our Special Issue, entitled “Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2 [...] Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)

Research

Jump to: Editorial, Review

15 pages, 1877 KiB  
Article
Pro-Inflammatory Adipokine and Cytokine Profiles in the Saliva of Obese Patients with Non-Alcoholic Fatty Liver Disease (NAFLD)—A Pilot Study
by Beata Zyśk, Lucyna Ostrowska, Joanna Smarkusz-Zarzecka, Katarzyna Witczak-Sawczuk, Agnieszka Gornowicz and Anna Bielawska
Int. J. Mol. Sci. 2023, 24(3), 2891; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032891 - 02 Feb 2023
Cited by 2 | Viewed by 1955
Abstract
Undiagnosed and untreated non-alcoholic fatty liver disease (NAFLD) can lead to the development of many complications, such as cirrhosis, hepatocellular carcinoma, or cardiovascular diseases. Obese people are at increased risk of developing NAFLD. Due to the current lack of routine diagnostics, it is [...] Read more.
Undiagnosed and untreated non-alcoholic fatty liver disease (NAFLD) can lead to the development of many complications, such as cirrhosis, hepatocellular carcinoma, or cardiovascular diseases. Obese people are at increased risk of developing NAFLD. Due to the current lack of routine diagnostics, it is extremely important to look for new diagnostic methods and markers for this disease. The aim of this study was to assess the concentration of selected pro-inflammatory adipokines and cytokines in the unstimulated saliva of obese people with fatty liver disease in various stages (with or without slight fibrosis) and to analyze them for possible use as early markers of NAFLD diagnosis. The study involved 96 people who were divided into 5 groups based on the criterion of body mass index (BMI) and the degree of fatty liver (liver elastography). There were statistically significant differences between the groups in the concentrations of MMP-9 (matrix metalloproteinase 9), resistin, and IL-1β (interleukin 1β) in saliva. Statistically significant, positive correlations between hepatic steatosis and the concentration of MMP-2 (matrix metalloproteinase 2), resistin, and IL-1β in saliva were also found. Statistically significant positive correlations were also found between the concentration of resistin in saliva and the concentration of ALT (alanine aminotransferase) and GGTP (gamma-glutamyl transpeptidase) in serum. MMP-2, IL-1β, and resistin may be potential markers of NAFLD development, assessed in saliva. However, further research is needed because this is the first study to evaluate the concentrations of the selected pro-inflammatory parameters in the saliva of patients with NAFLD. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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13 pages, 2728 KiB  
Article
Bempedoic Acid Restores Liver H2S Production in a Female Sprague-Dawley Rat Dietary Model of Non-Alcoholic Fatty Liver
by Núria Roglans, Elena Fauste, Roger Bentanachs, Ana M. Velázquez, Madelin Pérez-Armas, Cristina Donis, María I. Panadero, Marta Alegret, Paola Otero, Carlos Bocos and Juan C. Laguna
Int. J. Mol. Sci. 2023, 24(1), 473; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010473 - 28 Dec 2022
Cited by 3 | Viewed by 2241
Abstract
We previously demonstrated that treatment with BemA (bempedoic acid), an inhibitor of ATP citrate lyase, significantly reduces fatty liver in a model of liver steatosis (HFHFr—female Sprague-Dawley rat fed a high-fat high-fructose diet). Since the hepatic production of the gasotransmitter H2S [...] Read more.
We previously demonstrated that treatment with BemA (bempedoic acid), an inhibitor of ATP citrate lyase, significantly reduces fatty liver in a model of liver steatosis (HFHFr—female Sprague-Dawley rat fed a high-fat high-fructose diet). Since the hepatic production of the gasotransmitter H2S is impaired in liver disorders, we were interested in determining if the production of H2S was altered in our HFHFr model and whether the administration of BemA reversed these changes. We used stored liver samples from a previous study to determine the total and enzymatic H2S production, as well as the expression of CBS (cystathionine β-synthase), CSE (cystathionine γ-lyase), and 3MST (3-mercaptopiruvate sulfurtransferase), and the expression/activity of FXR (farnesoid X receptor), a transcription factor involved in regulating CSE expression. Our data show that the HFHFr diet reduces the total and enzymatic production of liver H2S, mainly by decreasing the expression of CBS and CSE. Furthermore, BemA treatment restored H2S production, increasing the expression of CBS and CSE, providing evidence for the involvement of FXR transcriptional activity and the mTORC1 (mammalian target of rapamycin1)/S6K1 (ribosomal protein S6 kinase beta-1)/PGC1α (peroxisome proliferator receptor gamma coactivator1α) pathway. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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16 pages, 1754 KiB  
Article
Plasma Calprotectin Levels Associate with Suspected Metabolic-Associated Fatty Liver Disease and All-Cause Mortality in the General Population
by Arno R. Bourgonje, Eline H. van den Berg, Lyanne M. Kieneker, Tom Nilsen, Clara Hidden, Stephan J. L. Bakker, Hans Blokzijl, Robin P. F. Dullaart, Harry van Goor and Amaal E. Abdulle
Int. J. Mol. Sci. 2022, 23(24), 15708; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415708 - 11 Dec 2022
Cited by 11 | Viewed by 2194
Abstract
Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis, metabolic dysregulation, and neutrophilic inflammation. In this study, we hypothesized that systemic levels of plasma calprotectin, as a biomarker of neutrophilic inflammation, may be associated with suspected MAFLD. Plasma calprotectin levels were measured [...] Read more.
Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis, metabolic dysregulation, and neutrophilic inflammation. In this study, we hypothesized that systemic levels of plasma calprotectin, as a biomarker of neutrophilic inflammation, may be associated with suspected MAFLD. Plasma calprotectin levels were measured in subjects (n = 5446) participating in the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort study. Suspected MAFLD was defined by the fatty liver index (FLI ≥ 60) and hepatic steatosis index (HSI ≥ 36) as proxies. Plasma calprotectin levels were significantly higher in subjects with FLI ≥ 60 (0.57 [IQR: 0.42–0.79] mg/L, n = 1592) (p < 0.001) compared to subjects with FLI < 60 (0.46 [0.34–0.65] mg/L, n = 3854). Multivariable logistic regression analyses revealed that plasma calprotectin levels were significantly associated with suspected MAFLD (FLI ≥ 60), even after adjustment for potential confounding factors, including current smoking, alcohol consumption, hypertension, diabetes, cardiovascular diseases, insulin resistance (HOMA-IR), hs-CRP, eGFR, and total cholesterol levels (OR 1.19 [95% CI: 1.06–1.33], p = 0.003). Interaction analyses revealed significant effect modifications for the association between plasma calprotectin and suspected MAFLD by BMI (p < 0.001) and hypertension (p = 0.003), with the strongest associations in subjects with normal BMI and without hypertension. Prospectively, plasma calprotectin levels were significantly associated with all-cause mortality after adjustment for potential confounding factors, particularly in subjects without suspected MAFLD (FLI < 60) (hazard ratio (HR) per doubling: 1.34 (1.05–1.72), p < 0.05). In conclusion, higher plasma calprotectin levels are associated with suspected MAFLD and with the risk of all-cause mortality, the latter especially in subjects without suspected MAFLD. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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12 pages, 972 KiB  
Article
Accuracy of FIB-4 to Detect Elevated Liver Stiffness Measurements in Patients with Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study in Referral Centers
by Mauro Viganò, Nicola Pugliese, Federica Cerini, Federica Turati, Vincenzo Cimino, Sofia Ridolfo, Simone Rocchetto, Francesca Foglio, Maria Terrin, Carlo La Vecchia, Maria Grazia Rumi and Alessio Aghemo
Int. J. Mol. Sci. 2022, 23(20), 12489; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012489 - 18 Oct 2022
Cited by 7 | Viewed by 1723
Abstract
The identification of advanced fibrosis by applying noninvasive tests is still a key component of the diagnostic algorithm of NAFLD. The aim of this study is to assess the concordance between the FIB-4 and liver stiffness measurement (LSM) in patients referred to two [...] Read more.
The identification of advanced fibrosis by applying noninvasive tests is still a key component of the diagnostic algorithm of NAFLD. The aim of this study is to assess the concordance between the FIB-4 and liver stiffness measurement (LSM) in patients referred to two liver centers for the ultrasound-based diagnosis of NAFLD. Fibrosis 4 Index for Liver Fibrosis (FIB-4) and LSM were assessed in 1338 patients. A total of 428 (32%) had an LSM ≥ 8 kPa, whereas 699 (52%) and 113 (9%) patients had an FIB-4 < 1.3 and >3.25, respectively. Among 699 patients with an FIB-4 < 1.3, 118 (17%) had an LSM ≥ 8 kPa (false-negative FIB-4). This proportion was higher in patients ≥60 years, with diabetes mellitus (DM), arterial hypertension or a body mass index (BMI) ≥ 27 kg/m2. In multiple adjusted models, age ≥ 60 years (odds ratio (OR) = 1.96, 95% confidence interval (CI) 1.19–3.23)), DM (OR = 2.59, 95% CI 1.63–4.13), body mass index (BMI) ≥ 27 kg/m2 (OR = 2.17, 95% CI 1.33–3.56) and gamma-glutamyltransferase ≥ 25 UI/L (OR = 2.68, 95% CI 1.49–4.84) were associated with false-negative FIB-4. The proportion of false-negative FIB-4 was 6% in patients with none or one of these risk factors and increased to 16, 31 and 46% among those with two, three and four concomitant risk factors, respectively. FIB-4 is suboptimal to identify patients to refer to liver centers, because about one-fifth may be false negative at FIB-4, having instead an LSM ≥ 8 KPa. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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13 pages, 279 KiB  
Article
Long-Term Adverse Effect of Liver Stiffness on Glycaemic Control in Type 2 Diabetic Patients with Nonalcoholic Fatty Liver Disease: A Pilot Study
by Alessandro Mantovani, Antonio Taverna, Davide Cappelli, Giorgia Beatrice, Alessandro Csermely, Elena Sani, Christopher D. Byrne and Giovanni Targher
Int. J. Mol. Sci. 2022, 23(20), 12481; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012481 - 18 Oct 2022
Cited by 5 | Viewed by 1404
Abstract
Currently, there are limited data regarding the long-term effect of liver stiffness on glycaemic control in patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). We prospectively followed an outpatient sample of 61 consecutive postmenopausal women with T2DM and [...] Read more.
Currently, there are limited data regarding the long-term effect of liver stiffness on glycaemic control in patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). We prospectively followed an outpatient sample of 61 consecutive postmenopausal women with T2DM and NAFLD who had baseline data on liver ultrasonography and Fibroscan®-assessed liver stiffness measurement (LSM) in 2017 and who underwent follow-up in 2022. Haemoglobin A1c (HbA1c) was measured both at baseline and follow-up. At baseline, 52 patients had NAFLD (hepatic steatosis) alone, and 9 had NAFLD with coexisting clinically significant fibrosis (defined as LSM ≥ 7 kPa on Fibroscan®). At follow-up, 16 patients had a worsening of glycaemic control (arbitrarily defined as HbA1c increase ≥ 0.5% from baseline). The prevalence of NAFLD and coexisting clinically significant fibrosis at baseline was at least three times greater among patients who developed worse glycaemic control at follow-up, compared with those who did not (31.3% vs. 8.9%; p = 0.030). In logistic regression analysis, the presence of NAFLD and clinically significant fibrosis was associated with an approximately 4.5-fold increased likelihood of developing worse glycaemic control at follow-up (odds ratio 4.66, 95% confidence interval 1.07–20.3; p = 0.041), even after adjustment for baseline confounding factors, such as age, body mass index, haemoglobin A1c (or HOMA-estimated insulin resistance) and use of some glucose-lowering agents that may positively affect NAFLD and liver fibrosis. In conclusion, our results suggest that the presence of Fibroscan®-assessed significant fibrosis was associated with a higher risk of developing worse glycaemic control in postmenopausal women with T2DM and NAFLD. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
16 pages, 4426 KiB  
Article
Alterations of Central Liver Metabolism of Pediatric Patients with Non-Alcoholic Fatty Liver Disease
by Nikolaus Berndt, Christian A. Hudert, Johannes Eckstein, Christoph Loddenkemper, Stephan Henning, Philip Bufler, David Meierhofer, Ingolf Sack, Susanna Wiegand, Iwona Wallach and Hermann-Georg Holzhütter
Int. J. Mol. Sci. 2022, 23(19), 11072; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911072 - 21 Sep 2022
Cited by 4 | Viewed by 1615
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and is associated with overweight and insulin resistance (IR). Almost nothing is known about in vivo alterations of liver metabolism in NAFLD, especially in the early stages of non-alcoholic [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and is associated with overweight and insulin resistance (IR). Almost nothing is known about in vivo alterations of liver metabolism in NAFLD, especially in the early stages of non-alcoholic steatohepatitis (NASH). Here, we used a complex mathematical model of liver metabolism to quantify the central hepatic metabolic functions of 71 children with biopsy-proven NAFLD. For each patient, a personalized model variant was generated based on enzyme abundances determined by mass spectroscopy. Our analysis revealed statistically significant alterations in the hepatic carbohydrate, lipid, and ammonia metabolism, which increased with the degree of obesity and severity of NAFLD. Histologic features of NASH and IR displayed opposing associations with changes in carbohydrate and lipid metabolism but synergistically decreased urea synthesis in favor of the increased release of glutamine, a driver of liver fibrosis. Taken together, our study reveals already significant alterations in the NASH liver of pediatric patients, which, however, are differently modulated by the simultaneous presence of IR. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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10 pages, 3741 KiB  
Article
Endoplasmic Reticulum and Mitochondria Contacts Correlate with the Presence and Severity of NASH in Humans
by Chaonan Jin, Eric Felli, Naomi Franziska Lange, Annalisa Berzigotti, Jordi Gracia-Sancho and Jean-François Dufour
Int. J. Mol. Sci. 2022, 23(15), 8348; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158348 - 28 Jul 2022
Cited by 7 | Viewed by 1986
Abstract
The interaction between the mitochondria and the endoplasmic reticulum (ER) is essential for hepatocyte function. An increase in ER–mitochondria contacts (ERMCs) is associated with various metabolic diseases. Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes, and its progressive [...] Read more.
The interaction between the mitochondria and the endoplasmic reticulum (ER) is essential for hepatocyte function. An increase in ER–mitochondria contacts (ERMCs) is associated with various metabolic diseases. Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes, and its progressive form non-alcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma. However, the role of ERMCs in the progression of NAFL to NASH is still unclear. We assessed whether ERMCs could correlate with NAFLD severity. We used a proximity ligation assay to measure the abundance of ERMCs in liver biopsies from patients with biopsy-proven NAFLD (n = 48) and correlated the results with histological and metabolic syndrome (MetS) features. NAFLD patients were included according to inclusion and exclusion criteria, and then assigned to NAFL (n = 9) and NASH (n = 39) groups. ERMCs density could discriminate NASH from NAFL (sensitivity 61.5%, specificity 100%). ERMCs abundance correlated with hepatocellular ballooning. Moreover, the density of ERMCs increased with an increase in the number of MetS features. In conclusion, ERMCs increased from NAFL to NASH, in parallel with the number of MetS features, supporting a role for this interaction in the pathophysiology of NASH. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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24 pages, 2753 KiB  
Article
Adaptation of Oxidative Phosphorylation Machinery Compensates for Hepatic Lipotoxicity in Early Stages of MAFLD
by Pia Fahlbusch, Aleksandra Nikolic, Sonja Hartwig, Sylvia Jacob, Ulrike Kettel, Cornelia Köllmer, Hadi Al-Hasani, Stefan Lehr, Dirk Müller-Wieland, Birgit Knebel and Jörg Kotzka
Int. J. Mol. Sci. 2022, 23(12), 6873; https://doi.org/10.3390/ijms23126873 - 20 Jun 2022
Cited by 6 | Viewed by 2168
Abstract
Alterations in mitochondrial function are an important control variable in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), while also noted by increased de novo lipogenesis (DNL) and hepatic insulin resistance. We hypothesized that the organization and function of a mitochondrial electron [...] Read more.
Alterations in mitochondrial function are an important control variable in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), while also noted by increased de novo lipogenesis (DNL) and hepatic insulin resistance. We hypothesized that the organization and function of a mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. We addressed this question using a transgenic mouse model with increased hepatic insulin resistance and DNL due to constitutively active human SREBP-1c. The abundance of ETC complex subunits and components of key metabolic pathways are regulated in the liver of these animals. Further omics approaches combined with functional assays in isolated liver mitochondria and primary hepatocytes revealed that the SREBP-1c-forced fatty liver induced a substrate limitation for oxidative phosphorylation, inducing enhanced complex II activity. The observed increased expression of mitochondrial genes may have indicated a counteraction. In conclusion, a shift of available substrates directed toward activated DNL results in increased electron flows, mainly through complex II, to compensate for the increased energy demand of the cell. The reorganization of key compounds in energy metabolism observed in the SREBP-1c animal model might explain the initial increase in mitochondrial function observed in the early stages of human MAFLD. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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12 pages, 3089 KiB  
Article
Histone Demethylase KDM7A Contributes to the Development of Hepatic Steatosis by Targeting Diacylglycerol Acyltransferase 2
by Ji-Hyun Kim, Arulkumar Nagappan, Dae Young Jung, Nanjoo Suh and Myeong Ho Jung
Int. J. Mol. Sci. 2021, 22(20), 11085; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011085 - 14 Oct 2021
Cited by 12 | Viewed by 1965
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. While the development of NAFLD is correlated with aberrant histone methylation, modifiers of histone methylation involved in this event remain poorly understood. Here, we studied the functional role of the histone [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. While the development of NAFLD is correlated with aberrant histone methylation, modifiers of histone methylation involved in this event remain poorly understood. Here, we studied the functional role of the histone demethylase KDM7A in the development of hepatic steatosis. KDM7A overexpression in AML12 cells upregulated diacylglycerol acyltransferase 2 (DGAT2) expression and resulted in increased intracellular triglyceride (TG) accumulation. Conversely, KDM7A knockdown reduced DGAT2 expression and TG accumulation, and significantly reversed free fatty acids-induced TG accumulation. Additionally, adenovirus-mediated overexpression of KDM7A in mice resulted in hepatic steatosis, which was accompanied by increased expression of hepatic DGAT2. Furthermore, KDM7A overexpression decreased the enrichment of di-methylation of histone H3 lysine 9 (H3K9me2) and H3 lysine 27 (H3K27me2) on the promoter of DGAT2. Taken together, these results indicate that KDM7A overexpression induces hepatic steatosis through upregulation of DGAT2 by erasing H3K9me2 and H3K27me2 on the promoter. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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Review

Jump to: Editorial, Research

16 pages, 684 KiB  
Review
Fibroblast Growth Factors for Nonalcoholic Fatty Liver Disease: Opportunities and Challenges
by Haoyu Tian, Shuairan Zhang, Ying Liu, Yifan Wu and Dianbao Zhang
Int. J. Mol. Sci. 2023, 24(5), 4583; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054583 - 26 Feb 2023
Cited by 8 | Viewed by 2886
Abstract
Nonalcoholic fatty liver disease (NAFLD), a chronic condition associated with metabolic dysfunction and obesity, has reached epidemic proportions worldwide. Although early NAFLD can be treated with lifestyle changes, the treatment of advanced liver pathology, such as nonalcoholic steatohepatitis (NASH), remains a challenge. There [...] Read more.
Nonalcoholic fatty liver disease (NAFLD), a chronic condition associated with metabolic dysfunction and obesity, has reached epidemic proportions worldwide. Although early NAFLD can be treated with lifestyle changes, the treatment of advanced liver pathology, such as nonalcoholic steatohepatitis (NASH), remains a challenge. There are currently no FDA-approved drugs for NAFLD. Fibroblast growth factors (FGFs) play essential roles in lipid and carbohydrate metabolism and have recently emerged as promising therapeutic agents for metabolic diseases. Among them, endocrine members (FGF19 and FGF21) and classical members (FGF1 and FGF4) are key regulators of energy metabolism. FGF-based therapies have shown therapeutic benefits in patients with NAFLD, and substantial progress has recently been made in clinical trials. These FGF analogs are effective in alleviating steatosis, liver inflammation, and fibrosis. In this review, we describe the biology of four metabolism-related FGFs (FGF19, FGF21, FGF1, and FGF4) and their basic action mechanisms, and then summarize recent advances in the biopharmaceutical development of FGF-based therapies for patients with NAFLD. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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18 pages, 1972 KiB  
Review
Non-Alcoholic Fatty Liver Disease (NAFLD) Pathogenesis and Natural Products for Prevention and Treatment
by Xiangyu Guo, Xunzhe Yin, Zuojia Liu and Jin Wang
Int. J. Mol. Sci. 2022, 23(24), 15489; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415489 - 07 Dec 2022
Cited by 47 | Viewed by 14594
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting approximately one-quarter of the global population, and has become a world public health issue. NAFLD is a clinicopathological syndrome characterized by hepatic steatosis, excluding ethanol and other definite liver damage [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting approximately one-quarter of the global population, and has become a world public health issue. NAFLD is a clinicopathological syndrome characterized by hepatic steatosis, excluding ethanol and other definite liver damage factors. Recent studies have shown that the development of NAFLD is associated with lipid accumulation, oxidative stress, endoplasmic reticulum stress, and lipotoxicity. A range of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the pathogenesis of NAFLD and some natural products that have been shown to have therapeutic effects on NAFLD. Our work shows that natural products can be a potential therapeutic option for NAFLD. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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15 pages, 1256 KiB  
Review
Hydrogen Sulfide and Its Donors: Keys to Unlock the Chains of Nonalcoholic Fatty Liver Disease
by Xianghui Li, Kaixin Jiang, Yantian Ruan, Siyuan Zhao, Yiming Zhao, Yuhua He, Zhili Wang, Jiacun Wei, Qiming Li, Changyong Yang, Yanzhang Li and Tieshan Teng
Int. J. Mol. Sci. 2022, 23(20), 12202; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012202 - 13 Oct 2022
Cited by 4 | Viewed by 1989
Abstract
Hydrogen sulfide (H2S) has emerged as the third “gasotransmitters” and has a crucial function in the diversity of physiological functions in mammals. In particular, H2S is considered indispensable in preventing the development of liver inflammation in the case of [...] Read more.
Hydrogen sulfide (H2S) has emerged as the third “gasotransmitters” and has a crucial function in the diversity of physiological functions in mammals. In particular, H2S is considered indispensable in preventing the development of liver inflammation in the case of excessive caloric ingestion. Note that the concentration of endogenous H2S was usually low, making it difficult to discern the precise biological functions. Therefore, exogenous delivery of H2S is conducive to probe the physiological and pathological roles of this gas in cellular and animal studies. In this review, the production and metabolic pathways of H2S in vivo, the types of donors currently used for H2S release, and study evidence of H2S improvement effects on nonalcoholic fatty liver disease are systematically introduced. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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19 pages, 1198 KiB  
Review
Pathogenesis and Therapeutic Strategies Related to Non-Alcoholic Fatty Liver Disease
by Tieshan Teng, Shuai Qiu, Yiming Zhao, Siyuan Zhao, Dequan Sun, Lingzhu Hou, Yihang Li, Ke Zhou, Xixi Yu, Changyong Yang and Yanzhang Li
Int. J. Mol. Sci. 2022, 23(14), 7841; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147841 - 16 Jul 2022
Cited by 14 | Viewed by 2876
Abstract
Non-alcoholic fatty liver disease (NAFLD), one of the most common types of chronic liver disease, is strongly correlated with obesity, insulin resistance, metabolic syndrome, and genetic components. The pathological progression of NAFLD, consisting of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and liver [...] Read more.
Non-alcoholic fatty liver disease (NAFLD), one of the most common types of chronic liver disease, is strongly correlated with obesity, insulin resistance, metabolic syndrome, and genetic components. The pathological progression of NAFLD, consisting of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and liver cirrhosis, is characterized by a broad spectrum of clinical phenotypes. Although patients with mild NAFL are considered to show no obvious clinical symptoms, patients with long-term NAFL may culminate in NASH and further liver fibrosis. Even though various drugs are able to improve NAFLD, there are no FDA-approved medications that directly treat NAFLD. In this paper, the pathogenesis of NAFLD, the potential therapeutic targets, and their underlying mechanisms of action were reviewed. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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11 pages, 2244 KiB  
Review
MAFLD and CKD: An Updated Narrative Review
by Alessandro Mantovani, Rosa Lombardi, Filippo Cattazzo, Chiara Zusi, Davide Cappelli and Andrea Dalbeni
Int. J. Mol. Sci. 2022, 23(13), 7007; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137007 - 23 Jun 2022
Cited by 12 | Viewed by 3819
Abstract
Accumulating evidence now indicates that non-alcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease observed in clinical practice worldwide, is independently associated with an increased risk of incident chronic kidney disease (CKD). Given that NAFLD is linked to insulin [...] Read more.
Accumulating evidence now indicates that non-alcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease observed in clinical practice worldwide, is independently associated with an increased risk of incident chronic kidney disease (CKD). Given that NAFLD is linked to insulin resistance, obesity and type 2 diabetes mellitus, an international panel of experts have recently proposed a name change from NAFLD to metabolic associated fatty liver disease (MAFLD). Since the diagnostic criteria for NAFLD and MAFLD are different, observational studies assessing the potential concordance (or even superiority) of MAFLD, compared with NAFLD, in detecting patients at increased risk of hepatic and extra-hepatic complications (including CKD) are required. Hence, in the last two years, some observational studies have investigated the potential relationship between MAFLD and CKD. The result is that, at present, evidence regarding the concordance or even superiority of MAFLD, compared with NAFLD, in detecting patients at higher risk of CKD is still preliminary, although some data indicate that MAFLD identifies patients with CKD as accurately as NAFLD. In this narrative review, we will discuss: (a) the epidemiological evidence assessing the association between NAFLD and risk of incident CKD, (b) the epidemiological data investigating the association between MAFLD and risk of CKD and (c) the biological mechanisms underlying the association between NAFLD/MAFLD and CKD. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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14 pages, 661 KiB  
Review
Fibrogenic Pathways in Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)
by Pallavi Subramanian, Jochen Hampe, Frank Tacke and Triantafyllos Chavakis
Int. J. Mol. Sci. 2022, 23(13), 6996; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23136996 - 23 Jun 2022
Cited by 10 | Viewed by 3517
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD), recently also re-defined as metabolic dysfunction associated fatty liver disease (MAFLD), is rapidly increasing, affecting ~25% of the world population. MALFD/NAFLD represents a spectrum of liver pathologies including the more benign hepatic steatosis and the [...] Read more.
The prevalence of nonalcoholic fatty liver disease (NAFLD), recently also re-defined as metabolic dysfunction associated fatty liver disease (MAFLD), is rapidly increasing, affecting ~25% of the world population. MALFD/NAFLD represents a spectrum of liver pathologies including the more benign hepatic steatosis and the more advanced non-alcoholic steatohepatitis (NASH). NASH is associated with enhanced risk for liver fibrosis and progression to cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSC) activation underlies NASH-related fibrosis. Here, we discuss the profibrogenic pathways, which lead to HSC activation and fibrogenesis, with a particular focus on the intercellular hepatocyte–HSC and macrophage–HSC crosstalk. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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27 pages, 15597 KiB  
Review
Nuclear Receptors Linking Metabolism, Inflammation, and Fibrosis in Nonalcoholic Fatty Liver Disease
by Tobias Puengel, Hanyang Liu, Adrien Guillot, Felix Heymann, Frank Tacke and Moritz Peiseler
Int. J. Mol. Sci. 2022, 23(5), 2668; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052668 - 28 Feb 2022
Cited by 42 | Viewed by 8679
Abstract
Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) comprise a spectrum of chronic liver diseases in the global population that can lead to end-stage liver disease and hepatocellular carcinoma (HCC). NAFLD is closely linked to the metabolic syndrome, and [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) comprise a spectrum of chronic liver diseases in the global population that can lead to end-stage liver disease and hepatocellular carcinoma (HCC). NAFLD is closely linked to the metabolic syndrome, and comorbidities such as type 2 diabetes, obesity and insulin resistance aggravate liver disease, while NAFLD promotes cardiovascular risk in affected patients. The pathomechanisms of NAFLD are multifaceted, combining hepatic factors including lipotoxicity, mechanisms of cell death and liver inflammation with extrahepatic factors including metabolic disturbance and dysbiosis. Nuclear receptors (NRs) are a family of ligand-controlled transcription factors that regulate glucose, fat and cholesterol homeostasis and modulate innate immune cell functions, including liver macrophages. In parallel with metabolic derangement in NAFLD, altered NR signaling is frequently observed and might be involved in the pathogenesis. Therapeutically, clinical data indicate that single drug targets thus far have been insufficient for reaching patient-relevant endpoints. Therefore, combinatorial treatment strategies with multiple drug targets or drugs with multiple mechanisms of actions could possibly bring advantages, by providing a more holistic therapeutic approach. In this context, peroxisome proliferator-activated receptors (PPARs) and other NRs are of great interest as they are involved in wide-ranging and multi-organ activities associated with NASH progression or regression. In this review, we summarize recent advances in understanding the pathogenesis of NAFLD, focusing on mechanisms of cell death, immunometabolism and the role of NRs. We outline novel therapeutic strategies and discuss remaining challenges. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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16 pages, 1015 KiB  
Review
Emerging Roles of Calcium Signaling in the Development of Non-Alcoholic Fatty Liver Disease
by Chien-Chih Chen, Li-Wen Hsu, Kuang-Den Chen, King-Wah Chiu, Chao-Long Chen and Kuang-Tzu Huang
Int. J. Mol. Sci. 2022, 23(1), 256; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010256 - 27 Dec 2021
Cited by 16 | Viewed by 3808
Abstract
The liver plays a central role in energy metabolism. Dysregulated hepatic lipid metabolism is a major cause of non-alcoholic fatty liver disease (NAFLD), a chronic liver disorder closely linked to obesity and insulin resistance. NAFLD is rapidly emerging as a global health problem [...] Read more.
The liver plays a central role in energy metabolism. Dysregulated hepatic lipid metabolism is a major cause of non-alcoholic fatty liver disease (NAFLD), a chronic liver disorder closely linked to obesity and insulin resistance. NAFLD is rapidly emerging as a global health problem with currently no approved therapy. While early stages of NAFLD are often considered benign, the disease can progress to an advanced stage that involves chronic inflammation, with increased risk for developing end-stage disease including fibrosis and liver cancer. Hence, there is an urgent need to identify potential pharmacological targets. Ca2+ is an essential signaling molecule involved in a myriad of cellular processes. Intracellular Ca2+ is intricately compartmentalized, and the Ca2+ flow is tightly controlled by a network of Ca2+ transport and buffering proteins. Impaired Ca2+ signaling is strongly associated with endoplasmic reticulum stress, mitochondrial dysfunction and autophagic defects, all of which are etiological factors of NAFLD. In this review, we describe the recent advances that underscore the critical role of dysregulated Ca2+ homeostasis in lipid metabolic abnormalities and discuss the feasibility of targeting Ca2+ signaling as a potential therapeutic approach. Full article
(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 2.0)
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