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Growth differentiation factor 15 (GDF15) is a cell stress-response cytokine within the transforming growth factor-β (TGFβ) superfamily. It is known to exert diverse effects on many metabolic pathways through its receptor GFRAL, which is expressed in the hindbrain, and transduces signals through the downstream receptor tyrosine kinase Ret. Since the liver is the core organ of metabolism, summarizing the functions of GDF15 is highly important. In this review, we assessed the relevant literature regarding the main metabolic, inflammatory, fibrogenic, tumorigenic and other effects of GDF15 on different liver diseases, including Metabolic dysfunction-associated steatotic liver disease(MASLD), alcohol and drug-induced liver injury, as well as autoimmune and viral hepatitis, with a particular focus on the pathogenesis of MASLD progression from hepatic steatosis to MASH, liver fibrosis and even hepatocellular carcinoma (HCC). Finally, we discuss the prospects of the clinical application potential of GDF15 along with its research and development progress. With better knowledge of GDF15, increasing in-depth research will lead to a new era in the field of liver diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The hepatic sinusoids are composed of liver sinusoidal endothelial cells (LSECs), which are surrounded by hepatic stellate cells (HSCs) and contain liver-resident macrophages called Kupffer cells, and other patrolling immune cells. All these cells communicate with each other and with hepatocytes to maintain sinusoidal homeostasis and a spectrum of hepatic functions under healthy conditions. Sinusoidal homeostasis is disrupted by metabolites, toxins, viruses, and other pathological factors, leading to liver injury, chronic liver diseases, and cirrhosis. Alterations in hepatic sinusoids are linked to fibrosis progression and portal hypertension. LSECs are crucial regulators of cellular crosstalk within their microenvironment via angiocrine signaling. This review discusses the mechanisms by which angiocrine signaling orchestrates sinusoidal homeostasis, as well as the development of liver diseases. Here, we summarise the crosstalk between LSECs, HSCs, hepatocytes, cholangiocytes, and immune cells in health and disease and comment on potential novel therapeutic methods for treating liver diseases., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Chronic liver inflammation, a pervasive global health issue, results in millions of annual deaths due to its progression from fibrosis to the more severe forms of cirrhosis and hepatocellular carcinoma (HCC). This insidious condition stems from diverse factors such as obesity, genetic conditions, alcohol abuse, viral infections, autoimmune diseases, and toxic accumulation, manifesting as chronic liver diseases (CLDs) such as metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), alcoholic liver disease (ALD), viral hepatitis, drug-induced liver injury, and autoimmune hepatitis. Late detection of CLDs necessitates effective treatments to inhibit and potentially reverse disease progression. However, current therapies exhibit limitations in consistency and safety. A potential breakthrough lies in nanoparticle-based drug delivery strategies, offering targeted delivery to specific liver cell types, such as hepatocytes, Kupffer cells, and hepatic stellate cells. This review explores molecular targets for CLD treatment, ongoing clinical trials, recent advances in nanoparticle-based drug delivery, and the future outlook of this research field. Early intervention is crucial for chronic liver disease. Having a comprehensive understanding of current treatments, molecular biomarkers and novel nanoparticle-based drug delivery strategies can have enormous impact in guiding future strategies for the prevention and treatment of CLDs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Liver disease poses a substantial burden in Latin America. This burden is primarily attributed to a high level of alcohol consumption and the increasing prevalence of risk factors associated with metabolic dysfunction-associated steatotic liver disease (MASLD), such as sedentary lifestyles, easy access to ultra-processed foods, obesity, and type 2 diabetes mellitus. These epidemiological trends are cause for concern, especially considering that there are significant challenges in addressing them due to disparities in access to liver disease screening and care. In this article, we aim to provide an overview of the current situation regarding liver disease in Latin America. We also discuss recent multinational proposals designed to address the growing MASLD burden via its integration into existing non-communicable diseases policies, at both local and global levels. Additionally, we emphasize the urgent need to establish effective public health policies that target both MASLD risk factors and excessive alcohol consumption. Furthermore, we discuss the development of liver transplantation programs, areas for improvement in medical education and research capabilities, and how the fostering of extensive collaboration among all stakeholders is crucial for addressing liver disease in the region., Competing Interests: Conflicts of interest J.V.L. acknowledges grants and speaker fees from AbbVie, Gilead Sciences, MSD, and Roche Diagnostics to his institution, speaker fees from Echosens, Janssen, Novo Nordisk, and ViiV, and consulting fees from GSK and Novavax, outside of the submitted work. L.A.D., M.V.-R., F.B., and M.A. declare no conflicts of interest., (Copyright © 2023 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

The liver fulfils a plethora of metabolic and immunological functions. Liver macrophages are a heterogeneous immune cell population with high plasticity and are important for maintaining normal liver function but are also critically involved in disease processes. In this chapter, we review the heterogeneity and multifaceted functions of hepatic macrophages in liver health and in disease conditions, including acute liver injury, chronic liver diseases, and hepatocellular carcinoma. Under homeostatic conditions, the tissue resident Kupffer cells are phagocytic cells that have important functions in immune surveillance, antigen presentation, and metabolic regulation while the roles of other populations such as capsular, peritoneal, or monocyte-derived macrophages in liver health are less clearly defined. Upon liver injury, Kupffer cell numbers are markedly reduced while monocyte-derived macrophages significantly expand and take critical roles in driving and resolving liver injury, including important pathogenic involvements in inflammation, fibrosis, and regeneration. They also create and maintain an immunosuppressive and immune-excluded microenvironment in hepatocellular carcinoma. Single-cell and spatial omics technologies are significantly expanding our understanding of the diversity and plasticity of macrophage populations under different conditions and enable the reliable identification of specific hepatic macrophage subsets. This knowledge can now be applied to dissect the exact contributions of distinct macrophage populations to disease processes and hopefully will pave the way for new therapeutic interventions., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

ABSTRACT Background Methods Results Conclusion Major society guidelines recommend the fibrosis‐4 index (FIB‐4) as the initial step to risk stratifying people with metabolic dysfunction‐associated steatotic liver disease (MASLD). We aimed to evaluate the proportion of people with MASLD‐related hepatocellular carcinoma (HCC) and a low FIB‐4.This cohort study included 613 consecutive adults (33% female) diagnosed with MASLD‐related HCC from January 2008 to August 2023 at seven international centres in Australia, India, Japan, South Korea, Singapore and the United States. The primary objective was to determine the proportion of participants with a low FIB‐4, defined as FIB‐4 < 1.3, or < 2 if age > 65 years, in people without cirrhosis.The mean (±SD) age and body mass index were 71 (±11) years and 27 (±7) kg/m2, respectively. Overall, 235 participants (38%) did not have known cirrhosis. The median FIB‐4 was 3.90 (IQR 2.42–6.42). A total of 78 participants (13%) had a low FIB‐4. Among participants without known cirrhosis (n = 235), 62 participants (26%) had a low FIB‐4. Participants with a low FIB‐4 had larger median total tumour diameter (p < 0.001) and lower median serum alpha‐fetoprotein (p = 0.005), compared to participants without a low FIB‐4. Cirrhosis was associated with lower odds of low FIB‐4, but not other factors such as male sex, type 2 diabetes, or obesity.More than a quarter of those with MASLD‐related HCC without cirrhosis have a low FIB‐4. The proposed clinical care pathways may not identify these people for further evaluation. [ABSTRACT FROM AUTHOR]

In recent years, there has been a rapid expansion in our understanding of regulated cell death, leading to the discovery of novel mechanisms that govern diverse cell death pathways. One recently discovered type of cell death is pyroptosis, initially identified in the 1990s as a caspase-1-dependent lytic cell death. However, further investigations have redefined pyroptosis as a regulated cell death that relies on the activation of pore-forming proteins, particularly the gasdermin family. Among the key regulators of pyroptosis is the inflammasome sensor NOD-like receptor 3 (NLRP3), a critical innate immune sensor responsible for regulating the activation of caspase-1 and gasdermin D. A deeper understanding of pyroptosis and its interplay with other forms of regulated cell death is emerging, shedding light on a complex regulatory network controlling pore-forming proteins and cell fate. Cell death processes play a central role in diseases such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, autoinflammatory disorders, and cancer. Cell death often acts as a starting point in these diseases, making it an appealing target for drug development. Yet, the complete molecular mechanisms are not fully understood, and new discoveries reveal promising novel avenues for therapeutic interventions. In this review, we summarize recent evidence on pathways and proteins controlling pyroptosis and gasdermins. Furthermore, we will address the role of pyroptosis and the gasdermin family in metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Additionally, we highlight new potential therapeutic targets for treating metabolic dysfunction-associated steatohepatitis and other inflammatory-associated diseases. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods Results Conclusions Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a growing public health problem. The secondary stage in MASLD is steatohepatitis (MASH), the co‐existence of steatosis and inflammation, a leading cause of progression to fibrosis and mortality. MASH resolution alone improves survival. Currently, MASH diagnosis is via liver biopsy. This study sought to evaluate the accuracy of imaging‐based tests for MASH diagnosis, which offer a non‐invasive method of diagnosis.Eight academic literature databases were searched and references of previous systematic reviews and included papers were checked for additional papers. Liver biopsy was used for reference standard.We report on 69 imaging‐based studies. There were 31 studies on MRI, 27 on ultrasound, five on CT, 13 on transient elastography, eight on controlled attenuation parameter (CAP) and two on scintigraphy. The pathological definition of MASH was inconsistent, making it difficult to compare studies. 55/69 studies (79.71%) were deemed high‐risk of bias as they had no preset thresholds and no validation. The two largest groups of imaging papers were on MRI and ultrasound. AUROCs were up to 0.93 for MRE, 0.90 for MRI, 1.0 for magnetic resonance spectroscopy (MRS) and 0.94 for ultrasound‐based studies.Our study found that the most promising imaging tools are MRI techniques or ultrasound‐based scores and confirmed there is potential to utilise these for MASH diagnosis. However, many publications are single studies without independent prospective validation. Without this, there is no clear imaging tool or score currently available that is reliably tested to diagnose MASH. [ABSTRACT FROM AUTHOR]

The liver macrophage population comprises resident Kupffer cells (KCs) and monocyte-derived macrophages with distinct pro- or anti-inflammatory properties that affect the severity and course of liver diseases. The mechanisms underlying macrophage differentiation and functions in metabolic dysfunction-associated steatotic liver disease and/or steatohepatitis (MASLD/MASH) remain mostly unknown. Using single-cell RNA sequencing (scRNA-seq) and fate mapping of hepatic macrophage subpopulations, we unraveled the temporal and spatial dynamics of distinct monocyte and monocyte-derived macrophage subsets in MASH. We revealed a crucial role for the Notch-Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) signaling pathway in controlling the monocyte-to-macrophage transition, with Rbpj deficiency blunting inflammatory macrophages and monocyte-derived KC differentiation and conversely promoting the emergence of protective Ly6Clo monocytes. Mechanistically, Rbpj deficiency promoted lipid uptake driven by elevated CD36 expression in Ly6Clo monocytes, enhancing their protective interactions with endothelial cells. Our findings uncover the crucial role of Notch-RBPJ signaling in monocyte-to-macrophage transition and will aid in the design of therapeutic strategies for MASH treatment. [Display omitted] • Notch-RBPJ signaling regulates the monocyte-to-macrophage transition in liver disease • Rbpj deficiency reduces inflammatory macrophage development • Rbpj deficiency promotes protective Ly6Clo monocyte generation • Inhibiting RBPJ with a selective antagonist decreases the severity of MASH Liver macrophages, including Kupffer cells and monocyte-derived macrophages, play diverse roles in liver diseases. However, the mechanisms underlying their differentiation and functions in MASLD/MASH are not well understood. Guo et al. reveal that Notch-RBPJ signaling controls macrophage development, impacting inflammation and disease severity, with RBPJ inhibition decreasing MASH severity. [ABSTRACT FROM AUTHOR]

ABSTRACT The prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) has increased exponentially over the past three decades, in parallel with the global rise in obesity and type 2 diabetes. It is currently the most common cause of liver‐related morbidity and mortality. Although obesity has been identified as a key factor in the increased prevalence of MASLD, individual differences in susceptibility are significantly influenced by genetic factors. PNPLA3 I148M (rs738409 C>G) is the variant with the greatest impact on the risk of developing progressive MASLD and likely other forms of steatotic liver disease. This variant is prevalent across the globe, with the risk allele (G) frequency exhibiting considerable variation. Here, we review the contribution of PNPLA3 I148M to global burden and regional differences in MASLD prevalence, focusing on recent evidence emerging from population‐based sequencing studies and prevalence assessments. We calculated the population attributable fraction (PAF) as a means of quantifying the impact of the variant on MASLD. Furthermore, we employ quantitative trait locus (QTL) analysis to ascertain the associations between rs738409 and a range of phenotypic traits. This analysis suggests that these QTLs may underpin pleiotropic effects on extrahepatic traits. Finally, we outline potential avenues for further research and identify key areas for investigation in future studies. [ABSTRACT FROM AUTHOR]

The clinical significance of change in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in patients with non-alcoholic fatty liver disease (NAFLD) is not well-understood. We prospectively defined rates of progression to and regression from LSM-defined compensated advanced chronic liver disease (cACLD) and their associations with liver-related events (LREs). Participants in the NASH Clinical Research Network-led NAFLD Database 2 and 3 studies were included. Progression to cACLD was defined as reaching LSM ≥10 kPa in participants with LSM <10 kPa on initial VCTE; regression from cACLD was defined as reaching LSM <10 kPa in participants with baseline LSM ≥10 kPa. LREs were defined as liver-related death, liver transplant, hepatocellular carcinoma, MELD >15, development of varices, or hepatic decompensation. Univariate and multivariable interval-censored Cox regression analyses were used to compare the cumulative LRE probability by LSM progression and regression status. In 1,403 participants, 89 LREs developed over a mean follow-up of 4.4 years, with an annual incidence rate for LREs of 1.5 (95% CI 1.2-1.8). In participants at risk, progression to LSM ≥10 or ≥15 kPa occurred in 29% and 17%, respectively, whereas regression to LSM <10 or <15 kPa occurred in 44% and 49%, respectively. Progressors to cACLD (≥10 kPa) experienced a higher cumulative LRE rate vs. non-progressors (16% vs. 4%, adjusted hazard ratio 4.0; 95% (1.8-8.9); p < 0.01). Regressors from cACLD (to LSM <10 kPa) experienced a lower LRE rate than non-regressors (7% vs. 32%, adjusted hazard ratio 0.25; 95% CI 0.10-0.61; p < 0.01). Change in LSM over time is independently and bi-directionally associated with risk of LRE and is a non-invasive surrogate for clinical outcomes in patients with NAFLD. The prognostic value of change in LSM in patients with NAFLD is not well understood. In this large prospective study of patients with NAFLD and serial vibration-controlled transient elastography exams, baseline and dynamic changes in LSM were associated with the risk of developing liver-related events. LSM is a useful non-invasive surrogate of clinical outcomes in patients with NAFLD. [Display omitted] • The clinical significance of changes in LSM over time in NAFLD is not well-studied. • Of 1,403 prospectively followed patients with NAFLD, 89 developed liver-related events over 4.4 years. • Of those at risk, 29% progressed to LSM ≥10 kPa, and 44% regressed from LSM >10 kPa. • Progressors had a four-fold increase whereas regressors had a 75% decrease in risk of liver-related events. • Changes in LSM over time are a useful surrogate for clinical outcomes in NAFLD. [ABSTRACT FROM AUTHOR]

RNA splicing is an essential post-transcriptional mechanism that facilitates the excision of introns and the connection of exons to produce mature mRNA, which is essential for gene expression and proteomic diversity. In the liver, precise splicing regulation is critical for maintaining metabolic balance, detoxification, and protein synthesis. This review explores the mechanisms of RNA splicing and the role of splicing factors, particularly in the context of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). This review also highlights how RNA splicing dysregulation can lead to aberrant splicing and impact the progression of liver diseases such as MASLD, with a particular focus on Metabolic Dysfunction-Associated Steatohepatitis (MASH), which represents the advanced stage of MASLD. Recent advances in the clinical application of antisense oligonucleotides (ASOs) to correct splicing errors offer promising therapeutic strategies for restoring normal liver function. Additionally, the dysregulation of splicing observed in liver diseases may serve as a potential diagnostic marker, offering new opportunities for early identification of individuals more susceptible to disease progression. This review provides insights into the molecular mechanisms that govern splicing regulation in the liver, with a particular emphasis on MASLD, and discusses potential therapeutic approaches targeting RNA splicing to treat MASLD and related metabolic disorders. [ABSTRACT FROM AUTHOR]

The gold standard for enrollment and endpoint assessment in metabolic dysfunction‐associated steatosis clinical trials is histologic assessment of a liver biopsy performed on glass slides. However, obtaining the evaluations from several expert pathologists on glass is challenging, as shipping the slides around the country or around the world is time‐consuming and comes with the hazards of slide breakage. This study demonstrated that pathologic assessment of disease activity in steatohepatitis, performed using digital images on the AISight whole slide image management system, yields results that are comparable to those obtained using glass slides. The accuracy of scoring for steatohepatitis (nonalcoholic fatty liver disease activity score ≥4 with ≥1 for each feature and absence of atypical features suggestive of other liver disease) performed on the system was evaluated against scoring conducted on glass slides. Both methods were assessed for overall percent agreement with a consensus "ground truth" score (defined as the median score of a panel of three pathologists' glass slides). Each case was also read by three different pathologists, once on glass and once digitally with a minimum 2‐week washout period between the modalities. It was demonstrated that the average agreement across three pathologists of digital scoring with ground truth was noninferior to the average agreement of glass scoring with ground truth [noninferiority margin: −0.05; difference: −0.001; 95% CI: (−0.027, 0.026); and p < 0.0001]. For each pathologist, there was a similar average agreement of digital and glass reads with glass ground truth (pathologist A, 0.843 and 0.849; pathologist B, 0.633 and 0.605; and pathologist C, 0.755 and 0.780). Here, we demonstrate that the accuracy of digital reads for steatohepatitis using digital images is equivalent to glass reads in the context of a clinical trial for scoring using the Clinical Research Network scoring system. [ABSTRACT FROM AUTHOR]

Risk of disease progression and clinical outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with fibrosis stage and presence of "at-risk metabolic dysfunction-associated steatohepatitis (MASH)." Although liver biopsy is considered the gold standard to diagnose MASH and stage of fibrosis, biopsy is infrequently performed in clinical practice and has associated sampling error, lack of interrater reliability, and risk for procedural complications. Noninvasive tests (NITs) are routinely used in clinical practice for risk stratification of patients with MASLD. Several NITs are being developed for detecting "at-risk MASH" and cirrhosis. Clinical care guidelines apply NITs to identify patients needing subspecialty referral. With recently approved Food and Drug Administration treatment for MASH and additional emerging pharmacotherapy, NITs will identify patients who will most benefit from treatment, monitor treatment response, and assess risk for long-term clinical outcomes. In this review, we examine the performance of NITs to detect "at-risk MASH," fibrosis stage, response to treatment, and risk of clinical outcomes in MASLD and MASH. [ABSTRACT FROM AUTHOR]

Metabolic-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome, represents a growing global health concern. The intricate pathogenesis of MASLD, driven by genetic, metabolic, epigenetic, and environmental factors, leads to considerable clinical variability. Dysregulation of hepatic lipid metabolism, particularly cholesterol homeostasis, is a critical factor in the progression of MASLD and its more severe form, metabolic dysfunction-associated steatohepatitis (MASH). This review elucidates the multifaceted roles of cholesterol metabolism in MASLD, focusing on its absorption, transportation, biosynthesis, efflux, and conversion. We highlight recent advancements in understanding these processes and explore the therapeutic potential of natural products such as curcumin, berberine, and resveratrol in modulating cholesterol metabolism. By targeting key molecular pathways, these natural products offer promising strategies for MASLD management. Finally, this review also covers the clinical studies of natural products in MASLD, providing new insights for future research and clinical applications. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study investigates the applicability of the new metabolic dysfunction-associated steatotic liver disease (MASLD) nomenclature to the real-world TARGET-NASH US adult cohort. METHODS: The new MASLD/metabolic steatohepatitis nomenclature was applied to patients enrolled with pragmatic diagnoses of nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), and NASH cirrhosis and concordance were determined between the definitions. RESULTS: Approximately 99% of TARGET-NASH participants met the new MASLD diagnostic criteria. Approximately 1,484/1,541 (96.3%, kappa 0.974) nonalcoholic fatty liver patients (metabolic dysfunction-associated steatotic liver), 2,195/2,201 (99.7%, kappa 0.998) NASH patients (metabolic steatohepatitis), and 1,999/2,003 (99.8%, kappa 0.999) NASH cirrhosis patients met the new criteria. DISCUSSION: The new MASLD nomenclature is highly concordant with the previous TARGET-NASH pragmatic definitions. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly nonalcoholic fatty liver disease – NAFLD) is a chronic liver condition linked to obesity and metabolic syndrome. It affects one-third of people globally and, in some cases, can lead to metabolic dysfunction-associated steatohepatitis (MASH, formerly nonalcoholic steatohepatitis, NASH) and fibrosis. Weight loss is crucial for the treatment of MASLD, but diet and lifestyle modifications often fail. Areas covered: In recent years, endoscopic sleeve gastroplasty (ESG) has gained popularity as an effective and minimally invasive option for obesity treatment, with widespread use worldwide. We present a current overview of the most significant studies conducted on ESG for the management of obesity and MASLD. Our report includes data from published studies that have evaluated the impact of ESG on noninvasive hepatic parameters used to estimate steatosis and fibrosis. However, at present, there are no data available on liver histology. Expert opinion: ESG has shown promising results in treating MASLD evaluated by noninvasive tests, but current data is limited to small, nonrandomized studies. More research is needed, particularly on the effects of ESG on histologically proven MASH. If future research confirms its efficacy, ESG may be incorporated into treatment guidelines in the future. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as nonalcoholic fatty liver disease, impacts 30% of the global population. This educational pilot focused on the role primary care providers may play in the delivery of guidelines-based metabolic dysfunction-associated steatohepatitis (MASH) care. Objective: Accelerate the application of guidelines-based MASH care pathways to clinical workflows. Methods: A panel of six hepatologists was convened in 2021 to develop the care pathway and the subsequent pilot occurred between 2022 – 2023. The pilot was conducted across three U.S. health systems: Boston Medical Center (Boston), Methodist Health System (Dallas), and Weill Cornell Medicine (New York). Clinicians were educated on the care pathway and completed baseline/follow-up assessments. 19 primary care clinicians participated in the educational pilot baseline assessment, nine primary care clinicians completed the two-month assessment, and 15 primary care clinicians completed the four-month assessment. The primary endpoint was to assess clinician-reported adherence to and satisfaction with the care pathway. The pilot was deemed exempt by the Western Consensus Group Institutional Review Board. Results: At baseline, 38.10% (n = 8) of respondents felt they had received sufficient training on when to refer a patient suspected of metabolic dysfunction-associated liver disease to hepatology, and 42.86% (n = 9) had not referred any patients suspected of metabolic dysfunction-associated liver disease to hepatology within a month. At four months post-intervention, 79% (n = 15) of respondents agreed or strongly agreed they received sufficient training on when to refer a patient suspected of metabolic dysfunction-associated liver disease to hepatology, and there was a 25.7% increase in self-reported adherence to the institution's referral guidelines. Barriers to care pathway adherence included burden of manually calculating fibrosis-4 scores and difficulty ordering non-invasive diagnostics. Conclusions: With therapeutics anticipated to enter the market this year, health systems leadership must consider opportunities to streamline the identification, referral, and management of patients with metabolic dysfunction-associated steatohepatitis. Electronic integration of metabolic dysfunction-associated steatohepatitis care pathways may address implementation challenges. [ABSTRACT FROM AUTHOR]

Firsocostat is an oral, liver‐targeted inhibitor of acetyl‐coenzyme A carboxylase in development for the treatment of metabolic dysfunction‐associated steatohepatitis. Hepatic organic anion transporting polypeptides play a significant role in the disposition of firsocostat with minimal contributions from uridine diphospho‐glucuronosyltransferase and cytochrome P450 3A enzymes. This phase 1 study evaluated the pharmacokinetics and safety of firsocostat in participants with mild, moderate, or severe hepatic impairment. Participants with stable mild, moderate, or severe hepatic impairment (Child–Pugh A, B, or C, respectively [n = 10 per cohort]) and healthy matched controls with normal hepatic function (n = 10 per cohort) received a single oral dose of firsocostat (20 mg for mild and moderate hepatic impairment; 5 mg for severe hepatic impairment) with intensive pharmacokinetic sampling over 96 h. Safety was monitored throughout the study. Firsocostat plasma exposure (AUCinf) was 83%, 8.7‐fold, and 30‐fold higher in participants with mild, moderate, and severe hepatic impairment, respectively, relative to matched controls. Firsocostat was generally well tolerated, and all reported adverse events were mild in nature. Dose adjustment is not necessary for the administration of firsocostat in patients with mild hepatic impairment. However, based on the observed increases in firsocostat exposure, dose adjustment should be considered for patients with moderate or severe hepatic impairment, and additional safety and efficacy data from future clinical trials will further inform dose adjustment. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a key determinant of the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Its increasing prevalence and a lack of effective treatments make it a major health problem worldwide, particularly in people living with HIV, among whom the prevalence of advanced fibrosis is higher. We have published preclinical data showing that Rilpivirine (RPV), a widely used anti-HIV drug, selectively triggers hepatic stellate cell (HSC) inactivation and apoptosis through signal transducer and activator of transcription (STAT)1-mediated pathways, effects that clearly attenuate liver fibrosis and promote regeneration. We performed a retrospective, cross-sectional study of RPV-induced effects on steatosis, inflammation, and fibrosis in liver biopsies from well-controlled HIV-infected subjects diagnosed with MASLD. Patients on RPV exhibited similar levels of HIV-related parameters to those not receiving this drug, while showing a tendency toward improved liver function and lipid profile, as well as an enhanced activation of STAT1 in hepatic non-parenchymal cells in those with identified liver injury. This protective effect, promoting STAT1-dependent HSC inactivation, was observed at different stages of MASLD. Our results suggest that RPV-based therapy is especially indicated in HIV-infected patients with MASLD-derived liver injury and highlight the potential of RPV as a new therapeutic strategy for liver diseases. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is characterized by intense deposition of fat globules in the hepatic parenchyma that could potentially progress to liver cirrhosis and hepatocellular carcinoma. Here, we evaluated a rat model to study the molecular pathogenesis of the spectrum of MASLD and to screen therapeutic agents. SHRSP5/Dmcr rats were fed a high‐fat and cholesterol (HFC) diet for a period of 12 weeks and evaluated for the development of steatosis (MASLD), steatohepatitis, fibrosis and cirrhosis. A group of animals were sacrificed at the end of the 4th, 6th, 8th and 12th weeks from the beginning of the experiment, along with the control rats that received normal diet. Blood and liver samples were collected for biochemical and histopathological evaluations. Immunohistochemical staining was performed for α‐SMA and Collagen Type I. Histopathological examinations demonstrated steatosis at the 4th week, steatohepatitis with progressive fibrosis at the 6th week, advanced fibrosis with bridging at the 8th week and cirrhosis at the 12th week. Biochemical markers and staining for α‐SMA and Collagen Type I demonstrated the progression of steatosis to steatohepatitis, hepatic fibrosis and liver cirrhosis in a stepwise manner. Control animals fed a normal diet did not show any biochemical or histopathological alterations. The results of the present study clearly demonstrated that the HFC diet‐induced model of steatosis, steatohepatitis, hepatic fibrosis and cirrhosis is a feasible, quick and appropriate animal model to study the molecular pathogenesis of the spectrum of MASLD and to screen potent therapeutic agents. [ABSTRACT FROM AUTHOR]

Over the past 10 years, the biological role of lipid droplets (LDs) has gained significant attention in the context of both physiological and pathological conditions. Considerable progress has been made in elucidating key aspects of these organelles, yet much remains to be accomplished to fully comprehend the myriad functions they serve in the progression of hepatic tumors. Our current perception is that LDs are complex and active structures managed by a distinct set of cellular processes. This understanding represents a significant paradigm shift from earlier perspectives. In this review, we aim to recapitulate the function of LDs within the liver, highlighting their pivotal role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) (Hsu and Loomba, 2024) and their contribution to the progression towards more advanced pathological stages up to hepatocellular carcinoma (HC) (Farese and Walther, 2009). We are aware of the molecular complexity and changes occurring in the neoplastic evolution of the liver. Our attempt, however, is to summarize the most important and recent roles of LDs across both healthy and all pathological liver states, up to hepatocarcinoma. For more detailed insights, we direct readers to some of the many excellent reviews already available in the literature (Gluchowski et al., 2017; Hu et al., 2020; Seebacher et al., 2020; Paul et al., 2022). [ABSTRACT FROM AUTHOR]

Objective: Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime‐reducing component 1 (MARC1) results in an aminoacidic substitution (p.Ala165Thr) and associates with protection against MASLD. However, the mechanisms behind this protective effect are unknown. In this study, we examined the consequences of this aminoacidic substitution on protein stability and subcellular localization. Methods: We overexpressed the human MARC1 A165 (wild‐type) or 165T (mutant) in vivo in mice and in vitro in human hepatoma cells (HepG2 and HuH‐7), generated several mutants at position 165 by in situ mutagenesis and then examined protein levels. We also generated HepG2 cells stably overexpressing MARC1 A165 or 165T to test the effect of this substitution on MARC1 subcellular localization. Results: MARC1 165T overexpression resulted in lower protein levels than A165 both in vivo and in vitro. Similarly, any mutant at position 165 showed lower protein levels compared to the wild‐type protein. We showed that the 165T mutant protein is polyubiquitinated and its degradation is accelerated through lysine‐48 ubiquitin‐mediated proteasomal degradation. We also showed that the 165T substitution does not affect the MARC1 subcellular localization. Conclusions: This study shows that alanine at position 165 in MARC1 is crucial for protein stability, and the threonine substitution at this position leads to a hypomorphic protein variant due to lower protein levels. Our result supports the notion that lowering hepatic MARC1 protein level may be a successful therapeutic strategy for treating MASLD. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a common complication of chronic liver diseases and remains a relevant cause of cancer-related mortality worldwide. The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocarcinogenesis is on the rise. Early detection of HCC has been crucial in improving the survival outcomes of patients with metabolic dysfunction-associated steatohepatitis (MASH), even in the absence of cirrhosis. Understanding how hepatocarcinogenesis develops in MASH is increasingly becoming a current research focus. Additive risk factors such as type 2 diabetes mellitus (T2DM), genetic polymorphisms, and intestinal microbiota may have specific impacts. Pathophysiological and epidemiological associations between MASH and HCC will be discussed in this review. We will additionally review the available tumor therapies concerning their efficacy in MASH-associated HCC treatment. [ABSTRACT FROM AUTHOR]

Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is common and closely associated with type 2 diabetes (T2D). We assessed the prevalence of NAFLD/MASLD in the general population and among patients with T2D in the Middle East and North Africa (MENA) region. Methods: We searched PubMed and Embase for English‐language articles published between 1990 and 2023 according to PRISMA. Each country's NAFLD/MASLD prevalence in the general population and in T2D patients was predicted by using a multivariable meta regression model. Input data were extracted from our systematic review, GBD and NCD Risk Factor Collaboration. Confidence intervals were constructed by using prediction intervals with the delta method. Results: Meta‐analytic pooling estimated the prevalence of NAFLD/MASLD as 39.43% in the general population and 68.71% among T2D patients. NAFLD/MASLD prevalence has increased from 35.42% (2008–2016) to 46.20% (2017–2020). Using GBD‐2019 dataset, it was predicted that there are 141.51 million cases of NAFLD/MASLD in the MENA region. The highest number of NAFLD/MASLD cases were expected in Egypt (25.71 million), followed by Türkiye (23.33 million) and Iran (19.85 million). Estimated NAFLD prevalence exceeded 40% in 10 of 21 countries with the top countries being Kuwait (45.37%), Egypt (45.0%), Qatar (44.4%), and Jordan (43.3%). Furthermore, it was predicted that there are 24.96 million cases of NAFLD/MASLD with T2D in the MENA region. Conclusions: In the MENA region, prevalence of NAFLD/MASLD is very high and growing, necessitating an urgent need for regional public policy to deal with this growing burden. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously non-alcoholic fatty liver disease (NAFLD), is a leading cause of chronic liver disease worldwide. In 20%-30% of MASLD patients, the disease progresses to metabolic dysfunction-associated steatohepatitis (MASH, previously NASH) which can lead to fibrosis/cirrhosis, liver failure as well as hepatocellular carcinoma (HCC). Here we investigated the role of histidine-rich glycoprotein (HRG), a plasma protein produced by hepatocytes, in MASLD/MASH progression and HCC development. Methods: The role of HRG was investigated by morphological, cellular, and molecular biology approaches in (a) HRG knock-out mice (HRG-/- mice) fed on a CDAA dietary protocol or a MASH related diethyl-nitrosamine/CDAA protocol of hepatocarcinogenesis, (b) THP1 monocytic cells treated with purified HRG, and (c) well-characterized cohorts of MASLD patients with or without HCC. Results: In non-neoplastic settings, murine and clinical data indicate that HRG increases significantly in parallel with disease progression. In particular, in MASLD/MASH patients, higher levels of HRG plasma levels were detected in subjects with extensive fibrosis/cirrhosis. When submitted to the procarcinogenic protocol, HRG-/- mice showed a significant decrease in the volume and number of HCC nodules in relation to decreased infiltration of macrophages producing pro-inflammatory mediators, including IL-1b, IL-6, IL-12, IL-10, and VEGF as well as impaired angiogenesis. The histopathological analysis (H-score) of MASH-related HCC indicate that the higher HRG positivity in peritumoral tissue significantly correlates with a lower overall patient survival and an increased recurrence. Moreover, a significant increase in HRG plasma levels was detected in cirrhotic (F4) patients and in patients carrying HCC vs. F0/F1 patients. Conclusion: Murine and clinical data indicate that HRG plays a significant role in MASLD/MASH progression to HCC by supporting a specific population of tumorassociated macrophages with pro-inflammatory response and pro-angiogenetic capabilities which critically support cancer cell survival. Furthermore, our data suggest HRG as a possible prognostic predictor in HCC patients with MASLD/MASH-related HCCs. [ABSTRACT FROM AUTHOR]

Background: The gut microbiome modulates the liver immune microenvironment and is deeply integrated into the pathophysiology of metabolic dysfunction-associated steatotic liver disease (MASLD). Appendectomies, which are performed in almost all patients diagnosed with appendicitis, cause long-term alterations to the gut microbiome, providing a potential link with the development of MASLD. We therefore investigated a potential link between appendicitis and the presence of MASLD in a large cohort of outpatients in Germany. Methods: The present study included 26,717 individuals with and 26,717 without appendicitis. Univariable Cox-regression analyses were conducted to assess the association between appendicitis and MASLD. Results: During the long-term follow-up, 4.8% of patients with appendicitis and 3.4% of those in the non-appendicitis group were diagnosed with MASLD (p < 0.001), corresponding to an incidence of 5.4 (appendicitis cohort) versus 3.5 (non-appendicitis cohort) cases per 1000 patient years. These findings were confirmed in regression analysis, revealing a strong and statistically significant association between appendicitis and the development of MASLD (HR: 1.57; 95% CI: 1.39–1.78). This link was observed for all age groups and was independent of patients' sex. Conclusion: We provide evidence from a large cohort of outpatients in Germany suggesting a link between appendicitis and MASLD. This might help to better stratify patients according to their individual risk for the development of chronic liver diseases. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for what used to be called nonalcoholic steatohepatitis (NASH). It is characterized by inflammation and injury of the liver in the presence of cardiometabolic risk factors and may eventually result in the development of hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Several pathogenic mechanisms are involved in the transition from MASH to HCC, encompassing metabolic injury, inflammation, immune dysregulation and fibrosis. In this context, Gas6 (Growth Arrest-Specific 6) and TAM (Tyro3, Axl, and MerTK) receptors may play important roles. The Gas6/TAM family is involved in the modulation of inflammation, lipid metabolism, fibrosis, tumor progression and metastasis, processes which play an important role in the pathophysiology of acute and chronic liver diseases. In this review, we discuss MASH-associated HCC and the potential involvement of the Gas6/TAM system in disease development and progression. In addition, since therapeutic strategies for MASH and HCC are limited, we also speculate regarding possible future treatments involving the targeting of Gas6 or TAM receptors. [ABSTRACT FROM AUTHOR]

Metabolic-associated steatotic liver disease (MASLD) is a cluster of pathological conditions primarily developed due to the accumulation of ectopic fat in the hepatocytes. During the severe form of the disease, i.e., metabolic-associated steatohepatitis (MASH), accumulated lipids promote lipotoxicity, resulting in cellular inflammation, oxidative stress, and hepatocellular ballooning. If left untreated, the advanced form of the disease progresses to fibrosis of the tissue, resulting in irreversible hepatic cirrhosis or the development of hepatocellular carcinoma. Although numerous mechanisms have been identified as significant contributors to the development and advancement of MASLD, altered lipid metabolism continues to stand out as a major factor contributing to the disease. This paper briefly discusses the dysregulation in lipid metabolism during various stages of MASLD. [ABSTRACT FROM AUTHOR]

Background: Obesity, characterized by visceral adipose tissue (VAT) expansion, is closely associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Recent research has highlighted the crucial role of the adipose tissue—liver axis in the development of MASLD. In this study, we investigated the potential role of omentin-1, a novel adipokine expressed by VAT, in obesity-related MASLD pathogenesis. Methods: Through in silico analysis of differentially expressed genes in VAT from obese patients with and without MASH, we identified omentin-1 as a significant candidate. To validate our findings, we measured omentin-1 levels in VAT and plasma of lean controls and obese patients with biopsy-proven MASLD. Additionally, we assessed omentin-1 expression in the VAT of diet-induced mice MASLD model. In vitro and ex vivo studies were conducted to investigate the effects of omentin-1 on MASLD-related mechanisms, including steatosis, inflammation, endoplasmic reticulum (ER) stress, and oxidative stress. We also analyzed the impact of d-glucose and insulin on VAT omentin-1 levels ex vivo. Results: Compared to the lean group, the obese groups exhibited significantly lower VAT and plasma levels of omentin-1. Interestingly, within the obese groups, omentin-1 is further decreased in MASH groups, independent of fibrosis. Likewise, VAT of mice fed with high-fat diet, showing histological signs of MASH showed decreased omentin-1 levels as compared to their control diet counterpart. In vitro experiments on fat-laden human hepatocytes revealed that omentin-1 did not affect steatosis but significantly reduced TNF-α levels, ER stress, and oxidative stress. Similar results were obtained using ex vivo VAT explants from obese patients upon omentin-1 supplementation. Furthermore, omentin-1 decreased the mRNA expression of NF-κB and mitogen-activated protein kinases (ERK and JNK). Ex vivo VAT explants showed that d-glucose and insulin significantly reduced omentin-1 mRNA expression and protein levels. Conclusions: Collectively, our findings suggest that reduced omentin-1 levels contribute to the development of MASLD. Omentin-1 supplementation likely exerts its beneficial effects through the inhibition of the NF-κB and MAPK signaling pathways, and it may additionally play a role in the regulation of glucose and insulin metabolism. Further research is warranted to explore omentin-1 as a potential therapeutic target and/or biomarker for MASLD. [ABSTRACT FROM AUTHOR]

While the association of metabolic dysfunction-associated steatotic liver disease (MASLD) with obesity and insulin resistance is widely appreciated, there are a host of complex interactions between the liver and other endocrine axes. While it can be difficult to definitively distinguish direct causal relationships and those attributable to increased adipocyte mass, there is substantial evidence of the direct and indirect effects of endocrine dysregulation on the severity of MASLD, with strong evidence that low levels of growth hormone, sex hormones, and thyroid hormone promote the development and progression of disease. The impact of steroid hormones, e.g. cortisol and dehydroepiandrosterone, and adipokines is much more divergent. Thoughtful assessment, based on individual risk factors and findings, and management of non-insulin endocrine axes is essential in the evaluation and management of MASLD. Multiple therapeutic options have emerged that leverage various endocrine axes to reduce the fibroinflammatory cascade in MASH. [ABSTRACT FROM AUTHOR]

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction–associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction–associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction–associated steatotic liver disease, who consume greater amounts of alcohol per week (140–350 g/wk and 210–420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) describes a steatotic (or fatty) liver occurring as a consequence of a combination of metabolic, environmental, and genetic factors, in the absence of significant alcohol consumption and other liver diseases. NAFLD is a spectrum of conditions. Steatosis in the absence of inflammation is relatively benign, but the disease can progress into more severe forms like non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. NAFLD onset and progression are complex, as it is affected by many risk factors. The interaction between genetic predisposition and other factors partially explains the large variability of NAFLD phenotype and natural history. Numerous genes and variants have been identified through large-scale genome-wide association studies (GWAS) that are associated with NAFLD and one or more subtypes of the disease. Among them, the largest effect size and most consistent association have been patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) genes. Extensive in vitro and in vivo studies have been conducted on these variants to validate these associations. The focus of this review is to highlight the genetics underpinning the molecular mechanisms driving the onset and progression of NAFLD and how they could potentially be used to improve genetic-based diagnostic testing of the disease and develop personalized, targeted therapeutics. [ABSTRACT FROM AUTHOR]

• Precision medicine in MASLD predominantly focuses on genetics and diet. • Gut microbiota are important disease drivers that interact with genetics and diet. • Dietary substrates induce gut microbiota imbalances, influencing MASLD pathogenesis. • Crosstalk between microbes, diet, and genetics in MASLD is not fully understood. • Mechanistic insight is required to support the use of precision medicine in MASLD. Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing in prevalence, impacting over a third of the global population. The advanced form of MASLD, Metabolic dysfunction-associated steatohepatitis (MASH), is on track to become the number one indication for liver transplant. FDA-approved pharmacological agents are limited for MASH, despite over 400 ongoing clinical trials, with only a single drug (resmetirom) currently on the market. This is likely due to the heterogeneous nature of disease pathophysiology, which involves interactions between highly individualized genetic and environmental factors. To apply precision medicine approaches that overcome interpersonal variability, in-depth insights into interactions between genetics, nutrition, and the gut microbiome are needed, given that each have emerged as dynamic contributors to MASLD and MASH pathogenesis. Here, we discuss the associations and molecular underpinnings of several of these factors individually and outline their interactions in the context of both patient-based studies and preclinical animal model systems. Finally, we highlight gaps in knowledge that will require further investigation to aid in successfully implementing precision medicine to prevent and alleviate MASLD and MASH. [ABSTRACT FROM AUTHOR]

Metabolic-dysfunction associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a growing global health concern with significant implications for oncogenesis. This review synthesizes current evidence on the association between MASLD and cancer risk, highlighting its role as a risk factor for both intrahepatic and extrahepatic malignancies. MASLD is increasingly recognized as a major cause of hepatocellular carcinoma (HCC), with its incidence rising in parallel with the prevalence of metabolic dysfunction. Furthermore, MASLD is associated with an elevated risk of various gastrointestinal cancers, including colorectal, esophageal, stomach, and pancreatic cancers. Beyond the digestive tract, evidence suggests that MASLD may also contribute to an increased risk of other cancers such as breast, prostate, thyroid, gynecological, renal and lung cancers. Understanding the mechanisms underlying these associations and the impact of MASLD on cancer risk is crucial for developing targeted screening and prevention strategies. • Metabolic- dysfunction associated liver disease (MASLD) is a significant risk factor for intrahepatic and extrahepatic cancers. • The incidence of MASLD-related hepatocellular carcinoma (HCC) is increasing and becoming the predominant HCC cause even in non-cirrhotics. • MASLD is associated with increased risk for gastrointestinal cancers (e.g. colorectal, esophageal, stomach, and pancreatic). • MASLD has been linked to an increased risk of extraintestinal cancers. [ABSTRACT FROM AUTHOR]

Steatotic liver disease (SLD) refers to a spectrum of diseases caused by hepatic lipid accumulation. SLD has emerged as the leading cause of chronic liver disease worldwide. Despite this burden and many years, understanding the pathophysiology of this disease is challenging due to the inaccessibility to human liver specimens. Therefore, cell-based in vitro systems are widely used as models to investigate the pathophysiology of SLD. Culturing hepatic cells in monolayers causes the loss of their hepatocyte-specific phenotype and, consequently, tissue-specific function and architecture. Hence, three-dimensional (3D) culture models allow cells to mimic the in vivo microenvironment and spatial organization of the liver unit. The utilization of 3D in vitro models minimizes the drawbacks of two-dimensional (2D) cultures and aligns with the 3Rs principles to alleviate the number of in vivo experiments. This article provides an overview of liver 3D models highlighting advantages and limitations, and culminates by discussing their applications in pharmaceutical and biomedical research. [Display omitted] • Three-dimensional (3D) in vitro models recapitulate human hepatic pathophysiology. • Spheroids, organoids and buds are different 3D cell-based culture systems. • 3D liver-on-a-chip systems mimic the liver microenvironment. • 3D cultures represent a novel research tool to develop specific treatments for steatotic liver disease. [ABSTRACT FROM AUTHOR]

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing year by year and has become one of the leading causes of end-stage liver disease worldwide. Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) has been confirmed to play an essential role in the progression of MASLD, but its specific mechanism still needs to be clarified. This study aims to explore the role and mechanism of Trem2 in MASLD. Human liver tissues were obtained from patients with MASLD and controls. Myeloid-specific knockout mice (Trem2mKO) and myeloid-specific overexpression mice (Trem2TdT) were fed a high-fat diet, either AMLN or CDAHFD, to establish the MASLD model. Relevant signaling molecules were assessed through lipidomics and RNA-seq analyses after that. Trem2 is upregulated in human MASLD/MASH-associated macrophages and is associated with hepatic steatosis and inflammation progression. Hepatic steatosis and inflammatory responses are exacerbated with the knockout of myeloid Trem2 in MASLD mice, while mice overexpressing Trem2 exhibit the opposite phenomenon. Mechanistically, Trem2mKO can aggravate macrophage pyroptosis through the PI3K/AKT signaling pathway and amplify the resulting inflammatory response. At the same time, Trem2 promotes the inflammation resolution phenotype transformation of macrophages through TGFβ1, thereby promoting tissue repair. Myeloid Trem2 ameliorates the progression of Metabolic dysfunction-associated steatotic liver disease by regulating macrophage pyroptosis and inflammation resolution. We believe targeting myeloid Trem2 could represent a potential avenue for treating MASLD. [Display omitted] • Trem2 is upregulated in human MASLD and associated with hepatic steatosis and inflammation. • Knockout of Trem2 exacerbated hepatic steatosis and inflammatory response in MASLD mice. • Trem2 can ameliorate MoMF pyroptosis by activating the PI3K/AKT signaling pathway. • Trem2 promotes the MoMF inflammation resolution phenotype transformation through TGFβ1. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes frequently have metabolic dysfunction-associated steatotic liver disease (MASLD) including steatohepatitis (MASH). In obesity, the liver may adapt its oxidative capacity, but the role of mitochondrial turnover in MASLD remains uncertain. This cross-sectional study compared individuals with class III obesity (n = 8/group) without (control, OBE CON; NAFLD activity score: 0.4 ± 0.1) or with steatosis (OBE MASL, 2.3 ± 0.4), or MASH (OBE MASH, 5.3 ± 0.3, p < 0.05 vs. other groups). Hepatic mitochondrial ultrastructure was assessed by transmission electron microscopy, mitochondrial respiration by high-resolution respirometry, biomarkers of mitochondrial quality control and endoplasmic reticulum (ER) stress by Western Blot. Mitochondrial oxidative capacity was 31 % higher in OBE MASL, but 25 % lower in OBE MASH (p < 0.05 vs. OBE CON). OBE MASH showed ~1.5fold lower mitochondrial number, but ~1.2–1.5fold higher diameter and area (p < 0.001 vs. other groups). Biomarkers of autophagy (p62), mitophagy (PINK1, PARKIN), fission (DRP-1, FIS1) and fusion (MFN1/2, OPA1) were reduced in OBE MASH (p < 0.05 vs. OBE CON). OBE MASL showed lower p62, p-PARKIN/PARKIN, and p-DRP-1 (p < 0.05 vs. OBE CON). OBE MASL and MASH showed higher ER stress markers (PERK, ATF4, p-eIF2α-S51/eIF2α; p < 0.05 vs. OBE CON). Mitochondrial diameter associated inversely with fusion/fission biomarkers and with oxidative capacity, but positively with H 2 O 2. Humans with hepatic steatosis already exhibit impaired mitochondrial turnover, despite upregulated oxidative capacity, and evidence for ER stress. In MASH, oxidative stress likely mediates progressive decline of mitochondrial turnover, ultrastructure and respiration indicating that mitochondrial quality control is key for energy metabolism and may have potential for targeting MASH. ClinGovTrial: NCT01477957 • In progression of steatosis to steatohepatitis, mitochondrial turnover is impaired first. • In simple steatosis, first morphological abnormalities occur at ER with higher ER stress. • Steatohepatitis related megamitochondria are associated with impaired mitophagy. • In steatohepatitis, megamitochondria present in presence of higher oxidative emission. • In steatohepatitis, morphologic mitochondrial abnormalities are independent of respiratory function. [ABSTRACT FROM AUTHOR]

Over 65 % of people with obesity display the metabolic-associated fatty liver disease (MAFLD), which can manifest as steatohepatitis, fibrosis, cirrhosis, or liver cancer. The development and progression of MAFLD involve hepatic insulin resistance and reduced insulin clearance. This review discusses the relationships between altered insulin signaling, hepatic insulin resistance, and reduced insulin clearance in the development of MAFLD and how this provides the impetus for exploring the use of insulin sensitizers to curb this disease. The review also explores the role of the insulin receptor in hepatocytes and hepatic stellate cells and how it signals in metabolic and end-stage liver diseases. Finally, we discuss new research findings that indicate that advanced hepatic diseases may be an insulin-sensitive state in the liver and deliberate whether insulin sensitizers should be used to manage late-stage liver diseases. • The impact of hepatic insulin resistance and clearance in early-stage liver disease • Insulin signaling in hepatocytes and hepatic stellate cells in liver disease • End-stage liver disease may entail hyperactive insulin signaling and sensitivity. • Deliberate the efficacy of insulin-targeting therapy in late-stage liver disease [ABSTRACT FROM AUTHOR]

Metabolic-associated fatty liver disease (MAFLD), the main cause of chronic liver disease worldwide, is a progressive disease ranging from fatty liver to steatohepatitis (metabolic-associated steatohepatitis; MASH). Nevertheless, it remains underdiagnosed due to the lack of effective non-invasive methods for its diagnosis and staging. Although MAFLD has been found in lean individuals, it is closely associated with obesity-related conditions. Adipose tissue is the main source of liver triglycerides and adipocytes act as endocrine organs releasing a large number of adipokines and pro-inflammatory mediators involved in MAFLD progression into bloodstream. Among the adipocyte-derived molecules, fatty acid binding protein 4 (FABP4) has been recently associated with fatty liver and additional features of advanced stages of MAFLD. Additionally, emerging data from preclinical studies propose FABP4 as a causal actor involved in the disease progression, rather than a mere biomarker for the disease. Therefore, the FABP4 regulation could be considered as a potential therapeutic strategy to MAFLD. Here, we review the current knowledge of FABP4 in MAFLD, as well as its potential role as a therapeutic target for this disease. [ABSTRACT FROM AUTHOR]