Metabolic dysfunction-associated steatohepatitis (MASH) has become the dominant cause of liver disease in the United States. With the growing burden of this disease in gastroenterology practices, the identification and treatment of those at risk of developing adverse outcomes (cirrhosis, hepatocellular carcinoma, or liver-related death) has become urgent. In recent years, the development of noninvasive tests (NITs) to identify "at-risk MASH" patients have provided cost-effective algorithms to identify these patients. Although treatment has historically been limited to lifestyle modification, recent FDA approval of resmetirom for noncirrhosis MASH with stages 2 and 3 fibrosis has provided a new opportunity in the United States to provide these patients with novel treatment options. Other new effective treatment regimens are on the horizon. Given that gastroenterology and hepatology practices in the United States heavily rely on advanced practice providers (APPs) to manage patients with MASLD, the APP Committee of the Global NASH/MASH Council has curated the essentials of day-to-day MASH management for our busy gastrohepatology providers and their APP colleagues. The goal of this document is to equip and mobilize more GI providers with the requisite competencies for the management of at-risk MASH, given the rapidly evolving MASH treatment landscape.

In this study, a biothiol-sensitive near-infrared (NIR) fluorescent sensor, BDP-CYS, based on a coumarin-hemicyanine skeleton, was designed and developed based on thiol-halogen SNAr nucleophilic substitution. BDP-CYS was successfully implemented to ratiometrically monitor endogenous and exogenous Cys, Hcy, and GSH in living cells as well as to distinguish between normal and cancer cells. Furthermore, the probe was utilized to detect changes of biothiols in drug-induced hepatotoxicity and evaluate the treatment effectiveness of diabetes-associated liver injury in vivo. The advantages of BDP-CYS's Cys, Hcy, and GSH include practical sensitivity, high selectivity, rapidity of reaction, and stability across a range of pH and temperature conditions, thus introducing a new tool to better understand the roles of biothiols in oxidative stress.

Liver histology is the classic method for staging the severity of liver fibrosis, which in turn is an important predictor of clinical outcome. Here, we have hypothesized that the susceptibility to develop fibrosis varies among racial groups.

We examined the histology of all patients over 18 years of age who underwent liver biopsy at the Medical University of South Carolina from 1/1/2013 to 7/1/2021. Patients with malignancy, liver metastases, or missing data were excluded. Fibrosis was quantified using the Batts-Ludwig system (F0 = no fibrosis to F4 = histological cirrhosis). Racial groups were propensity matched based on age, gender, diabetes, alcohol consumption, and CDC/ATSDR Social Vulnerability Index Themes to mitigate the risk of selection bias.

We identified 1101 patients with liver biopsy histological fibrosis scores. The cohort included 23% Black patients. After propensity matching, Black patients were significantly more likely to have Hepatitis C (73/228 (32%) vs 45/228 (20%), p < 0.001) and autoimmune hepatitis (34/228 (15%) vs 6/228 (3%), p < 0.001) than White patients, while White patients were significantly more likely to have metabolic dysfunction associated steatotic liver disease (71/228 (31%) vs 18/228 (8%), p < 0.001). White patients were significantly more likely to have cirrhosis than Black patients (White - 89/228 (39%) vs Black - 68/228 (30%), p < 0.05).

White patients had a greater overall burden of advanced fibrosis (F4/cirrhosis) than Black patients, independent of etiology. The data suggest that fibrosis risk and/or progression may be worse in White than Black patients.

The proportion of non-B/non-C hepatocellular carcinoma cases is increasing, and the principal cause is metabolic dysfunction-associated steatotic liver disease (MASLD). The degree of intrahepatic natural killer (NK) cell infiltration has been reported to correlate with MASLD progression. However, reports on MASLD are limited. We aimed to investigate the involvement of NK cell-activating receptor ligands in MASLD pathogenesis.

This study cohort comprised 69 patients with biopsy-proven MASLD treated between 2012 and 2018 at our institute. The concentrations of major histocompatibility complex class I polypeptide-related sequences A and B (MICA and MICB, respectively) and B7H6 in patient sera were measured using enzyme-linked immunosorbent assay kits. Data were statistically compared between those with metabolic-associated steatotic liver (MASL, n = 25) and those with metabolic dysfunction-associated steatohepatitis (MASH, n = 44). The clinical characteristics related to higher concentrations of each NK cell-activating receptor ligand were also investigated.

The MASH group had a higher level of the ligands than the MASL group. Furthermore, the MASH group had a significantly higher level of the Mac-2-binding protein glycosylation isomer (M2BPGi) than the MASL group (p < 0.001). MICA and MICB were positively correlated, and all three ligands were strongly correlated with alpha-fetoprotein and protein induced by vitamin K absence 2. Although MICB levels positively correlated with aspartate transaminase and alanine transaminase levels (p < 0.005), patients with higher MICA and B7H6 levels had higher M2BPGi levels. Interestingly, concentrations of B7H6 were significantly correlated with portal inflammation (p < 0.001), rather than lobular inflammation.

The three NK-activating receptor ligands were higher in the sera of the MASH group than those of the MASL group and strongly correlated with tumor markers, indicating the potential for hepatocarcinogenesis. Higher concentrations of serum B7H6 were correlated with advanced fibrosis and the degree of portal inflammation, which is a potential biomarker for predicting the pathogenesis of MASH.

Iron is essential in various physiological processes, but its accumulation leads to oxidative stress and cell damage, thus iron homeostasis has to be tightly regulated. Ferroptosis is an iron-dependent non-apoptotic regulated cell death characterized by iron overload and reactive oxygen species accumulation. Mitochondria are organelles playing a crucial role in iron metabolism and involved in ferroptosis. MitoNEET, a protein of mitochondrial outer membrane, is a key element in this process. Ferroptosis, altering iron levels in several metabolically active organs, is linked to several non-communicable diseases. For example, iron overload in the liver leads to hepatic fibrosis and cirrhosis, accelerating non-alcholic fatty liver diseases progression, in the muscle cells contributes to oxidative damage leading to sarcopenia, and in the brain is associated to neurodegeneration. The aim of this review is to investigate the intricate balance of iron regulation focusing on the role of mitochondria and oxidative stress, and analyzing the ferroptosis implications in health and disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) includes simple steatosis and metabolic dysfuncion-associated steatohepatitis (MASH), with fibrosis in MASH serving as a critical prognostic marker. This study investigates the effects of Roux-en-Y gastric bypass (RYGB) on fibrotic MASH, assessed using the fibrotic NASH index (FNI) and the non-invasive NASH detection score (NI-NASH-DS), as well as provides further data on the diagnostic accuracy of both scores.

A retrospective cohort study was conducted involving 104 individuals (91.3% female, mean age 39.4 ± 8.6 years) who underwent RYGB. Histopathological evaluations during surgery identified fibrotic MASH, and FNI and NI-NASH-DS values were calculated at baseline and 1 year post-surgery.

At the time of surgery, participants had a mean BMI of 35.3 ± 2.8 kg/m2, which decreased to 27.1 ± 4.0 kg/m2 1 year after surgery. The mean % total weight loss (%TWL) was 23.8 ± 10.1%, and the mean % excess weight loss (%EWL) was 82.4 ± 37.3%. Fibrotic MASH was present in 17.3% of participants pre-operatively. The mean FNI score significantly decreased after surgery (p < 0.0001). Female gender (p < 0.001) and histological evidence of lobular inflammation (p < 0.001) were independently associated with the improvement of FNI. The FNI demonstrated high diagnostic accuracy (sensitivity: 61.1%, specificity: 96.4%, overall accuracy: 90.2%). NI-NASH-DS had a 60% accuracy in detecting MASH, alongside an 85.9% specificity.

RYGB seemingly promotes improvement of fibrotic MASH as evaluated by FNI, highlighting its potential as a therapeutic intervention to mitigate MASLD progression. Both FNI and NI-NASH-DS are helpful and inexpensive tools for assessing MASH.

Identifying patients with steatotic liver disease who are at a high risk of developing HCC remains challenging. We present a deep learning (DL) model to predict HCC development using hematoxylin and eosin-stained whole-slide images of biopsy-proven steatotic liver disease.

We included 639 patients who did not develop HCC for ≥7 years after biopsy (non-HCC class) and 46 patients who developed HCC <7 years after biopsy (HCC class). Paired cases of the HCC and non-HCC classes matched by biopsy date and institution were used for training, and the remaining nonpaired cases were used for validation. The DL model was trained using deep convolutional neural networks with 28,000 image tiles cropped from whole-slide images of the paired cases, with an accuracy of 81.0% and an AUC of 0.80 for predicting HCC development. Validation using the nonpaired cases also demonstrated a good accuracy of 82.3% and an AUC of 0.84. These results were comparable to the predictive ability of logistic regression model using fibrosis stage. Notably, the DL model also detected the cases of HCC development in patients with mild fibrosis. The saliency maps generated by the DL model highlighted various pathological features associated with HCC development, including nuclear atypia, hepatocytes with a high nuclear-cytoplasmic ratio, immune cell infiltration, fibrosis, and a lack of large fat droplets.

The ability of the DL model to capture subtle pathological features beyond fibrosis suggests its potential for identifying early signs of hepatocarcinogenesis in patients with steatotic liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD), more recently redefined as metabolic-associated fatty liver disease (MAFLD), is now recognized as the most prevalent cause of chronic liver disease. Its strong association with cardiovascular disease (CVD) underscores its emerging role in global morbidity and mortality. Objective: This review critically examines the pathophysiological mechanisms that link NAFLD/MAFLD with CVD. It focuses on shared metabolic disturbances, inflammatory pathways, and alterations in the gut microbiota that contribute to hepatic and cardiovascular pathology. Review and Gaps: Current evidence highlights insulin resistance, dyslipidemia, systemic inflammation, and gut dysbiosis as pivotal factors connecting NAFLD/MAFLD to CVD. Despite these insights, inconsistencies in diagnostic criteria and a lack of validated non-invasive biomarkers hinder a clear understanding of the causal relationship between liver and cardiovascular diseases. Conclusions: Addressing these knowledge gaps through standardized diagnostic protocols and large-scale longitudinal studies is essential. Improved biomarker validation and clearer delineation of the underlying mechanisms will improve cardiovascular risk stratification and enable more personalized therapeutic strategies for patients with NAFLD/MAFLD.

The link between cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD) is well-established at both the epidemiological and pathophysiological levels. Among the common pathophysiological mechanisms involved in the development and progression of both diseases, oxidative stress and inflammation, insulin resistance, lipid metabolism deterioration, hepatokines, and gut dysbiosis along with genetic factors have been recognized to play a pivotal role. Pharmacologic interventions with drugs targeting common modifiable cardiometabolic risk factors, such as T2DM, dyslipidemia, and hypertension, are a reasonable strategy to prevent CVD development and progression of MASLD. Recently, a novel drug for metabolic dysfunction-associated steatohepatitis (MASH), resmetirom, has shown positive effects regarding CVD risk, opening new opportunities for the therapeutic approach of MASLD and CVD. This review provides current knowledge on the epidemiologic association of MASLD to CVD morbidity and mortality and enlightens the possible underlying pathophysiologic mechanisms linking MASLD with CVD. The role of cardiometabolic drugs such as anti-hypertensive drugs, hypolipidemic agents, glucose-lowering medications, acetylsalicylic acid, and the thyroid hormone receptor-beta agonist in the progression of MASLD is also discussed. Metformin failed to prove beneficial effects in MASLD progression. Studies on the administration of thiazolinediones in MASLD suggest effectiveness in improving steatosis, steatohepatitis, and fibrosis, while newer categories of glucose-lowering agents such as GLP-1Ra and SGLT-2i are currently being tested for their efficacy across the whole spectrum of MASLD. Statins alone or in combination with ezetimibe have yielded promising results. The conduction of long-duration, large, high-quality, randomized-controlled trials aiming to assess by biopsy the efficacy of cardiometabolic drugs to reverse MASLD progression is of great importance.

Previous studies have shown that methyl tert-butyl ether (MTBE) could interfere with lipid metabolism. However, there is still a lack of epidemiological reports on the association between MTBE exposure and the risk of nonalcoholic fatty liver disease (NAFLD). In this study, a cross-sectional study was performed with data from the 2017-2020 cycles of the National Health and Nutrition Examination Survey (NHANES). The target population consisted of adults with reliable vibration controlled Transient elastography (VCTE) and blood MTBE concentration results. The hepatic steatosis and fibrosis were assessed by the values of the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. Generalized linear mixed model analysis was performed to evaluate the association between MTBE exposure and both steatosis and early liver fibrosis after adjustment for potential confounders. A total of 1303 subjects were enrolled and divided into NAFLD groups (CAP ≥ 248) and non-NAFLD groups (CAP < 248) based on the values of CAP in this study. Generalized linear mixed analysis suggested that blood MTBE concentration was positively associated with NAFLD risk in whole populations (OR: 2.153, 95% confidence interval [CI], 1.176-3.940) and female populations (OR: 11.019, 95% CI: 2.069-58.676). Blood MTBE concentration still showed an obvious positive correlation with the NAFLD risk after excluding factors such as diet and exercise in whole populations. Similarly, a positive correlation between blood MTBE concentration and liver fibrosis was also observed, although the results did not show significant statistical differences. In conclusion, our results indicate that MTBE exposure might be a potential important environmental pathogenic factor for NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. Accurate assessment of liver fibrosis is essential for the prognosis and management of NAFLD. Mean platelet volume (MPV), an index of platelet activation, has been associated with liver fibrosis in various chronic liver diseases; however, its role in NAFLD remains uncertain.

This study analyzed data from 70,830 patients with NAFLD who underwent a comprehensive health examination between 2015 and 2019. Patients were stratified into three groups based on the fibrosis-4 (FIB-4) index: low (<1.30), indeterminate (1.30-2.67), and high (>2.67). We evaluated the differences in MPV among these groups and analyzed the association between MPV and the FIB-4 index.

MPV varied significantly across the three groups categorized by the FIB-4 index (p < 0.001). Additionally, a weak but statistically significant positive correlation was observed between MPV and the FIB-4 index (rho =  0.170, p <  0.001). Multivariable linear regression adjusted for multiple covariates showed that MPV remained significantly associated with the FIB-4 index (β =  0.01, p <  0.001).

MPV may serve as a supplementary non-invasive marker for assessing liver fibrosis in patients with NAFLD. Further studies are required to validate these findings and explore the utility of MPV in conjunction with other non-invasive markers.

The pathological levels of reactive oxygen species (ROS) and oxidative stress has been recognized as a critical driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. ASK1 inhibitors are reported to have the potential to treat clinically important inflammatory pathologies including liver, pulmonary and renal disorders. In view of its biological and pathological significance, inhibition of ASK1 with small molecules has been pursued as an attractive strategy to combat human diseases such as non-alcoholic steatohepatitis (NASH). Despite several ASK1 inhibitors being developed, the failure in Phase 3 clinical trials of most advanced candidate selonsertib's, underscores to discover therapeutic agents with diverse chemical moiety. Here, by using structural pharmacophore and enumeration strategy on mining co-crystals of ASK1, different scaffolds were generated to enhance the chemical diversity keeping the critical molecular interaction in the catalytic site intact. A total of 15,772 compounds were generated from diverse chemical scaffolds and were evaluated using a virtual screening pipeline. Based on docking and MM-GBSA scores, a lead candidate, S3C-1-D424 was identified from top hits. A comparative molecular dynamics simulations (MD) of APO, Selonsertib and shortlisted potential candidates combined with pharmacokinetics profiling and thermodynamic analysis, demonstrating their suitability as potential ASK1 inhibitors to explore further for establishment towards hit-to-lead campaign.Communicated by Ramaswamy H. Sarma.

As the rates of obesity and type 2 diabetes (T2D) continue to increase globally, so does the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Currently, 38% of all adults and 7-14% of children and adolescents have MASLD. By 2040, the MASLD prevalence rate for adults is projected to increase to more than 55%. Although MASLD does not always develop into progressive liver disease, it has become the top indication for liver transplant in the United States for women and those with hepatocellular carcinoma (HCC). Nonetheless, the most common cause of mortality among patients with MASLD remains cardiovascular disease. In addition to liver outcomes (cirrhosis and HCC), MASLD is associated with an increased risk of developing de novo T2D, chronic kidney disease, sarcopenia, and extrahepatic cancers. Furthermore, MASLD is associated with decreased health-related quality of life, decreased work productivity, fatigue, increased healthcare resource utilization, and a substantial economic burden. Similar to other metabolic diseases, lifestyle interventions such as a heathy diet and increased physical activity remain the cornerstone of managing these patients. Although several obesity and T2D drugs are available to treat co-morbid disease, resmetirom is the only MASH-targeted medication for patients with stage 2-3 fibrosis that has approved by the Food and Drug Administration for use in the United States. This review discusses MASLD epidemiology and its related risk factors and outcomes and demonstrates that without further global initiatives, MASLD incidence could continue to increase.

Epidemiologic studies have suggested an association between the consumption of dietary advanced glycation end products (dAGEs) and the incidence of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanism by which dAGEs induce NAFLD development, particularly the pathogenic role of the gut-liver axis, remains poorly understood. In this study, by establishing a high-AGE diet (HAD)-fed C57BL/6 mouse model, we employed multiomics approaches combined with a series of biological analyses to investigate the effect of HAD on NAFLD in vivo. Our results showed that exposure to HAD led to fat accumulation, oxidative stress, inflammation, and fibrosis in the liver of mice. Transcriptome analysis further revealed that HAD exposure disrupted lipid metabolism and activated inflammation-related signaling pathways in the liver. Additionally, exposure to HAD induced perturbations in gut homeostasis, as evidenced by the compromised gut barrier function, reduced probiotic abundance, and increases in pathogenic bacterial proportions. Dysbiosis of gut homeostasis may further act as a trigger for the initiation and progression of NAFLD via the gut-liver axis. This study sheds light on the underlying mechanisms through which dAGEs contribute to the development of NAFLD and helps to understand the detrimental effects of food ultraprocessing products in modern diets. Future studies are needed to explore the in-depth mechanisms related to the gut-liver axis to consolidate our conclusions.

Recent studies have implicated altered ubiquitination/de-ubiquitination pathway in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the potential role of a deubiquitinase, ubiquitin-specific peptidase 25 (USP25), in MASLD. Analysis of mRNA profiling data showed that both human and mouse MASLD are associated with reduced expression of USP25 in hepatocytes. Usp25 deficiency exacerbated HFD-induced liver lipid accumulation and MASLD in mice. Rescue experiments with USP25 induction in hepatocytes protected mice against HFD-induced MASLD. Through comprehensive transcriptome sequence and pulldown-LC-MS/MS analysis, we identified that peroxisome proliferator-activated receptor α (PPARα) is involved in USP25's protective actions and may be the substrate protein of USP25. Cell-based experiments show that USP25 interacts with PPARα directly via its USP domain and the histidine at position 608 of USP25 exerts deubiquitination to increase protein stability by removing the K48 ubiquitin chain at PPARα's lysine at position 429. USP25 reduces palmitate (PA)-induced lipid accumulation in hepatocytes via increasing PPARα. Finally, we show that the protective effects of Usp25 induction are nullified in Ppara-deficient mice with HFD. In summary, this study presents a new USP25-PPARα axis in hepatocytes and highlights a novel function of USP25 in MASLD, suggesting that it may be targeted to combat the disease.

Non-alcoholic fatty liver disease (NAFLD) is a widespread liver condition associated with diabetes, metabolic syndrome, and cardiovascular diseases, yet public awareness remains low. Early detection of risk factors is crucial, but liver biopsy, the diagnostic gold standard, is invasive and costly. Non-invasive anthropometric indices provide a safer alternative. This study examines these indices to identify the most reliable predictor of NAFLD in adults.

In the present cross-sectional study, we used the Fasa Cohort Data, conducted on about 10,000 people, of whom 1,047 were diagnosed with NAFLD. NAFLD diagnosis in this study was confirmed by physicians based on medical history and ultrasonographic evaluations, ensuring accurate and reliable identification of cases. General, anthropometric, and dietary assessments were performed using interviews, tools, and valid questionnaires. Biochemical evaluation was also done. Waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), Body mass index (BMI), a body shape index (ABSI), body roundness index (BRI), and visceral fat index (VAI) were also calculated using these measurements and formulas. This study used descriptive tests, binary logistic regression, and ROC curve analysis.

In both crude and adjusted models, significant associations were found between WHR, WHtR, BMI, and VAI with NAFLD. ROC analysis revealed that WHtR and BMI were the most accurate predictors of NAFLD in both genders (WHtR: men AUC = 0.750, women AUC = 0.702; BMI: men AUC = 0.754, women AUC = 0.701). BRI showed significant accuracy, but WHR (men: AUC = 0.727, women: AUC = 0.640) and VAI (men: AUC = 0.621, women: AUC = 0.622) were less effective. ABSI demonstrated poor predictive power (men: AUC = 0.530, women: AUC = 0.505) and is not recommended for NAFLD prediction.

Based on the findings, BMI and WHtR emerge as the most practical and accessible indicators for early screening of NAFLD in both men and women, while ABSI shows minor effectiveness in identifying the disease.

Intermittent fasting (IF) can be an effective dietary therapy for weight loss and improving cardiometabolic health. However, there is scant evidence regarding the role of IF on indicators of liver function, particularly in adults with metabolic disorders. Therefore, we performed a systematic review and meta-analysis to investigate the effects of IF on liver function in adults with metabolic disorders.

Three primary electronic databases including PubMed, Web of Science, and Scopus, were searched from inception to September 2024 to identify original studies that used IF interventions with or without control groups in adults with metabolic disorders. Inclusion criteria were (1) studies of human participants with metabolic diseases, (2) interventions that evaluated the effects of IF, (3) with or without a control group, and (4) measured liver fat, liver steatosis, liver fibrosis, or liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as primary outcomes. Standardized mean differences (SMD) and 95% confidence intervals were calculated using random effects models. Heterogeneity was assessed using the Cochran's Q statistic and I-squared statistic (I2). Publication bias was assessed using the visual inspection of funnel plots and Egger's tests. The risk of bias was assessed using the PEDro scale and the NIH quality assessment tool.

A total 21 studies involving 1,226 participants with metabolic disorders were included in the meta-analysis. Overall, IF effectively decreased liver fat with a large effect size [SMD: -1.22 (95% CI: -1.63 to -0.80), p = 0.001], liver steatosis with a medium effect size [SMD: -0.73 (95% CI: -1.12 to -0.35), p = 0.001], ALT with a small effect size [SMD: -0.44 (95% CI: -0.58 to -0.30), p = 0.001], and AST with a small effect size [SMD: -0.30 (95% CI: -0.49 to -0.11), p = 0.001], but not liver fibrosis [SMD: -0.28 (95% CI: -0.59 to 0.02), p = 0.07]. Subgroup analyses showed that IF decreased liver fat and ALT significantly, independent of IF mode, participant age, health status, weight status, and intervention duration. IF significantly decreased liver fibrosis in those with obesity; and decreased AST following 5:2 diets, in middle-aged adults, adults with obesity, and regardless of health status or intervention duration.

IF seems to be an effective dietary therapy for improving liver function in adults with metabolic disorders, and many of liver function-related benefits occur regardless of IF mode, intervention duration, or participant health status.

Significant heterogeneity, small numbers of studies and inclusion of non-randomized trials or single-group pre-post trials were the main limitation of our meta-analysis. Further randomized clinical trials are needed to elucidate the effects of IF on liver function in adults with metabolic disorders.

We investigated the risk of cardiovascular events, all-cause mortality, and liver-related mortality according to the presence of metabolic syndrome (MetS) and fatty liver index (FLI). In this retrospective longitudinal population-based cohort study, we used Korean National Health Insurance Service data from 2009 to 2012. Nonalcoholic fatty liver disease (NAFLD) was defined as FLI ≥ 60. Risk of all-cause mortality, liver-related mortality, and major adverse cardiovascular events (MACE) including myocardial infarction (MI), stroke, heart failure (HF), and cardiovascular disease (CVD)-related mortality was assessed according to the presence of MetS and FLI among adults (aged 40 to 80 years) who underwent health examinations (n = 769,422). During a median 8.59 years of follow up, 44,356 (5.8%) cases of MACE, 24,429 (3.2%) cases of all-cause mortality, and 1114 (0.1%) cases of liver-related mortality were detected in the entire cohort. When the FLI < 30 without MetS group was set as a reference, the FLI ≥ 60 with MetS group had the highest risk of MACE (adjusted hazard ratio [aHR] 2.05, 95% confidence interval [CI] 1.98-2.13) and all-cause mortality (aHR 1.96, 95% CI 1.86-2.07). The risk of liver-related mortality (aHR 10.71, 95% CI 8.05-14.25) was highest in the FLI ≥ 60 without MetS group. The FLI ≥ 60 with MetS group had a higher risk of MACE (aHR 1.39, 95%CI 1.28-1.51), a lower risk of liver-related mortality (aHR 0.44, 95%CI 0.33-0.59), and no significant difference in all-cause mortality compared with the FLI ≥ 60 without MetS group. The FLI ≥ 60 with MetS group was associated with the highest risk of MACE and the FLI ≥ 60 without MetS group had the highest risk liver-related mortality, but there was no significant difference in all-cause mortality between two groups. In conclusion, as FLI levels increase, the risk of MACE increases, and the risk increases additively in the presence of MetS. The risk of liver-related mortality increases with higher FLI levels, the effect of high FLI on increased risk is more significant in groups without MetS compared to those with MetS.

Childhood obesity, a pressing global health issue, significantly increases the risk of metabolic complications, including metabolic dysfunction associated with steatotic liver disease (MASLD). Accurate non-invasive tests for early detection and screening of steatosis are crucial. In this study, we explored the serum proteome, identifying proteins as potential biomarkers for inclusion in non-invasive steatosis diagnosis tests.

Fifty-nine obese adolescents underwent ultrasonography to assess steatosis. Serum samples were collected and analyzed by targeted proteomics with the Proximity Extension Assay technology. Clinical and biochemical parameters were evaluated, and correlations among them, the individuated markers, and steatosis were performed. Receiver operating characteristic (ROC) curves were used to determine the steatosis diagnostic performance of the identified candidates, the fatty liver index (FLI), and their combination in a logistic regression model.

Significant differences were observed between subjects with and without steatosis in various clinical and biochemical parameters. Gender-related differences in the serum proteome were also noted. Five circulating proteins, including Cathepsin O (CTSO), Cadherin 2 (CDH2), and Prolyl endopeptidase (FAP), were identified as biomarkers for steatosis. CDH2, CTSO, Leukocyte Immunoglobulin Like Receptor A5 (LILRA5), BMI, waist circumference, HOMA-IR, and FLI, among others, significantly correlated with the steatosis degree. CDH2, FAP, and LDL combined in a logit model achieved a diagnostic performance with an AUC of 0.91 (95% CI 0.75-0.97, 100% sensitivity, 84% specificity).

CDH2 and FAP combined with other clinical parameters, represent useful tools for accurate diagnosis of fatty liver, emphasizing the importance of integrating novel markers into diagnostic algorithms for MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases' progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH.

We conducted a case-control observational research using a systems biology-based approach to analyse liver, abdominal subcutaneous adipose tissue (SAT), omental visceral adipose tissue (VAT), and blood of n = 100 patients undergoing bariatric surgery (NCT05554224). MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples. Lipidomics and proteomics profiles were determined on plasma samples.

Liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Paired adipose tissue biopsies had larger adipocyte areas in both fat depots in MASH. Enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics identified candidates with high diagnostic accuracy (AUC = 0.919, 95% CI 0.840-0.979) for screening MASH.

Mitochondrial dysfunction is also present in VAT in patients with obesity-associated MASH. This may cause a disruption in the metabolic equilibrium of lipid processing and storage, which impacts the liver and accelerates detrimental adaptative responses.

The project leading to these results has received funding from 'la Caixa' Foundation (HR21-00430), and from the Instituto de Salud Carlos III (ISCIII) (PI21/00510) and co-funded by the European Union.

The role of ubiquitin-specific protease 13 (USP13) in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. This study aimed to elucidate the role of USP13 in MASH progression.

THLE-2 cells were subjected to palmitate acid (PA) to generate an in vitro model of lipid accumulation and inflammation. Two in vivo models of MASH were established by feeding mice with a high-fat, high-fructose and high-cholesterol (HFFC) diet for 16 weeks and a methionine/choline-deficient diet (MCD) for 4 weeks, respectively. Usp13 overexpression and knockout (KO) techniques were employed to investigate its role in MASH.

USP13 expression was significantly downregulated in the livers of MASH mice and in the in vitro model of lipid accumulation and inflammation. Hepatic overexpression of Usp13 markedly alleviated liver steatosis, inflammation and fibrosis, while knockout of Usp13 exacerbated the MASH phenotype. Mechanistically, USP13 directly bound to phosphatase and tensin homolog (PTEN) and deubiquitinated it, thereby elevating the PTEN expression and improving the MASH phenotype. Notably, Pten overexpression in Usp13 knockout mice reversed the exacerbation of MASH brought from Usp13 deficiency.

Our findings revealed that USP13 alleviates MASH by directly binding to and deubiquitinating PTEN. The USP13-PTEN axis may represent a promising molecular target for MASH treatment.

Nonalcoholic fatty liver disease (NAFLD) is a common disease with severe inflammatory processes associated with numerous gastrointestinal diseases, such as inflammatory bowel disease (IBD). Therefore, we investigated the relationship between NAFLD and IBD and the possible risk factors associated with the diagnosis of IBD.

This longitudinal nationwide cohort study investigated the risk of IBD in patients with NAFLD alone. General characteristics, comorbidities, and incidence of IBD were also compared.

Patients diagnosed with NAFLD had a significant risk of developing IBD compared to control individuals, who were associated with a 2.245-fold risk of the diagnosis of IBD and a 2.260- and 2.231-fold of increased diagnosis of ulcerative colitis and Crohn's disease, respectively (P< 0.001). The cumulative risk of IBD increased annually during the follow-up of patients with NAFLD (P< 0.001).

Our results emphasize that NAFLD significantly impacts its incidence in patients with NAFLD. If patients with NAFLD present with risk factors, such as diabetes mellitus and dyslipidemia, these conditions should be properly treated with regular follow-ups. Furthermore, we believe that these causes may be associated with the second peak of IBD.

Inflammation is key to metabolic dysfunction-associated steatotic liver disease (MASLD) development. Nevertheless, the correlation between the inflammatory marker, neutrophil-to-lymphocyte ratio (NLR), and the MASLD prognosis remains unclear. We aim to determine the link between NLR and mortality risk in MASLD.

The MASLD adult participants from the 1999-2018 National Health and Nutrition Examination Survey (NHANES) database were evaluated. Utilizing restricted cubic spline (RCS) analyses, as well as Cox proportional hazards (PH) models, the associations between NLR and all-cause mortality (ACM) and cardiovascular mortality (CVM) were analyzed in MASLD. Subgroup analyses and interaction tests were conducted to validate these associations. Moreover, we used sensitivity analyses to ascertain the robustness of the results.

Through 115 months of median follow-up, 2,307 of the 16,859 participants with MASLD died, including 650 deaths from cardiovascular causes. RCS analyses showed positive linear associations between NLR and both ACM and CVM. In the multivariable-adjusted Cox PH model, a one-unit elevation in NLR was related to a hazard ratio (HR) of 1.16 (95% confidence interval [CI]: 1.12-1.21) for ACM and 1.21 (95% CI: 1.15-1.27) for CVM. Participants were classified into higher (≥ 2.88) and lower (< 2.88) NLR groups employing the maximally selected rank statistics. The higher NLR group had a significantly elevated ACM (HR 1.38, 95% CI: 1.23-1.55) and CVM (HR 1.64, 95% CI: 1.32-2.03) risk compared to the lower NLR group. The associations were consistent in subgroup analyses based on age, gender, BMI, hypertension, and diabetes, with no significant interaction between NLR and these characteristics. Sensitivity analyses affirmed the main outcome's robustness.

A raised NLR independently predicts escalated ACM and CVM in MASLD.

The classification of steatotic liver disease (SLD) has evolved, incorporating all conditions characterized by hepatic lipid accumulation. SLD represents a continuum of disorders that are shaped by the dynamic factors of alcohol intake and cardiometabolic risk factors. This updated classification has profound implications for both the management and research of SLD, especially with the new distinct category of patients with both metabolic and alcohol-related liver disease. In this Perspective, we highlight the pivotal role of alcohol within the SLD framework. We introduce the 'SLD burden paradox': a concept illustrating the disparity in which metabolic dysfunction-associated steatotic liver disease is more prevalent, yet individuals with SLD and excessive alcohol intake (such as in metabolic and alcohol-related liver disease and in alcohol-related liver disease) account for greater global liver-related morbidity and mortality. We explore strategies to mitigate the effect of SLD on morbidity and mortality, emphasizing the importance of early detection and reducing stigma associated with alcohol intake. Our discussion extends to methods for assessing and monitoring alcohol intake together with the critical role of managing cardiometabolic risk factors in patients across the SLD spectrum. Conclusively, we advocate for a coordinated care framework that adopts a person-centric approach when managing SLD, aiming to improve outcomes and patient care.

This study aims to investigate the association between serum uric acid (SUA) and both the risk and long-term mortality of dysfunction-associated steatotic liver disease (MASLD), and to explore differences between the pure MASLD and metabolic and alcohol related/associated liver disease (MetALD) subgroups.

We included 11,675 participants from the Third National Health and Nutrition Examination Survey, with matched mortality data up to 2019. Logistic regression and Cox proportional hazards regression evaluated the relationship between SUA and both the risk and mortality of MASLD. Non-linear correlations and threshold effects were explored using restricted cubic splines and a two-piecewise Cox proportional hazards model. We found that SUA was positively associated with the risk of MASLD [odds ratio (OR): 1.19, 95 % confidence interval (CI) 1.12-1.27]. For pure MASLD, SUA showed a positive association with all-cause mortality [<4.7 mg/dL: hazard ratio (HR): 1.34, 95 % CI 1.04-1.73; ≥4.7 mg/dL: HR: 1.08, 95 % CI 1.02-1.15] and cardiovascular mortality (HR: 1.12, 95 % CI 1.02-1.22). For MetALD, there was an inverse J-shaped relationship (threshold: 6.6 mg/dL) between SUA and all-cause mortality. Below the threshold, SUA was negatively correlated with all-cause mortality (HR: 0.42, 95 % CI 0.19-0.93), but no association was found above it (HR: 0.81, 95 % CI 0.54-1.21). Additionally, no association was observed between SUA and cardiovascular mortality.

SUA serves as an independent predictor of the risk and all-cause mortality of MASLD. The relationship between SUA and both all-cause and cardiovascular mortality differs between the pure MASLD and MetALD subgroups.

Palm oil is the most widely used type of oil in the world, which is oxidized by exposure to heat and leads to damage to body tissues and the creation of free fatty acids. This study aimed to show the harm of palm oil in both heated and non-heated states on liver tissue. For this purpose, twenty-four male Wistar rats were randomly divided into three groups and treated for 90days as follows: control (rats treated with their normal chew), palm oil (rats treated with 7.5% w/w of palm oil added to their normal chew), and heated palm oil (rats treated with 7.5% w/w of palm oil into their normal chew, which had been heated repeatedly 10 times at 180°C for 10min). After experimental treatments, the animals were euthanized. Liver samples were collected for histopathological assessment by hematoxylin and eosin (H&E) staining. In the groups treated with heated and unheated palm oil, In the groups that were treated with heated and unheated palm oil, the accumulation of fat droplets in hepatocytes, their ballooning and the infiltration of inflammatory cells around the hepatocytes were observed in different proportions. Histological evidence is an indication that heated and unheated palm oils can cause various degrees of nonalcoholic fatty liver disease. Therefore, palm oil consumption, especially when heated, may not be completely safe.

Preservation of brain health is a worldwide priority. The traditional view is that the major threats to the ageing brain lie within the brain itself. Consequently, therapeutic approaches have focused on protecting the brain from these presumably intrinsic pathogenic processes. However, an increasing body of evidence has unveiled a previously under-recognized contribution of peripheral organs to brain dysfunction and damage. Thus, in addition to the well-known impact of diseases of the heart and endocrine glands on the brain, accumulating data suggest that dysfunction of other organs, such as gut, liver, kidney and lung, substantially affects the development and clinical manifestation of age-related brain pathologies. In this Review, a framework is provided to indicate how organ dysfunction can alter brain homeostasis and promote neurodegeneration, with a focus on dementia. We delineate the associations of subclinical dysfunction in specific organs with dementia risk and provide suggestions for public health promotion and clinical management.

Steatotic liver disease (SLD) is associated with adverse cardiac events. Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a condition characterized by the abnormal accumulation of hepatic lipids that is closely linked to five metabolic disorders: overweight or obesity, impaired glucose regulation, hypertension, hypertriglyceridemia, and low high-density lipoprotein-cholesterol. This retrospective study aimed to stratify the risk of cardiac events in patients with MASLD.

Patients diagnosed with MASLD through ultrasonography were evaluated. We implemented a machine learning-based approach using a survival classification and regression tree (CART) model to stratify patients based on age, and the number of risk scores was investigated as a predictor of adverse outcomes in the derivation cohort. The primary outcomes were major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, and revascularization due to coronary artery disease.

Among 2,962 patients (median age, 62 years; men, 53.5 %), the distribution of risk factors was as follows: one (10.8 %), two (28.5 %), three (33.0 %), four (19.9 %), and five (7.8 %). Over a median follow-up period of 6.8 years, 170 (5.7 %) patients experienced MACE. In the derivation cohort of 2,073 patients, the CART model identified age ≥60 years old and risk factors ≥4 as significant predictors of MACE. These findings were corroborated in a validation cohort of 889 patients. Patients meeting both criteria exhibited the highest risk of MACE (log-rank test, p < 0.001).

Patients aged ≥60 years old with risk factors ≥4 indicates at high risk of MACE in patients with MASLD. This risk stratification system provides a practical tool for identifying high-risk individuals in the MASLD population.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by the misfolding and accumulation of the mutant variant of alpha-1 antitrypsin (AAT) within hepatocytes, which limits its access to the circulation and exposes the lungs to protease-mediated tissue damage. This results in progressive liver disease secondary to AAT polymerization and accumulation, and chronic obstructive pulmonary disease (COPD) due to deficient levels of AAT within the lungs. Our goal was to characterize the unique effects of COPD secondary to AATD on liver disease and gene expression.

A subcohort of AATD individuals with COPD (n = 33) and AATD individuals without COPD (n = 14) were evaluated in this study from our previously reported cross-sectional cohort. We used immunohistochemistry to assess the AATD liver phenotype, and RNA sequencing to explore liver transcriptomics. We observed a distinct transcriptomic profile in liver tissues from AATD individuals with COPD compared to those without.

A total of 339 genes were differentially expressed. Canonical pathways related to fibrosis, extracellular matrix remodeling, collagen deposition, hepatocellular damage, and inflammation were significantly upregulated in the livers of AATD individuals with COPD. Histopathological analysis also revealed higher levels of fibrosis and hepatocellular damage in these individuals.

Our data supports a relationship between the development of COPD and liver disease in AATD and introduces genes and pathways that may play a role in AATD liver disease when COPD is present. We believe addressing lung impairment and airway inflammation may be an approach to managing AATD-related liver disease.

Metabolic dysfunction-associated steatohepatitis (MASH), characterized by progressive inflammation and fibrosis, evolves from metabolic dysfunction-associated steatotic liver disease and significantly heightens the risk of cirrhosis and hepatocellular carcinoma. Understanding metabolic pathways that influence MASH progression is crucial for developing targeted therapies. Non-targeted metabolomics offer a comprehensive view of metabolic alterations, enabling identification of novel biomarkers and pathways without preconceived ideas. Conversely, targeted metabolomics deliver precise and reproducible measurements, focusing on predefined metabolites to accurately quantify established pathways. This study utilized hepatocyte-specific PTEN knockout mice as a model to explore metabolic shifts associated with MASH. By integrating non-targeted metabolomics and targeted metabolomics, we analyzed liver samples from three groups: normal, pathological (MASH-affected), and MASH-affected, but treated with apomorphine, an antioxidant and recently reported ferroptosis inhibitor with potential therapeutic effects. Metabolic profiling identified lysophospholipids (LPLs) as significantly altered metabolites, with elevated levels in the MASH model and a notable reduction after apomorphine treatment. This suggests that LPLs are central to the etiology of MASH and may serve as targets for therapeutic intervention. Our findings underscore the effectiveness of apomorphine in modulating disease-specific metabolic disruptions, offering insights into its potential as a treatment for human MASH.

Metabolic dysfunction-associated steatohepatitis (MASH) is a highly prevalent liver disease globally, with a significant risk of progressing to cirrhosis and even liver cancer. Efferocytosis, a process implicated in a broad spectrum of chronic inflammatory disorders, has been reported to be associated with the pathogenesis of MASH; however, its precise role remains obscure. Thus, we aimed to identify and validate efferocytosis linked signatures for detection of MASH.

We retrieved gene expression patterns of MASH from the GEO database and then focused on assessing the differential expression of efferocytosis-related genes (EFRGs) between MASH and control groups. This analysis was followed by a series of in-depth investigations, including protein-protein interaction (PPI), correlation analysis, and functional enrichment analysis, to uncover the molecular interactions and pathways at play. To screen for biomarkers for diagnosis, we applied machine learning algorithm to identify hub genes and constructed a clinical predictive model. Additionally, we conducted immune infiltration and single-cell transcriptome analyses in both MASH and control samples, providing insights into the immune cell landscape and cellular heterogeneity in these conditions.

This research pinpointed 39 genes exhibiting a robust correlation with efferocytosis in MASH. Among these, five potential diagnostic biomarkers-TREM2, TIMD4, STAB1, C1QC, and DYNLT1-were screened using two distinct machine learning models. Subsequent external validation and animal experimentation validated the upregulation of TREM2 and downregulation of TIMD4 in MASH samples. Notably, both TREM2 and TIMD4 demonstrated area under the curve (AUC) values exceeding 0.9, underscoring their significant potential in facilitating the diagnosis of MASH.

Our study comprehensively elucidated the relationship between MASH and efferocytosis, constructing a favorable diagnostic model. Furthermore, we identified potential therapeutic targets for MASH treatment and offered novel insights into unraveling the underlying mechanisms of this disease.

Background and Objectives: Metabolic syndrome (MetS) is a condition marked by a complex array of physiological, biochemical, and metabolic abnormalities, including central obesity, insulin resistance, high blood pressure, and dyslipidemia (characterized by elevated triglycerides and reduced levels of high-density lipoproteins). The pathogenesis develops from the accumulation of lipid droplets in the hepatocyte (steatosis). This accumulation, in genetically predisposed subjects and with other external stimuli (intestinal dysbiosis, high caloric diet, physical inactivity, stress), activates the production of pro-inflammatory molecules, alter autophagy, and turn on the activity of hepatic stellate cells (HSCs), provoking the low grade chronic inflammation and the fibrosis. This syndrome is associated with a significantly increased risk of developing type 2 diabetes mellitus (T2D), cardiovascular diseases (CVD), vascular, renal, pneumologic, rheumatological, sexual, cutaneous syndromes and overall mortality, with the risk rising five- to seven-fold for T2DM, three-fold for CVD, and one and a half-fold for all-cause mortality. The purpose of this narrative review is to examine metabolic syndrome as a "systemic disease" and its interaction with major internal medicine conditions such as CVD, diabetes, renal failure, and respiratory failure. It is essential for internal medicine practitioners to approach this widespread condition in a "holistic" rather than a fragmented manner, particularly in Western countries. Additionally, it is important to be aware of the non-invasive tools available for assessing this condition. Materials and Methods: We conducted an exhaustive search on PubMed up to July 2024, focusing on terms related to metabolic syndrome and other pathologies (heart, Lung (COPD, asthma, pulmonary hypertension, OSAS) and kidney failure, vascular, rheumatological (osteoarthritis, rheumatoid arthritis), endocrinological, sexual pathologies and neoplastic risks. The review was managed in accordance with the PRISMA statement. Finally, we selected 300 studies (233 papers for the first search strategy and 67 for the second one). Our review included studies that provided insights into metabolic syndrome and non-invasive techniques for evaluating liver fibrosis and steatosis. Studies that were not conducted on humans, were published in languages other than English, or did not assess changes related to heart failure were excluded. Results: The findings revealed a clear correlation between metabolic syndrome and all the pathologies above described, indicating that non-invasive assessments of hepatic fibrosis and steatosis could potentially serve as markers for the severity and progression of the diseases. Conclusions: Metabolic syndrome is a multisystem disorder that impacts organs beyond the liver and disrupts the functioning of various organs. Notably, it is linked to a higher incidence of cardiovascular diseases, independent of traditional cardiovascular risk factors. Non-invasive assessments of hepatic fibrosis and fibrosis allow clinicians to evaluate cardiovascular risk. Additionally, the ability to assess liver steatosis may open new diagnostic, therapeutic, and prognostic avenues for managing metabolic syndrome and its complications, particularly cardiovascular disease, which is the leading cause of death in these patients.

Previous studies indicate a link between non-alcoholic fatty liver disease (NAFLD) and unhealthy dietary patterns or nutrient intake. However, it remains unclear whether ultra-processed foods (UPF) contribute to an increased risk of NAFLD. This study aimed to explore how ultra-processed food consumption correlates with severe NAFLD using the UK Biobank data.

This prospective cohort study included 143,073 participants from the UK Biobank. UPF consumption levels were determined using the NOVA classification and quantified from 24-h dietary recall data. The association between UPF consumption and severe NAFLD (hospitalization or death) was initially examined using Cox proportional hazards models with intake quartiles. Nonlinear associations were investigated using penalized cubic splines fitted in the Cox proportional hazards models. Adjustments were made for general characteristics, sociodemographic factors, body mass index (BMI), and lifestyle.

Throughout the median follow-up period of 10.5 years, 1,445 participants developed severe NAFLD. The adjusted models indicated a significant increase in severe NAFLD risk in higher UPF intake groups compared to the lowest quartile (HR: 1.26 [95% CI: 1.11-1.43]). Subgroup analysis revealed that individuals with a BMI of 25 or higher were at greater risk in the highest quartile of UPF consumption. Sensitivity analyses yielded results consistent with these findings.

Higher consumption of UPF is associated with an increased risk of severe NAFLD. Reducing the intake of UPF can be a potential approach to lower the risk of NAFLD.

Growing evidence suggests an increased prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the context of immune-mediated inflammatory diseases (IMIDs). We aimed to clinically and mechanistically characterize steatotic liver disease (SLD) in a prospective cohort of patients with IMID compared to controls.

Cross-sectional, case-control study including a subset of patients with IMID. Controls from the general population were age-, sex-, type 2 diabetes-, and BMI-matched at a 1:2 ratio. SLD was established using controlled attenuation parameter. Liver biopsies were obtained when significant liver fibrosis was suspected. Total RNA was extracted from freshly frozen cases and analyzed by RNA-seq. Differential gene expression was performed with 'limma-voom'. Gene set-enrichment analysis was performed using the fgsea R package with a preranked "limma t-statistic" gene list.

A total of 1,456 patients with IMID and 2,945 controls were included. Advanced SLD (liver stiffness measurement ≥9.7 kPa) (13.46% vs. 3.79%; p <0.001) and advanced MASLD (12.8% vs. 2.8%; p <0.001) prevalence were significantly higher among patients with IMID than controls. In multivariate analysis, concomitant IMID was an independent, and the strongest, predictor of advanced SLD (adjusted odds ratio 3.318; 95% CI 2.225-4.947; p <0.001). Transcriptomic data was obtained in 109 patients and showed 87 significant genes differentially expressed between IMID-MASLD and control-MASLD. IMID-MASLD cases displayed an enriched expression of genes implicated in pro-tumoral activities or the control of the cell cycle concomitant with a negative expression of genes related to metabolism.

The prevalence of advanced SLD and MASLD is disproportionately elevated in IMID cohorts. Our findings suggest that IMIDs may catalyze a distinct MASLD pathway, divergent from classical metabolic routes, highlighting the need for tailored clinical management strategies.

The prevalence of steatotic liver disease with advanced fibrosis is increased in patients with immune-mediated inflammatory diseases, independent of classic metabolic risk factors or high-risk alcohol consumption. Transcriptomic analysis revealed a unique gene expression signature associated with cellular activities that are compatible with a liver condition leading to an accelerated and aggressive form of steatotic liver disease. Our findings underscore the importance of heightened screening for advanced liver disease risk across various medical disciplines overseeing patients with immune-mediated inflammatory diseases.

Since 1980, the cumulative effort of scientists and health-care stakeholders has advanced the prerequisites to address metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent chronic non-communicable liver disease. This effort has led to, among others, the approval of the first drug specific for metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis). Despite substantial progress, MASLD is still a leading cause of advanced chronic liver disease, including primary liver cancer. This Perspective contextualizes the nomenclature change from nonalcoholic fatty liver disease to MASLD and proposes important considerations to accelerate further progress in the field, optimize patient-centric multidisciplinary care pathways, advance pharmacological, behavioural and diagnostic research, and address health disparities. Key regulatory and other steps necessary to optimize the approval and access to upcoming additional pharmacological therapeutic agents for MASH are also outlined. We conclude by calling for increased education and awareness, enhanced health system preparedness, and concerted action by policy-makers to further the public health and policy agenda to achieve at least parity with other non-communicable diseases and to aid in growing the community of practice to reduce the human and economic burden and end the public health threat of MASLD and MASH by 2030.

Eukaryotic elongation factor 1A1 (EEF1A1), originally identified for its role in protein synthesis, has additional functions in diverse cellular processes. Of note, we previously discovered a role for EEF1A1 in hepatocyte lipotoxicity. We also demonstrated that a 2-wk intervention with the EEF1A1 inhibitor didemnin B (DB) (50 µg/kg) decreased liver steatosis in a mouse model of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) [129S6/SvEvTac mice fed Western diet (42% fat) for 26 wk]. Here, we further characterized the hepatic changes occurring in these mice by assessing lipid droplet (LD) size, bulk differential expression, and cell type-associated alterations in gene expression. Consistent with the previously demonstrated decrease in hepatic steatosis, we observed decreased median LD size in response to DB. Bulk RNA sequencing (RNA-Seq) followed by gene set enrichment analysis revealed alterations in pathways related to energy metabolism and proteostasis in DB-treated mouse livers. Deconvolution of bulk data identified decreased cell type association scores for cholangiocytes, mononuclear phagocytes, and mesenchymal cells in response to DB. Overrepresentation analyses of bulk data using cell type marker gene sets further identified hepatocytes and cholangiocytes as the primary contributors to bulk differential expression in response to DB. Thus, we show that chemical inhibition of EEF1A1 decreases hepatic LD size and decreases gene expression signatures associated with several liver cell types implicated in MASLD progression. Furthermore, changes in hepatic gene expression were primarily attributable to hepatocytes and cholangiocytes. This work demonstrates that EEF1A1 inhibition may be a viable strategy to target aspects of liver biology implicated in MASLD progression.NEW & NOTEWORTHY Chemical inhibition of EEF1A1 decreases hepatic lipid droplet size and decreases gene expression signatures associated with liver cell types that contribute to MASLD progression. Furthermore, changes in hepatic gene expression are primarily attributable to hepatocytes and cholangiocytes. This work highlights the therapeutic potential of targeting EEF1A1 in the setting of MASLD, and the utility of RNA-Seq deconvolution to reveal valuable information about tissue cell type composition and cell type-associated gene expression from bulk RNA-Seq data.