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Non-alcoholic steatohepatitis (NASH), an advanced form of non-alcoholic fatty liver disease (NAFLD), has emerged as the leading cause of liver failure and related death. Currently, no medication is specifically approved to treat NAFLD or NASH. Here we report that oral administration of honey vesicle-like nanoparticles (H-VLNs) to naturally aged mice protects the liver from NASH development. H-VLNs are dominantly taken up by Kupffer cells in the liver and suppress hepatic chronic inflammation and further development of fibrosis and nodule formation in aged mice. Besides their reported anti-inflammasome function, H-VLNs are found to inhibit the transcriptional activities of C-JUN and nuclear factor-kappa B (NF-κB). MicroRNAs miR5119 and miR5108 and phenolic compound luteolin in H-VLNs are identified in suppressing both the C-JUN and NF-κB pathways. Collectively, oral intake of H-VLNs represents a promising new user-friendly modality to prevent the development of NASH.

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BACKGROUND: Dietary interventions and increased physical activity are the cornerstones for management of the paediatric non-alcoholic fatty liver disease (NAFLD). Though, no specific diet has been proven superior, Indo-Mediterranean diet (IMD) has shown promise in adult literature. Thus, we aimed to compare the effect of IMD and a standard calorie-restricted diet (CRD) in Indian overweight children and adolescents with biopsy-proven NAFLD. METHODS: Thirty-nine consecutive biopsy-proven NAFLD children between the ages of 8 and 18 years were randomized into either IMD or CRD for 180 days, and various parameters were evaluated at baseline and then after 180 days (NCT05073588). RESULTS: A total of 34 subjects (18 in IMD and 16 in CRD group) completed the study. There was a significantly higher decrease in controlled attenuation parameter (CAP) values (as a marker of hepatic steatosis; on transient elastography) (95% CI: 4.2-73.4, p = 0.042), weight (95% CI: 0.75-5.5, p = 0.046) and body mass index (BMI) (95% CI: 0.21-2.05, p = 0.014) (but not in Pediatric NAFLD Fibrosis Index or PNFI; as a marker of hepatic fibrosis) in IMD group compared to the CRD group. Liver stiffness measurement, serum cholesterol and low-density lipoprotein levels and HOMA-IR decreased only in the IMD group (p < 0.001). Our statistical model showed that delta-Weight was the only independent variable associated with delta-CAP. CONCLUSION: Both IMD and CRD can improve the various anthropometric, clinical, imaging and biochemical parameters but IMD was superior to CRD in terms of reducing CAP values and weight/BMI over 180 days in overweight/obese NAFLD children.

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Non-alcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis (accumulation of fat in the liver to over 5% of its weight) in the absence of secondary causes of fat accumulation in the liver such as excessive alcohol use. NAFLD is divided into two types: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Therefore, in this clinical guideline, we sought to determine general and important policies for this disease and modify its managment approaches. We adapted this guideline for the management of NAFLD in Isfahan Province. This guideline was developed by clinical appraisal and review of the evidence, available clinical guidelines, and in consultation with members of the Isfahan Chamber of the Iranian Association of Gastroenterology and Hepatology. Biopsy is recommended as the most reliable method (gold standard) to diagnose steatohepatitis and fibrosis in patients with NAFLD. NAFLD fibrosis score (NFS) and fibrosis-4 (FIB-4) are recommended as the test with the highest predictive value for advanced fibrosis in patients with NAFLD compared to other serologic tests. Among the noninvasive methods used to assess liver fibrosis, transient elastography (TE) is preferable to other methods.

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OBJECTIVES: Artesunate (ART) is a water-soluble derivative of artemisinin, which has shown anti-inflammatory, anti-tumor, and immunomodulating effects. We aimed to investigate the potential therapeutic effects and mechanisms of ART in metabolic dysfunction-associated steatohepatitis (MASH). METHODS: The mice were randomly divided into the control group, high-fat, high-cholesterol diet-induced MASH group, and the MASH treated with ART (30 mg/kg once daily) group. Liver enzymes, lipids, and histological features were compared among groups. The molecular mechanisms were studied by transcriptomic and lipidomics analyses of liver tissues. RESULTS: The mice of the MASH group had significantly increased hepatic fat deposition and inflammation in terms of biochemical indicators and pathological manifestations than the control group. The ART-treated group had improved plasma liver enzymes and hepatic cholesterol, especially at week 4 of intervention (p < 0.05). A total of 513 differentially expressed genes and 59 differentially expressed lipids were identified in the MASH group and the MASH+ART group. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment test showed that ART regulated glycerolipid metabolism pathway and enhanced fatty acid degradation. Peroxisome proliferator-activated receptor (PPAR)-α acted as a key transcription factor in the treatment of MASH with ART, which was confirmed by cell experiment. CONCLUSIONS: ART significantly improved fat deposition and inflammatory manifestations in MASH mice, with potential therapeutic effects. The mechanism of artemisinin treatment for MASH may involve extensive regulation of downstream genes by upstream transcription factors, such as PPAR-α, to restore hepatic lipid homeostasis.

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No approved effective therapy for non-alcoholic steatohepatitis (NASH) is currently available. Trichinella spiralis (T. spiralis) infection and their products have positive impact on several metabolic diseases. Considering, we firstly investigated the effects of the T. spiralis-derived Excretory-Secretory antigens (ESA) on high fat diet (HFD)-induced NASH mouse models. To further elucidate the mechanism of action, HepG2 cells were incubated with palmitic acid (PA) to construct NASH-like cell model, and then the culture medium supernatant collected from ESA-treated macrophages was applied to intervene the cell model in vitro. In NASH mouse models, ESA significantly alleviated hepatic steatosis and hepatic inflammation, as reflected by reducing pro-inflammatory cytokines and inactivating TLR4/MYD88/NF-κB pathway and NLRP3 inflammasome. Meanwhile, the HFD-induced oxidative stress was restored by ESA through lessening the level of MDA, increasing the activity of T-SOD and enhancing Nrf2 signaling-related proteins, including p-Nrf2, NQO1, HO-1, GPX4, and p-AMPK. Notably, ESA preferentially promoted macrophages polarization toward M2 anti-inflammatory phenotype in vivo and vitro. Moreover, in vitro, intervention of PA-treated HepG2 cells with medium supernatant of ESA-treated macrophages attenuated lipid accumulation, inflammation, as well as oxidative stress. In conclusion, T. spiralis-derived ESA may serve as a novel promising candidate for the treatment of NASH via its properties of driving macrophage anti-inflammatory activity.

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In vivo molecular imaging tools hold immense potential to drive transformative breakthroughs by enabling researchers to visualize cellular and molecular interactions in real-time and/or at high resolution. These advancements will facilitate a deeper understanding of fundamental biological processes and their dysregulation in disease states. Here, we develop and characterize a self-assembling protein nanomicelle called collagen type I binding - thermoresponsive assembled protein (Col1-TRAP) that binds tightly to type I collagen in vitro with nanomolar affinity. For ex vivo visualization, Col1-TRAP is labeled with a near-infrared fluorescent dye (NIR-Col1-TRAP). Both Col1-TRAP and NIR-Col1-TRAP display approximately a 3.8-fold greater binding to type I collagen compared to TRAP when measured by surface plasmon resonance (SPR). We present a proof-of-concept study using NIR-Col1-TRAP to detect fibrotic type I collagen deposition ex vivo in the livers of mice with non-alcoholic steatohepatitis (NASH). We show that NIR-Col1-TRAP demonstrates significantly decreased plasma recirculation time as well as increased liver accumulation in the NASH mice compared to mice without disease over 4 hours. As a result, NIR-Col1-TRAP shows potential as an imaging probe for NASH with in vivo targeting performance after injection in mice. STATEMENT OF SIGNIFICANCE: Direct molecular imaging of fibrosis in NASH patients enables the diagnosis and monitoring of disease progression with greater specificity and resolution than do elastography-based methods or blood tests. In addition, protein-based imaging probes are more advantageous than alternatives due to their biodegradability and scalable biosynthesis. With the aid of computational modeling, we have designed a self-assembled protein micelle that binds to fibrillar and monomeric collagen in vitro. After the protein was labeled with near-infrared fluorescent dye, we injected the compound into mice fed on a NASH diet. NIR-Col1-TRAP clears from the serum faster in these mice compared to control mice, and accumulates significantly more in fibrotic livers.This work advances the development of targeted protein probes for in vivo fibrosis imaging.

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Numerous studies have suggested a strong association between paternal adverse environmental exposure and increased disease susceptibility in offspring. However, the impact of paternal pre-pregnant caffeine exposure (PPCE) on offspring health remains unexplored. This study elucidates the sperm reprogramming mechanism and potential intervention targets for PPCE-induced non-alcoholic steatohepatitis (NASH) in offspring. Here, male rats are administrated caffeine (15-60 mg kg-1/d) by gavage for 8 weeks and then mated with females to produce offspring. This study finds that NASH with transgenerational inheritance occurred in PPCE adult offspring. Mechanistically, a reduction of miR-142-3p is implicated in the occurrence of NASH, characterized by hepatic lipid metabolism dysfunction and chronic inflammation through an increase in ACSL4. Conversely, overexpression of miR-142-3p mitigated these manifestations. The origin of reduced miR-142-3p levels is traced to hypermethylation in the miR-142-3p promoter region of parental sperm, induced by elevated corticosterone levels rather than by caffeine per se. Similar outcomes are confirmed in offspring conceived via in vitro fertilization using miR-142-3pKO sperm. Overall, this study provides the first evidence of transgenerational inheritance of NASH in PPCE offspring and identifies miR-142-3p as a potential therapeutic target for NASH induced by paternal environmental adversities.

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Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder globally, characterized by fat accumulation in liver cells, which can progress to inflammation, fibrosis, and cirrhosis. The disease predominantly affects individuals with obesity and high body mass index (BMI). It is a globally prevalent condition, with variations in incidence across different regions. The pathophysiology of NAFLD involves insulin resistance, metabolic disturbances, and genetic and gut microbial factors. Current treatments primarily focus on lifestyle modifications and a limited range of pharmacological options. Bempedoic acid (BA), a novel cholesterol-lowering agent, targets adenosine triphosphate (ATP)-citrate lyase to reduce low-density lipoprotein (LDL) cholesterol and has shown potential in managing NAFLD by decreasing liver fat accumulation and improving lipid profiles. BA's unique mechanism offers a promising add-on therapy, particularly for the patient's intolerant to statins. Despite its potential, comprehensive clinical and preclinical studies are needed to further elucidate its efficacy and safety compared to other NAFLD treatments. Future research should focus on comparing BA with existing and emerging therapies to optimize its role in NAFLD management and enhance patient outcomes.

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Introduction: The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab (A + B) is equally effective in viral and nonviral patients. Methods: We retrospectively analyzed 885 HCC patients treated with the first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% nonviral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multivariate models to explore potential differences on overall survival (OS), time-to-progression (TTP), disease control rates (DCRs) based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to the second-line treatments and outcomes were also reported and compared between etiologies. Results: Overall, no statistically significant differences were found in median OS (mOS: viral 15.9 months; nonviral 16.3 months), TTP (mTTP: viral 8.3 months; nonviral 7.2 months), and DCRs (viral 78.1%; nonviral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and nonviral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e., NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of the second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups. Conclusion: Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and nonviral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice.

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Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its prevalence is rapidly increasing. Antioxidants, lipid-lowering medications, and lifestyle interventions are the most commonly used treatment options for NAFLD, but their efficacy in inhibiting steatosis progression is limited and their long-term ineffectiveness and adverse effects have been widely reported. Therefore, it is important to gain a deeper understanding of the pathogenesis of NAFLD and to identify more effective therapeutic approaches. Mitochondrial homeostasis governs cellular redox biology, lipid metabolism, and cell death, all of which are crucial to control hepatic function. Recent findings have indicated that disruption of mitochondrial homeostasis occurs in the early stage of NAFLD and mitochondrial dysfunction reinforces disease progression. In this review, we summarize the physical roles of the mitochondria and describe their response and dysfunction in the context of NAFLD. We also discuss the drug targets associated with the mitochondria that are currently in the clinical trial phase of exploration. From our findings, we hope that the mitochondria may be a promising therapeutic target for the treatment of NAFLD.

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Recently, we have demonstrated that mice, cultured embryos in α-minimum essential medium (αMEM) and subsequent fed a high-fat, high-sugar diet, developed steatohepatitis. In this study, we investigated using these samples whether the expression of lipid droplet formation genes in the liver is higher in MEM mice, whether these expressions are regulated by histone acetylation, writers/readers of histone acetylation, and the transcriptional factors of endoplasmic reticulum stress. Mice were produced by two-cell embryos in αMEM or standard potassium simplex-optimized medium (control) in vitro for 48 h, and implanted into an oviduct for spontaneous delivery. MEM and control-mice were fed a high-fat, high-sugar diet for 18 wk, and then liver samples were collected and analyzed by histology, qRT-PCR, and chromatin immunoprecipitation assay. Gene expression of Cidea, Cidec, and Plin4 were higher in MEM mice and histone H3K9 acetylation, BRD4, and CBP were higher in MEM mice than in control mice around those genes. However, the binding of endoplasmic reticulum stress-related transcription factors (ATF4, CHOP and C/EBPα) around those genes in the liver, was not clearly differed between MEM mice and control mice. The increased expression of Cidea, Cidec and Plin4 in the liver, accompanied by the development of steatohepatitis in mice induced is positively associated with increased histone H3K9 acetylation and CBP and BRD4 binding around these genes.

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Non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat within the cytoplasm of hepatocytes (exceeding 5% of liver weight) in individuals without significant alcohol consumption, has rapidly evolved into a pressing global health issue, affecting approximately 25% of the world population. This condition, closely associated with obesity, type 2 diabetes, and the metabolic syndrome, encompasses a spectrum of liver disorders ranging from simple steatosis without inflammation to non-alcoholic steatohepatitis (NASH) and cirrhotic liver disease. Recent research has illuminated the complex interplay between metabolic and immune responses in the pathogenesis of NASH, underscoring the critical role played by T and B lymphocytes. These immune cells not only contribute to necroinflammatory changes in hepatic lobules but may also drive the onset and progression of liver fibrosis. This narrative review aims to provide a comprehensive exploration of the effector mechanisms employed by T cells, B cells, and their respective subpopulations in the pathogenesis of NASH. Understanding the immunological complexity of NASH holds profound implications for the development of targeted immunotherapeutic strategies to combat this increasingly prevalent and burdensome metabolic liver disease.

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Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most common liver disorder worldwide, with an estimated global prevalence of more than 31%. Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive form of MASLD characterized by hepatic steatosis, inflammation, and fibrosis. This review aims to provide a comprehensive analysis of the extrahepatic manifestations of MASH, focusing on chronic diseases related to the cardiovascular, muscular, and renal systems. A systematic review of published studies and literature was conducted to summarize the findings related to the systemic impacts of MASLD and MASH. The review focused on the association of MASLD and MASH with metabolic comorbidities, cardiovascular mortality, sarcopenia, and chronic kidney disease. Mechanistic insights into the concept of lipotoxic inflammatory "spill over" from the MASH-affected liver were also explored. MASLD and MASH are highly associated (50%-80%) with other metabolic comorbidities such as impaired insulin response, type 2 diabetes, dyslipidemia, hypertriglyceridemia, and hypertension. Furthermore, more than 90% of obese patients with type 2 diabetes have MASH. Data suggest that in middle-aged individuals (especially those aged 45-54), MASLD is an independent risk factor for cardiovascular mortality, sarcopenia, and chronic kidney disease. The concept of lipotoxic inflammatory "spill over" from the MASH-affected liver plays a crucial role in mediating the systemic pathological effects observed. Understanding the multifaceted impact of MASH on the heart, muscle, and kidney is crucial for early detection and risk stratification. This knowledge is also timely for implementing comprehensive disease management strategies addressing multi-organ involvement in MASH pathogenesis.

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Microplastics (MPs) have attracted significant attention due to their global distribution in living environments. Although some studies have reported MP-induced hepatotoxicity in mouse models, a systematic approach to MP-mediated liver toxicity was still lacking. Therefore, we used a mouse model to study the sub-chronic effects of MP exposure on the liver. Female C57BL/6 mice, aged 6 weeks, received an oral administration of 0.3 mg of Nile Red-labeled polystyrene (PS) microplastics, with particle sizes of 0.5 µm (submicron) and 5 µm (micron), via gavage, while control mice received vehicle only. Each mouse was exposed to MPs twice a week for 12 weeks. After sacrifice, the levels of MP accumulation, oxidative stress, inflammation, and pathological changes were measured in the mouse liver, and blood samples were collected for serum biochemistry analysis. Our results demonstrated that 0.5 µm PS-MPs were accumulated in mouse livers post-MP exposure, but not in the 5 µm MP exposure group. Simultaneously, increased levels of glucose, triglyceride, alanine transaminase (ALT), aspartate transaminase (AST), superoxide dismutase, 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), interleukin-6, and lipid droplets were found in the 0.5 µm MP exposure group, while the fewer responses, including elevated liver weight index, glucose, high-density lipoprotein, AST, and decreased HNE-MA were observed in 5 µm MP exposure group. These results indicate that sub-chronic exposure to submicron MPs causes MP deposition in mouse livers, which further induces oxidative stress, increases inflammatory cytokines and perturbs glucose and lipid homeostasis, which might trigger more severe metabolic dysfunction or non-alcoholic steatohepatitis-like hepatotoxicity.

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BACKGROUND: Non-Alcoholic Steatohepatitis (NASH) is a crucial stage in the progression of Non-Alcoholic Fatty Liver Disease(NAFLD). The purpose of this study is to explore the clinical value of ultrasound features and radiological analysis in predicting the diagnosis of Non-Alcoholic Steatohepatitis. METHOD: An SD rat model of hepatic steatosis was established through a high-fat diet and subcutaneous injection of CCl4. Liver ultrasound images and elastography were acquired, along with serum data and histopathological results of rat livers.The Pyradiomics software was used to extract radiomic features from 2D ultrasound images of rat livers. The rats were then randomly divided into a training set and a validation set, and feature selection was performed through dimensionality reduction. Various machine learning (ML) algorithms were employed to build clinical diagnostic models, radiomic models, and combined diagnostic models. The efficiency of each diagnostic model for diagnosing NASH was evaluated using Receiver Operating Characteristic (ROC) curves, Clinical Decision Curve Analysis (DCA), and calibration curves. RESULTS: In the machine learning radiomic model for predicting the diagnosis of NASH, the Area Under the Curve (AUC) of ROC curve for the clinical radiomic model in the training set and validation set were 0.989 and 0.885, respectively. The Decision Curve Analysis revealed that the clinical radiomic model had the highest net benefit within the probability threshold range of > 65%. The calibration curve in the validation set demonstrated that the clinical combined radiomic model is the optimal method for diagnosing Non-Alcoholic Steatohepatitis. CONCLUSION: The combined diagnostic model constructed using machine learning algorithms based on ultrasound image radiomics has a high clinical predictive performance in diagnosing Non-Alcoholic Steatohepatitis.

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BACKGROUND AND AIM: Multiple clinical trials have been conducted to study the potential benefits of vitamin E for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Despite available evidence, vitamin E is not widely used. This study aimed to assess the effect of vitamin E on serum markers of liver inflammation, specifically serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and histology, including resolution of metabolic dysfunction-associated steatohepatitis (MASH), in adult patients with MASLD. METHODS: A systematic literature search on randomized controlled trials published in English was conducted using electronic databases. Standardized mean difference (SMD) and mean difference (MD) were used for continuous outcomes, while risk ratio (RR) was used for dichotomous outcomes, with corresponding 95% confidence interval (CI). RESULTS: A total of eight studies were included in the qualitative synthesis while seven studies were included in the meta-analysis. Vitamin E significantly reduced serum ALT and AST levels with SMD of -0.82 (95% CI, -1.13 to -0.51) and -0.68 (95% CI, -0.94 to -0.41), respectively. Vitamin E significantly reduced steatosis, lobular inflammation, and hepatocyte ballooning with a MD of -0.60 (95% CI, -0.83 to -0.37), -0.34 (95% CI, -0.53 to -0.16), -0.32 (95% CI, -0.53 to -0.12), and increased MASH resolution with a RR of 1.9 (95%CI, 1.20 to 3.02). However, vitamin E did not reduce fibrosis, with a MD of -0.23 (95% CI, -0.51 to 0.05). CONCLUSION: Vitamin E resulted in significant improvement in serum markers of liver inflammation and histology in patients with MASLD.

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Background: Non-alcoholic steatohepatitis (NASH), an escalating global health concern, is a primary factor behind cirrhosis, liver transplantation, and hepatocellular carcinoma. Effective treatments remain elusive. Danggui-Shaoyao-San (DGSY), a classic famous prescription employed in treating NASH, could hold promise, although its molecular underpinnings are still under investigation. This study undertakes an exploration of the impacts of DGSY on NASH and seeks to illuminate the mechanisms at play. Methods: UHPLC-Q-Orbitrap HRMS was employed to identify compounds within DGSY. Mice underwent a 25-week regimen of HFHC diet and high-sugar water, with 4 weeks of DGSY treatment for efficacy and pathogenic mechanism exploration in vivo. L02 cells were cultured with 0.2 mM FFA for 24 h, exposed to DGSY at 1 mg/ml and 2 mg/ml for efficacy and pathogenic mechanism exploration in vitro. Using online databases, we sought potential targets for NASH treatment, and through PPI networks, identified key targets. Expression levels of genes and proteins were examined by western blotting, RT-PCR, and immunofluorescence staining. Results: Thirty-four compounds were identified within DGSY. DGSY brought about marked reductions in biochemical indicators and yielded significant improvements in NASH mice histological features. Additionally, it mitigated hepatic steatosis and inflammation both in vivo and in vitro. The top 10 targets from two network pharmacology analyses, one focusing on structural prediction and the other on literature mining, identified APOE and APP as potential therapeutic targets for DGSY in NASH treatment. PCR validation confirmed that DGSY reduced APP expression after treatment, and further investigation revealed that DGSY significantly suppressed hepatic APP and Aß expression, indicating its effectiveness in treating NASH. Furthermore, it inhibited Aß-induced Cathepsin B lysosomal release, reducing hepatic inflammation. Conclusion: Danggui-Shaoyao-San has anti-steatohepatitis effects in ameliorating hepatic APP protein expression, reducing hepatic lysosomal CTSB release, and suppressing hepatic NF-κB activation. The study provided a more theoretical basis for the future clinical application of DGSY.

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Background: At present, there is a dearth of comprehensive data at the global, national, and regional levels regarding the adult non-alcoholic fatty liver disease (NAFLD) prevalence. This cross-sectional study aims at ascertaining the prevalence of NAFLD and non-alcoholic steatohepatitis (NASH), utilizing body mass index (BMI) as a determining factor. Methods: Based on the NHANES database, sigmoidal fitting curves were generated to establish the relationship between BMI and the risk of NAFLD/NASH. Utilizing BMI data from the NCD Risk Factor Collaboration (NCD-RisC) database at both global and regional levels, the prevalence of NAFLD/NASH among adults was estimated from 1975 to 2016, encompassing global, regional, and national perspectives. Additionally, projections were made to forecast the prevalence of adult NAFLD/NASH from 2017 to 2030. Results: In 2016, the global prevalence of NAFLD was 41.12% for males and 37.32% for females, while the global prevalence of NASH was 15.79% for males and 16.48% for females. The prevalence of NAFLD/NASH increased with higher BMI in both genders. Over the period from 1975 to 2016, there has been a gradual increase in the global prevalence of NAFLD/NASH in adults, and this trend is expected to continue between 2017 and 2030. In males, the prevalence of adult NAFLD/NASH was found to be highest in High-income Western countries, while it was highest in Central Asia, Middle East, and North African countries after 1995. Conclusions: The prevalence of adult NAFLD/NASH has been observed to increase annually, with significant variations in burden across different countries and regions.

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health problem owing to its high prevalence and associated morbidity and mortality secondary to progressive liver disease and cardiovascular events. Resmetirom, a selective thyroid hormone receptor-ß agonist has been developed as a therapeutic modality for MASLD. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of resmetirom compared to a placebo in the treatment of MASLD. Eligible studies were systematically identified by screening PubMed, Scopus, Web of Science, Cochrane library, Embase, and ClinicalTrials.gov from 2014 to 2024. Only randomized controlled trials comparing the efficacy and safety of resmetirom in the treatment of MASLD against placebo were included in the analysis. Meta-analysis was performed using RevMan 5.4 software. Four studies with low risk of bias and involving a total of 2359 participants were identified. The metanalysis included only three clinical trials with 2234 participants. A significant reduction in MRI-proton density fat fraction (MRI-PDFF) with 80 mg Resmetirom compared to that with placebo [SMD - 27.74 (95% CI - 32.05 to - 32.42), p < 0.00001] at 36-52 weeks as well as at 12-16 weeks [SMD - 30.92 (95% CI - 36.44 to - 25.40), p < 0.00001]. With Resmetirom 100 mg dose at 36-52 weeks [SMD - 36.05 (95% CI - 40.67 to - 31.43), p < 0.00001] and 12-16 weeks [SMD - 36.89 (95% CI - 40.73 to - 33.05), p < 0.00001] were observed. Resmetirom treatment was associated with a significant reduction in LDL-c triglyceride, lipoproteins. and liver enzymes. There was significant reduction FT4 and increase in SHBG and sex steroids with Resmetirom compared to placebo. There was no major difference in the overall treatment emergent adverse events at 80 mg [OR 1.55 (95% CI 0.84 to 2.87), and 100 mg [OR 1.13 (95% CI 0.78 to 1.63), doses of Resmetirom compared to placebo. However, gastrointestinal adverse events diarrhoea and nausea occurred in ≥ 10% in the Resmetirom group compared to placebo at < 12 week. Resmetirom treatment showed modest efficacy in treating MASLD with reduction in MRI-PDFF, LDL-c, triglyceride, lipoproteins, liver enzymes and NASH biomarkers without significant safety concerns. Larger and long-term RCTs may further confirm this promising outcomes of Resmetirom use in MASLD.

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SCOPE: Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide that can progress to liver fibrosis (LF). Probiotics have beneficial roles in reducing intestinal inflammation and gut-associated diseases, but their effects and mechanisms beyond the gut in attenuating the progression of LF are remained unclear. METHODS AND RESULTS: In a mouse model of NASH/LF induced by a methionine-choline deficient (MCD) diet, immunobiotics are administered to investigate their therapeutic effects. Results show that the MCD diet leads to liver inflammation, steatosis, and fibrosis, which are alleviated by immunobiotics. Immunobiotics reduces serum endotoxin and inflammatory markers while increasing regulatory cytokines and liver weight. They also suppress Th17 cells, known for producing inflammatory cytokines. Furthermore, immunobiotics mitigate collagen deposition and fibrogenic signaling in the liver, while restoring gut-barrier integrity and microbiota composition. Additionally, immunobiotics enhance the activation of the aryl hydrocarbon receptor (AhR) pathway in both colonic and liver tissues. CONCLUSIONS: Overall, these results demonstrate a novel insight into the mechanisms through which immunobiotic administration improves the gut health which in turn increases the AhR pathway and inhibits HSCs activation and fibrosis progression beyond the gut in the liver tissue of NASH/LF mice.

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