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Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) 4.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 December 2024) | Viewed by 11039

Special Issue Editors

Dr. Mariapia Vairetti

E-Mail Website
Guest Editor
Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
Interests: liver; NAFLD/NASH; farnesoid X receptor; oxidative stress; metalloproteinases; signal transduction
Special Issues, Collections and Topics in MDPI journals
Dr. Giuseppe Colucci

E-Mail Website
Guest Editor
Department of Medical and Surgical, Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
Interests: chronic hepatitis; NAFLD-NASH; immunopatholoy; liver fibrosis
Special Issues, Collections and Topics in MDPI journals
Dr. Andrea Ferrigno

E-Mail Website
Guest Editor
Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
Interests: liver; ischemia/reperfusion; metabotropic glutamate receptor 5; inflammation; G protein-coupled receptors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nonalcoholic fatty liver disease (NAFLD) is among the most common liver diseases worldwide, affecting up to 20–30% of the human population. NAFLD is usually associated with the metabolic syndrome that is characterized by increased abdominal fat, insulin resistance, high blood pressure, and high blood triglycerides. In about 10% of individuals, NAFLD progresses to steatohepatitis (NASH), with a long-term risk of cirrhosis and hepatocellular carcinoma, among the most important causes of liver transplantation in US with consequent relevant social and economic impact. Nonetheless, specific pharmacological targets and treatment have not been found yet, leaving important medical needs still to be met. The Special Issue, “Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH)”, of the International Journal of Molecular Sciences, will include a selection of original research papers and reviews on novel molecular and cellular targets to prevent and treat NAFLD. This Special Issue will also include an update on the management of liver steatosis, inflammation, and fibrosis.

Dr. Mariapia Vairetti
Dr. Giuseppe Colucci
Dr. Andrea Ferrigno
Guest Editors

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Keywords

  • fatty liver
  • steatosis
  • steatohepatitis
  • inflammation
  • fibrosis
  • cytochines
  • chemokine receptors
  • insulin sensitizing drugs
  • farnesoid X receptor agonists
  • bile acids
  • oxidative stress
  • mitochondrial function
  • peroxisome proliferator-activated receptors (PPARs)

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Published Papers (3 papers)

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Research

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20 pages, 2385 KiB  
Article
A Comprehensive Analysis of Liver Lipidomics Signature in Adults with Metabolic Dysfunction-Associated Steatohepatitis—A Pilot Study
by Thomai Mouskeftara, Georgios Kalopitas, Theodoros Liapikos, Konstantinos Arvanitakis, Eleni Theocharidou, Georgios Germanidis and Helen Gika
Int. J. Mol. Sci. 2024, 25(23), 13067; https://doi.org/10.3390/ijms252313067 - 5 Dec 2024
Cited by 1 | Viewed by 1571
Abstract
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disorder in Western countries, encompassing a range of conditions from steatosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), which can potentially progress to cirrhosis. Lipidomics approaches have revealed significant alterations in the hepatic [...] Read more.
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disorder in Western countries, encompassing a range of conditions from steatosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), which can potentially progress to cirrhosis. Lipidomics approaches have revealed significant alterations in the hepatic lipidome associated with both steatosis and steatohepatitis, with these changes correlating with disease manifestation. While the transition from steatosis to MASH remains poorly understood, recent research indicates that both the quantity and quality of deposited lipids play a pivotal role in MASLD progression. In our study, we utilized untargeted and targeted analyses to identify intact lipids and fatty acids in liver biopsies from healthy controls and MASLD patients, categorized based on their histological findings. In total, 447 lipid species were identified, with 215 subjected to further statistical analysis. Univariate and multivariate analyses revealed alterations in triglyceride species and fatty acids, including FA 16:0, FA 16:1, FA 18:3 n6, the sum of MUFA, and the Δ9-desaturase activity ratio. This research provides insights into the connection between dysregulated lipid metabolism in the progression of MASLD, supporting previous findings. Further studies on lipid metabolism could improve risk assessment methods, particularly given the current limited understanding of the transition from steatosis to MASH. Full article
(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) 4.0)
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Review

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28 pages, 695 KiB  
Review
NAFLD and NAFLD Related HCC: Emerging Treatments and Clinical Trials
by Tripti Khare, Karina Liu, Lindiwe Oslee Chilambe and Sharad Khare
Int. J. Mol. Sci. 2025, 26(1), 306; https://doi.org/10.3390/ijms26010306 - 1 Jan 2025
Cited by 4 | Viewed by 3188
Abstract
Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most prevalent liver disease worldwide. It is associated with an increased risk of developing hepatocellular carcinoma (HCC) in the background of cirrhosis or without cirrhosis. The prevalence of NAFLD-related [...] Read more.
Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most prevalent liver disease worldwide. It is associated with an increased risk of developing hepatocellular carcinoma (HCC) in the background of cirrhosis or without cirrhosis. The prevalence of NAFLD-related HCC is increasing all over the globe, and HCC surveillance in NAFLD cases is not that common. In the present review, we attempt to summarize promising treatments and clinical trials focused on NAFLD, nonalcoholic steatohepatitis (NASH), and HCC in the past five to seven years. We categorized the trials based on the type of intervention. Most of the trials are still running, with only a few completed and with conclusive results. In clinical trial NCT03942822, 25 mg/day of milled chia seeds improved NAFLD condition. Completed trial NCT03524365 concluded that Rouxen-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) results in histological resolution of NASH without worsening of fibrosis, while NCT04677101 validated sensitivity/accuracy of blood biomarkers in predicting NASH and fibrosis stage. Moreover, trials with empagliflozin (NCT05694923), curcuvail (NCT06256926), and obeticholic acid (NCT03439254) were completed but did not provide conclusive results. However, trial NCT03900429 reported effective improvement in fibrosis by at least one stage, without worsening of NAFLD activity score (NAS), as well as improvement in lipid profile of the NASH patients by 80 or 100 mg MGL-3196 (resmetirom). Funded by Madrigal Pharmaceuticals, Rezdiffra (resmetirom), used in the clinical trial NCT03900429, is the first FDA-approved drug for the treatment of NAFLD/NASH. Full article
(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) 4.0)
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26 pages, 3210 KiB  
Review
NAFLD (MASLD)/NASH (MASH): Does It Bother to Label at All? A Comprehensive Narrative Review
by Consolato M. Sergi
Int. J. Mol. Sci. 2024, 25(15), 8462; https://doi.org/10.3390/ijms25158462 - 2 Aug 2024
Cited by 5 | Viewed by 5507
Abstract
Nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated steatotic liver disease (MASLD), is a liver condition that is linked to overweight, obesity, diabetes mellitus, and metabolic syndrome. Nonalcoholic steatohepatitis (NASH), or metabolic dysfunction-associated steatohepatitis (MASH), is a form of NAFLD/MASLD that progresses over [...] Read more.
Nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated steatotic liver disease (MASLD), is a liver condition that is linked to overweight, obesity, diabetes mellitus, and metabolic syndrome. Nonalcoholic steatohepatitis (NASH), or metabolic dysfunction-associated steatohepatitis (MASH), is a form of NAFLD/MASLD that progresses over time. While steatosis is a prominent histological characteristic and recognizable grossly and microscopically, liver biopsies of individuals with NASH/MASH may exhibit several other abnormalities, such as mononuclear inflammation in the portal and lobular regions, hepatocellular damage characterized by ballooning and programmed cell death (apoptosis), misfolded hepatocytic protein inclusions (Mallory–Denk bodies, MDBs), megamitochondria as hyaline inclusions, and fibrosis. Ballooning hepatocellular damage remains the defining feature of NASH/MASH. The fibrosis pattern is characterized by the initial expression of perisinusoidal fibrosis (“chicken wire”) and fibrosis surrounding the central veins. Children may have an alternative form of progressive NAFLD/MASLD characterized by steatosis, inflammation, and fibrosis, mainly in Rappaport zone 1 of the liver acinus. To identify, synthesize, and analyze the scientific knowledge produced regarding the implications of using a score for evaluating NAFLD/MASLD in a comprehensive narrative review. The search for articles was conducted between 1 January 2000 and 31 December 2023, on the PubMed/MEDLINE, Scopus, Web of Science, and Cochrane databases. This search was complemented by a gray search, including internet browsers (e.g., Google) and textbooks. The following research question guided the study: “What are the basic data on using a score for evaluating NAFLD/MASLD?” All stages of the selection process were carried out by the single author. Of the 1783 articles found, 75 were included in the sample for analysis, which was implemented with an additional 25 articles from references and gray literature. The studies analyzed indicated the beneficial effects of scoring liver biopsies. Although similarity between alcoholic steatohepatitis (ASH) and NASH/MASH occurs, some patterns of hepatocellular damage seen in alcoholic disease of the liver do not happen in NASH/MASH, including cholestatic featuring steatohepatitis, alcoholic foamy degeneration, and sclerosing predominant hyaline necrosis. Generally, neutrophilic-rich cellular infiltrates, prominent hyaline inclusions and MDBs, cholestasis, and obvious pericellular sinusoidal fibrosis should favor the diagnosis of alcohol-induced hepatocellular injury over NASH/MASH. Multiple grading and staging methods are available for implementation in investigations and clinical trials, each possessing merits and drawbacks. The systems primarily used are the Brunt, the NASH CRN (NASH Clinical Research Network), and the SAF (steatosis, activity, and fibrosis) systems. Clinical investigations have utilized several approaches to link laboratory and demographic observations with histology findings with optimal platforms for clinical trials of rapidly commercialized drugs. It is promising that machine learning procedures (artificial intelligence) may be critical for developing new platforms to evaluate the benefits of current and future drug formulations. Full article
(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) 4.0)
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