Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes without significant alcohol consumption. It is closely associated with sedentarism, hypercaloric diets, obesity, dyslipidemia, insulin resistance, type 2 diabetes mellitus, and genetic predisposition. NAFLD comprises a spectrum of liver disorders, from simple steatosis to non-alcoholic (NASH) and liver cirrhosis. The complex etiological mechanisms include oxidative stress, inflammation, apoptosis, and fibrosis; therefore, its management is challenging. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), a class of antidiabetic drugs, have emerged as promising therapeutic agents due to their ability to improve key metabolic parameters, including obesity, dyslipidemia, insulin resistance, and hyperglycemia. This review explores the cellular mechanisms by which SGLT2i, either as monotherapy or combined with other treatments, modulate signaling pathways involved in lipid and carbohydrate metabolism. Additionally, we examine their effects on oxidative stress, inflammation, fibrosis, and apoptosis, which are critical drivers of NAFLD progression. This review is intended to summarize the multiple benefits of SGLT2 inhibitors and to educate healthcare providers on the therapeutic potential of these drugs in order to foster their incorporation into effective NAFLD management plans.

Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder, where the underlying molecular mechanisms are mostly not well-understood and therefore, warrants the need for therapeutic interventions targeting several metabolic pathways as a unified response. Of late, promising outcomes have been observed with mesenchymal stem cell-derived exosomes. However, reduced bioavailability due to systemic delivery and the need for repeated fresh isolation hinders their feasibility for clinical applications. In this regard, an 'off-the-shelf' 3D bioprinted hyaluronic acid-based hepatic patch to deliver encapsulated exosomes alone/or with hepatocytes (as dual-therapy) is developed as a holistic approach for ameliorating the disease condition and promoting tissue regeneration. The bioprinted hepatic patch demonstrated sustained and localized release of exosomes (∼82 % in 21 days), and healthy liver tissue-like mechanical properties while being biocompatible and biodegradable. Assessment in NAFLD rat models displayed alleviation of the altered biochemical parameters such as fat deposition, deranged liver functions, disrupted lipid, glucose, and insulin metabolism along with a reduction in localized inflammation, and associated liver fibrosis. The study suggests that a synergistic effect between the miRNA population of released exosomes, cell therapy, and the bioprinted matrix materials is crucial in targeting multiple complex metabolic pathways associated with the severity of the disease.

The liver is considered a target organ for the accumulation and toxic effects of nanomaterials exposed to the body, especially after oral exposure, but the key toxic pathways have not been fully defined. This study focused on the hepatotoxicity of titanium dioxide nanoparticles (TiO2 NPs) in vivo and in vitro, and tried to identify key toxic pathways using the concept of systems biology and multi-omics methods. In vivo, protein and metabolomic sequencing were performed on the liver of SD rats (0, 50 mg/kg, 90 days), and 386 differential proteins and 29 differential metabolites were screened out, respectively, and the joint analysis found that they were significantly enriched in alanine, aspartate and glutamate metabolism, and butanoate metabolism. In vitro, exposure to TiO2 NPs could induce cytotoxicity and omics changes at different molecular levels in human hepatocellular carcinoma cells. Single omic analysis showed that differentially expressed proteins and metabolites were 80 and 222, respectively. The enriched pathways related to steroid biosynthesis, cholesterol metabolism at the combine levels of proteome and metabolome. KEGG enrichment analysis showed that PI3K-Akt signaling pathway and PPAR signaling pathway were both significantly affected in vitro and in vivo. Through multi-omics analysis, this work offered fresh perspectives and avenues for research on the toxicity mechanism of TiO2 NPs.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant health concern worldwide, exhibiting an increasing incidence that necessitates immediate intervention. Epigallocatechin-3-gallate (EGCG) has shown significant pharmacological benefits for liver diseases, including NAFLD. However, its efficacy in this context has not been systematically evaluated.

This meta-analysis aimed to consolidate preclinical evidence on the effectiveness and mechanisms of EGCG in treating NAFLD.

We conducted a comprehensive literature search for preclinical studies from the inception of each database to April 2024, including Excerpta Medica Database, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang, and China Science and Technology Journal Database. These studies were manually screened based on predefined criteria. Data extraction was followed by pooled effect size calculations using Stata 16.0. A machine learning approach was also utilized to examine the temporal relationships among variables.

Seventeen studies, involving 293 animals, were analyzed. Our analysis indicates that EGCG significantly reduces ALT, AST, hepatic triglyceride, serum TG, hepatic TC, serum TC. The targets of EGCG may include antioxidants, regulation of lipid metabolism, anti-inflammation, improvement of insulin resistance, and inhibition of hepatic fibrosis. EGCG exerted its effects on NAFLD by modulating key signaling pathways, including PI3K/Akt/AMPK, TGF-β/Smad, Nrf2, NF-κB, and ROS/MAPK, highlighting its multifaceted mechanisms of action. The machine learning methods employed to ascertain the temporal relationship between the intervention and the outcome indicated that the optimal duration of the intervention was 10 to 15 weeks.

The efficacy of EGCG in treating NAFLD has been predicted within a time frame of 10-15 weeks. It may exert its effects primarily through the NF-κB and Nrf2 pathways, which regulate the ROS phenotype. EGCG may represent a promising target for the treatment of NAFLD.

Fatty liver disease, a growing global health issue, is closely tied to metabolic disorders. The 2023 definition of metabolic-associated steatotic liver disease (MASLD) incorporates cardiometabolic risk factors, but the potential role of persistent organic pollutants (POPs) like polychlorinated biphenyls (PCBs), remains underexplored. Investigating the impact of environmental toxins on liver health is crucial for understanding emerging public health risks.

1080 participants were included from the 1999-2018 National Health and Nutrition Examination Survey (NHANES). We employed weighted generalized linear models, weighted quantile sum regression, and Bayesian kernel machine regression to assess the relationship between serum PCB levels and MASLD, with NAFLD included for comparison. Protein interaction and enrichment analyses were also conducted to explore the underlying mechanisms.

PCB146, PCB156, PCB187, PCB174, and PCB180 were significantly associated with an increased MASLD risk in the GLM. Significant positive associations were found between serum PCB mixtures and MASLD in the WQS model (β: 0.411, p: 0.0056) and BKMR model (p < 0.05), with PCB180 contributing the most (β: 0.644, PIP: 0.903). NAFLD did not show significant associations. Network pharmacological analysis demonstrated enrichment in the regulation of lipolysis of adipocytes and the cAMP signaling pathway, and PPAR-γ and MAOA show significant importance in the protein-protein interaction networks.

This study underscores the epidemiological and mechanical link between MASLD and PCB exposure, highlighting the superiority of MASLD in identifying the impact of POPs on liver disease risk and particularly identifying PCB180 as a sentinel marker for PCB surveillance.

Metabolic dysfunction-associated steatotic liver disease (MASLD) constitutes a global health threat with its ability to develop into liver cirrhosis and hepatocellular carcinoma (HCC). Emerging data suggests that oxidative stress and regulated cell death are major driving forces for liver inflammation in MASH. Febuxostat (Feb.), one of the Xanthine oxidase (XO) inhibitors, has shown promise in significantly improving the prognosis of MASH by reducing inflammatory cytokines and cell death. However, the underlying molecular mechanisms remain unclear. In this study, we evaluated the therapeutic effects of febuxostat on MASH through the modulation of cell death, inflammation, and intestinal permeability, focusing on hepatic mRNAs (HGS, SNF8, TSG101) and their epigenetic regulators (rno-miR-6216, rno-miR-1224). MASH was induced in Wistar rats via a High-sucrose high-fat (HSHF) diet over 14 weeks, followed by febuxostat treatment at doses of 1.5, 3, and 6 mg/kg/day for 4 weeks. Febuxostat treatment significantly improved liver function and lipid profiles, reduced hepatic steatosis, intralobular inflammation, and ballooning, and restored normal expression of the hepatic RNA panel by downregulating HGS, SNF8, and TSG101 mRNAs and their epigenetic regulators. Furthermore, febuxostat decreased serum levels of inflammatory (IL6), fibrosis (TGFB1), and cell death (TSG101) markers while reducing apoptosis and regulated cell death via modulation of Caspase-3 and LC3B expression. Improvements in intestinal permeability were evident via reductions in serum haptoglobin (Hpt) and TMAO and restoration of occludin expression. These findings highlight febuxostat as a promising therapeutic candidate for MASH by targeting key molecular mechanisms of liver inflammation and gut-liver axis dysfunction.

A healthy diet has been recommended for non-alcoholic fatty liver disease (NAFLD). We aim to investigate the associations of diet quality indices with the risk of developingmetabolic-associated fatty liver disease (MAFLD).

We conducted this nested case-control study by recruiting 968 cases with MAFLD and 964 controls from the participants of the baseline phase of the Sabzevar Persian Cohort Study (SPCS). MAFLD was defined as having a fatty liver index ≥ 60 plus at least one of the following: overweight or obese, Type II diabetes mellitus, or evidence of metabolic dysregulation. Healthy Eating Index-2015 (HEI-2015) and Alternative Healthy Eating Index-2010 (AHEI-2010) were calculated from a validated food frequency questionnaire. We estimated the associations of HEI-2015 and AHEI-2010 with MAFLD risk using multivariable logistic regression.

Among those in the highest relative to the lowest quintile of HEI-2015 and AHEI-2010, the multivariable-adjusted odds ratios (OR) were 0.45 (95% CI [confidence interval] 0.29-0.69; P trend = 0.002) and 0.55 (95% CI 0.35-0.85; P trend = 0.04), respectively.

The results of our study suggest that there is a significant associationbetween adherence to a healthy diet, indicated by a higher score of HEI or AHEI, and a reduced likelihood of developingMAFLD.

The online version contains supplementary material available at 10.1007/s40200-024-01544-x.

The transition in terminology from fatty liver disease to metabolic dysfunction-associated steatotic liver disease (MASLD) marks a considerable evolution in diagnostic standards. This new definition focuses on liver fat accumulation in the context of overweight/obesity, type 2 diabetes, or metabolic dysfunction, without requiring the exclusion of other concurrent liver diseases. The new definition also provides clear guidelines for defining alcohol consumption in relation to the disease. MASLD is currently acknowledged as the most widespread liver disorder globally, affecting ~25% of the population. Despite the extensive array of clinical trials conducted in recent years, the number of approved treatments for metabolic dysfunction-associated fatty liver disease is very limited. In the review critically evaluates the results of clinical trials of related drugs and assesses the future directions for drug development trials. The renaming of MASLD presents new challenges and opportunities for the design of clinical trials and the selection of target populations for drug development.

Liver fibrosis resulting from nonalcoholic fatty liver disease (NAFLD) and metabolic disorders is highly prevalent in patients with severe obesity and poses a significant health challenge. However, there is a lack of data on the effectiveness of noninvasive factors in predicting liver fibrosis. Therefore, this study aimed to assess the relationship between these factors and liver fibrosis through a machine learning approach.

This study involved 512 patients who underwent bariatric surgery at an outpatient clinic in Mashhad, Iran, between December 2015 and September 2021. Patients were divided into fibrosis and non-fibrosis groups and demographic, clinical, and laboratory variables were applied to develop four machine learning models: Naive Bayes (NB), logistic regression (LR), Neural Network (NN) and Support Vector Machine (SVM).

Among the 28 variables considered, six variables including (fasting blood sugar (FBS), skeletal muscle mass (SMM), hemoglobin, alanine transaminase (ALT), aspartate transaminase (AST) and triglycerides) showed high area under the curve (AUC) values for the diagnosis of liver fibrosis using 2D shear wave elastography (SWE) with LR (0.73, 95% CI: 0.65, 0.81) and SVM (0.72, 59% CI: 0.64, 0.80) models. Furthermore, the highest sensitivities were reported with SVM (0.83, 95% CI: 0.72, 0.91) and NB (0.66, 95% CI: 0.53, 0.77) models, respectively.

The predictive performance of six noninvasive factors of liver fibrosis was significantly superior to other factors, showing high application and accuracy in the diagnosis and prognosis of liver fibrosis.

The online version contains supplementary material available at 10.1007/s40200-025-01564-1.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and is considered the hepatic manifestation of metabolic syndrome, triggering out adverse outcomes. A stacked multimodal machine learning model is constructed and validated for early identification and prognosis stratification of NAFLD by integrating genetic and clinical data sourced from 36 490 UK Biobank and 9 007 Nanfang Hospital participants and extracted its probabilities as in-silico scores for NAFLD (ISNLD). The efficacy of ISNLD is evaluated for the early prediction of severe liver disease (SeLD) and analyzed its association with metabolism-related outcomes. The multimodal model performs satisfactorily in classifying individuals into low- and high-risk groups for NAFLD, achieving area under curves (AUCs) of 0.843, 0.840, and 0.872 within training, internal, and external test sets, respectively. Among high-risk group, ISNLD is significantly associated with intrahepatic and metabolism-related complications after lifestyle factors adjustment. Further, ISNLD demonstrates notable capability for early prediction of SeLD and further stratifies high-risk subjects into three risk subgroups of elevated risk for adverse outcomes. The findings emphasize the model's ability to integrate multimodal features to generate ISNLD, enabling early detection and prognostic prediction of NAFLD. This facilitates personalized stratification for NAFLD and metabolism-related outcomes based on digital non-invasive markers, enabling preventive interventions.

Our previous study demonstrated that Lactobacillus acidophilus KLDS1.0901 significantly alleviated symptoms of high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and showed a strong association with the gut microbiota; however, the underlying mechanisms remained unclear. In this study, we focused on changes in intestinal metabolic pathways in mice following intervention with Lactobacillus acidophilus KLDS1.0901, using non-targeted metabolomics. Tryptophan metabolism was found to be closely associated with NAFLD alleviation, and indole-3-aldehyde (IAld) was identified as a key target. Animal experiments showed no significant differences in the levels of liver triglycerides, fasting blood glucose, alanine aminotransferase, aspartate aminotransferase, IL-6, IL-1β, TNF-α, and IL-10 between the direct-feeding IAld group and the Lactobacillus acidophilus KLDS1.0901 group. This suggests that the IAId, produced by Lactobacillus acidophilus KLDS1.0901, is the key intermediate mediator responsible for its improvement of NAFLD. The alleviating effect of Lactobacillus acidophilus KLDS1.0901 on NAFLD symptoms was suppressed after the inhibition of the IAld receptor aromatic hydrocarbon receptor (AhR), suggesting that the bacterium relies on the AhR signaling pathway to mediate its effect on NAFLD. Cellular experiments showed that IAld significantly reduced triglyceride content, decreased lipid accumulation, and increased glycogen levels in oleic acid-induced cells. The effects of IAld on gene transcription levels in oleic acid-induced HepG2 cells were further analyzed using high-throughput sequencing. Transcriptomic analysis revealed that IAld regulates key pathways, including the NF-κB, chemokine and AGE-RAGE signaling pathways. Our study identified the ameliorative effects of tryptophan metabolites, particularly IAld, on NAFLD, along with the underlying mechanisms, offering new insights into potential treatment strategies for NAFLD.

This study aims to explore the effects of various hepatic steatosis conditions on histological outcomes in patients with significant inflammation and fibrosis in chronic hepatitis B (CHB) and analyze their impact on HBV virological suppression outcomes and biochemical improvement.

This retrospective study included 219 chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogues therapy. Each of these patients underwent two liver biopsies. Patients were categorized into four groups based on hepatic steatosis status: sustained non-hepatic steatosis (n = 118), new-onset hepatic steatosis (n = 33), sustained hepatic steatosis (n = 37), and disappeared hepatic steatosis (n = 31). We compared the liver biochemical parameters and histological changes before and after treatment. Logistic regression analysis was performed to evaluate characteristics associated with the improvement of significant liver inflammation (G ≥ 2), significant fibrosis (S ≥ 2), and the persistence of hepatic steatosis.

After treatment, the sustained non-steatosis group exhibited the highest rate of improvement in baseline significant inflammation (75.31%), while the sustained steatosis group had the lowest (42.31%, p = 0.008). The sustained steatosis group also had the highest rate of inflammation progression (15.38%, p = 0.020) and was identified as a risk factor for inadequate baseline inflammation improvement (p = 0.006, OR = 0.244, 95% CI 0.090-0.665). In terms of baseline significant liver fibrosis improvement, the sustained non-hepatic steatosis group showed the highest improvement rate (67.14%), while the sustained hepatic steatosis group had the lowest (28.00%, p = 0.006). The new-onset steatosis group had the highest rate of liver fibrosis progression (15.00%, p = 0.027), and sustained hepatic steatosis was a risk factor for poor baseline fibrosis improvement (p = 0.001, OR = 0.180, 95% CI 0.064-0.507). Furthermore, the sustained hepatic steatosis group showed the smallest decrease in liver enzyme markers ALT, GGT, and ALP post-treatment, with reductions of 22.11% (p = 0.023), 13.86% (p = 0.003), and 1.98% (p = 0.025), respectively. Logistic regression analysis revealed that high baseline BMI and LDL-C levels were significantly associated with persistent fatty liver, with high BMI (p = 0.042, OR = 1.109, 95% CI 1.004-1.226) and high LDL-C (p < 0.001, OR = 2.570, 95% CI 1.524-4.332).

In CHB patients with significant inflammation and fibrosis, the persistence of hepatic steatosis during antiviral treatment may impede the improvement of inflammation and fibrosis, leading to disease progression and biochemical abnormalities.

Relative fat mass (RFM) is a novel, easily calculated, and cost-effective index of fat content and distribution in the body, associated with the odds of developing various obesity-related diseases. However, its association with metabolic dysfunction associated steatotic liver disease (MASLD) and severe hepatic steatosis (SHS) is underexplored. This study aims to examine the relationship between RFM and the odds of having MASLD or SHS in the general adult population.

This was a population-based cross-sectional study using data from the National Health and Nutrition Examination Survey (2017.01-2020.03). The aim of the statistical analysis was to examine the association between RFM and the prevalence of MASLD and SHS. Logistic regression was applied to explore this relationship. Nonlinear associations between RFM levels and MASLD or SHS prevalence were assessed using smoothed curve fitting and threshold effect models. Subgroup analyses were conducted to evaluate the consistency of this association across different population groups.

A total of 6699 participants were included in this study, of whom 2825 had MASLD and 1834 had SHS. After adjusting for confounders, significant positive associations were observed between RFM and the prevalence of MASLD and SHS (odds ratio [OR]: 1.22, 95% confidence interval [CI: ] 1.18-1.26 and OR: 1.26, 95% CI: 1.21-1.30). Smoothed curve fitting and threshold effect analysis showed a nonlinear relationship between RFM and the prevalence of MASLD and SHS, with thresholds of 41.96 for MASLD prevalence and 40.42 for SHS prevalence. When the subgroups were analyzed according to sex, age, race, education level, smoking status, household income, body mass index, hypertension, and diabetes, no significant interactions were found between RFM and most subgroups.

Our results demonstrated a positive nonlinear relationship between RFM and the prevalence of MASLD and SHS, with a threshold effect. Lower RFM levels are associated with lower odds of MASLD and SHS. These findings suggest that RFM may serve as a simple, cost-effective tool for identifying individuals at increased odds of NAFLD and SHS in the general population.

Nonalcoholic fatty liver disease (NAFLD) is a significant global health burden. It comprises a broad pathological spectrum ranging from simple liver steatosis to steatohepatitis with variable degrees of fibrosis, and liver failure. Patients with NAFLD have an increased risk of liver-related and overall mortality. While the trials to assess the efficacy of the medications are ongoing, lifestyle modification is the first line of therapy recommended. The primary aim of this review paper is to synthesize literature related to current evidence-based lifestyle interventions for preventing and managing NAFLD. The review and synthesis of the literature reveal that personalized nutritional, exercise, and behavior change interventions are effective in managing NAFLD. Evidence suggests that there are several gaps in managing NAFLD. The gaps discussed in this paper include a lack of awareness of the disease, ineffective patient-provider communication, shortage of specialists, under-recognition of the disease, and liver health disparities. This paper highlights the evidence-based opportunities to overcome those gaps, such as utilizing comprehensive models of care, clinical care pathways, and clinical practice guidelines. Primary care physicians and endocrinologists, who are the first point of contact must utilize these opportunities for diagnosing and managing patients with NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and it poses a significant threat to public health. There is insufficient documented evidence about the problems and needs of patients and physicians in managing NAFLD. This study aimed to explore the challenges and needs in managing NAFLD from the perspective of gastroenterology and hepatology (GH) specialists.

This qualitative study was conducted from January to September 2023. Fifteen Iranian GH specialists selected by purposive sampling. Data were collected through semi-structured interviews. The interviews were analyzed inductively using the Elo and Kyngas content analysis approach. The criteria proposed by Guba and Lincoln were used to ensure the study's validity.

The identified challenges were divided into thirteen main categories (34 subcategories and 117 primary codes), and the identified needs were divided into eight main categories (21 subcategories and 97 primary codes). The main categories of the challenges were chronic nature and time-consuming differential diagnosis, complex treatment process, defects in the patient management process, shortcomings of the healthcare system, the effect of unhealthy eating and cultural and social factors on the diet, incorrect attitude of patients, lack of knowledge and awareness of patients, lack of comprehensive treatment plans based on patients' conditions, defect in knowledge and awareness of physicians, inadequate cooperation of patients, defects in the process of recording and monitoring information and providing feedback, insufficient policies and plans in the prevention of NAFLD, and economic problems. The main categories of needs included developing a comprehensive treatment plan, updating physicians' knowledge and creating standard treatment protocols, changing attitudes and empowering patients, informing and educating patients, establishing multi-specialty clinics for NAFLD treatment, establishing peer support groups and facilitating communication, utilizing digital technology to track patient information and monitor their progress, and supportive, educational, prevention, and management policies in the treatment of NAFLD.

This study showed that managing NAFLD involves physical, psychological, nutritional, sports, economic, and social aspects and requires multidisciplinary clinical approaches, digital technologies, and supportive and educational policies. These findings have important implications that can help patients, physicians, and policymakers design better lifestyle prescriptions to manage NAFLD.

Choline has been proven to be effective in maintaining liver function. However, the effect of choline, in combination with other nutrients, on the improvement of non-alcoholic fatty liver disease (NAFLD) remains unclear. This study aimed to investigate the potential effect of the nutraceutical complex containing choline bitartrate, zinc citrate, and dl-α-Tocopheryl acetate on NAFLD in the zebrafish model. The NAFLD model was induced in zebrafish by administering thioacetamide. Experimental groups were established, including a normal control group, the model control group, the positive control group, the nutraceutical complex intervention group, and the choline bitartrate alone intervention group. The intervention was administered to the zebrafish in a water-soluble form, while the positive control group received polyene phosphatidylcholine at a concentration of 50.0 μg/mL. Notably, the protective effect of the nutraceutical complex against NAFLD is more pronounced than that observed with choline bitartrate supplementation alone. The results of transcriptomics and quantitative real-time PCR showed that the potential mechanisms underlying the effects of the nutraceutical complex might involve the upregulation of acacia, acsl1a, fbp2 gene expression, and the downregulation of tbc1d1 gene expression. These results were further validated by western blotting and overexpression experiments. Our findings indicated that choline bitartrate, zinc citrate, and dl-α-Tocopheryl acetate can help improve NAFLD. The results of this study provide evidence for the application of the nutraceutical complex in the improvement of NAFLD.

We investigated the association between fasting serum and urinary nitric oxide metabolite (NOx) levels and fatty liver index (FLI), a non-invasive surrogate of non-alcoholic fatty liver disease (NAFLD) and liver steatosis.

This cross-sectional study included 598 adults (aged≥18 years, 48.6% men) who participated in the Tehran Lipid and Glucose Study (2015-2017). Serum and urine NOx concentrations were quantified using a spectrophotometric method following the Griess reaction. FLI values were calculated using γ-glutamyl transferase, triglycerides, body mass index, and waist circumference. The associations between urinary and serum NOx-to-creatinine (Cr) ratio [either as a categorical variable, i.e., tertiles, or as a continuous variable, i.e., per 1 SD) with NAFLD (i.e., FLI≥60) were assessed using multivariable-adjusted binary logistic regression.

The study participants' mean (SD) age was 42.5±14.6 y. The mean (SD) of serum and urinary NOx was 37.5±16.7 and 1310±751 μmol/L, respectively. The mean (SD) of FLI was 43.3±30.2, and the prevalence of NAFLD was 32.4%. Serum NOx-to-Cr ratio was not associated with the chance of having NAFLD (OR=1.66, 95% CI=0.98-2.82; P value=0.058). Higher urinary NOx-to-Cr ratio was significantly associated with a reduced probability of NAFLD (OR=0.61, 95% CI=0.38-0.95, and OR=0.54, 95% CI=0.34-0.87, in the second and third tertiles).

Higher dietary nitrate (NO3) intake, indicated by increased urinary NOx-to-Cr ratio, is associated with a reduced probability of NAFLD, highlighting the potential role of dietary NO3 in liver health.

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) represents a growing concern in the context of metabolic disorders, particularly among individuals diagnosed with type 2 diabetes mellitus (T2DM). This study aimed to investigate the prevalence of MASLD among newly diagnosed T2DM patients and identify the risk factors for MASLD in this population. Methods: This prospective study included 128 patients with newly diagnosed T2DM between January 2022 and June 2023. Demographic, clinical, anthropometric (BMI, waist circumference), and laboratory data (glucose, HbA1c, lipid profile, ALT, AST, creatinine, platelet count) were collected. MASLD was diagnosed based on ultrasonographic evidence of hepatic steatosis with at least one cardiometabolic risk factor after excluding other causes. Linear regression models were used to determine independent predictors. Results: MASLD was detected in 80.4% of patients. Compared with the MASLD (-) group, the MASLD (+) group had significantly higher ALT (47.1 ± 23 U/L vs. 24.9 ± 8 U/L, p < 0.001) and non-HDL cholesterol (189 ± 57 mg/dL vs. 167 ± 28 mg/dL, p = 0.047). Spearman correlation showed positive associations of MASLD severity with waist circumference, LDL cholesterol, and platelet count. ALT and BMI were independently associated with MASLD in linear regression analysis. Conclusions: This study underscores the significant prevalence of MASLD in newly diagnosed T2DM patients, emphasizing the relevance of early detection in addressing this common comorbidity in the diabetic population.

Non-alcoholic fatty liver disease (NAFLD) represents the most widespread liver disease globally, ranging from non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH) to fibrosis/cirrhosis, with potential progression to hepatocellular carcinoma (HCC). Genome-wide association studies (GWASs) have identified several single nucleotide polymorphisms (SNPs) associated with NAFLD. However, numerous GWAS signals associated with NAFLD locate in non-coding regions, posing a challenge for interpreting their functional annotation.

In this study, we utilized the Activity-by-Contact (ABC) model to construct the enhancer-gene maps of liver by integrating epigenomic data from 15 liver tissues and cell lines. We constructed the most comprehensive genome-wide regulatory maps of the liver, identifying 543,486 enhancer-gene connections, including 267,857 enhancers and 16,872 target genes. Enrichment analyses revealed that the ABC SNPs are significantly enriched in active chromatin regions and active chromatin state. By combining the ABC regulatory maps and NAFLD GWAS data, we systematically identified ABC SNPs associated with NAFLD risk. Through the functional annotations, such as pathway enrichment and drug-gene interaction analyses, we identified 6 genes (GGT1, ACTG1, SPP1, EPHA2, PROZ and SHMT1) as candidate NAFLD genes, with SHMT1 previously reported. Among the SNPs connected to the candidate genes, the ABC SNP rs2017869 (odds ratio [OR] for the C allele = 1.10, 95% CI = 1.04-1.16, P = 5.97 × 10- 4) had the highest ABC score. According to the ABC maps, rs2017869 links to GGT1, and several drugs targeting this gene, such as liothyronine, showed potential benefits to patients with NAFLD. Furthermore, we identified that another novel gene, EPHA2, may play a crucial role in NAFLD by regulating the GGT levels.

Our study provides the most comprehensive ABC regulatory maps of the liver to date. This resource offers a valuable reference for identifying regulatory variants and prioritizing susceptibility genes of liver diseases, such as NAFLD.

In the 21st century, significant breakthroughs have been made in the research of chronic liver disease. New biochemical markers of pathogenicity and corresponding drugs continue to emerge. However, current treatment strategies remain unsatisfactory due to complex pathological changes in the liver, including vascular dysfunction, myofibroblast-like transition, and local tissue necrosis in liver sinusoids. These challenges have created an urgent need for innovative, synergistic treatments. Mechanical mechanics is a growing field, with increasing evidence suggesting that mechanical signals play a role similar to that of biochemical markers. These signals influence response speed, conduction intensity, and functional diversity in regulating cell activities.

This review summarizes the three main mechanical characteristics involved in the progression of "liver fibrosis-cirrhosis-hepatocellular carcinoma" and provides an in-depth interpretation of several mechanically-related targets. Finally, current and cutting-edge therapeutic strategies are proposed from a cellular perspective. Despite the many challenges that remain, this review is both relevant and significant.

Interleukin-22 (IL-22), a cytokine from the IL-10 family produced by T cells and innate lymphoid cells, plays a crucial role in immune responses and tissue regeneration. Its association with liver disease has garnered significant attention; however, its exact impact remains controversial. This review aims to enhance the current understanding of the dual role of IL-22 in liver disease by exploring its protective and pathogenic effects. First, we provide an overview of IL-22 biology, including its source, receptors, and signaling pathways. Subsequently, we offer a comprehensive overview of the dual function of IL-22 in non-neoplastic liver disease, emphasizing its antiapoptotic and regenerative properties. We also discuss the applicability of the conclusions drawn from studies on nonalcoholic fatty liver disease to metabolic dysfunction-associated steatotic liver disease. Furthermore, we elaborate on the intricate role of IL-22 in hepatocellular carcinoma, particularly its influence on the tumor microenvironment, proliferation, and immune evasion. In conclusion, IL-22 is paradoxical in liver disease, acting as a friend and foe. It is imperative to understand this paradox to develop targeted therapies that capitalize on the beneficial effects of IL-22 while mitigating its detrimental effects.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent and progressive liver disorder posing a global health challenge. Oroxylin A, a naturally occurring flavonoid, with a broad spectrum of pharmacological activities. This study aimed to explore the therapeutic potential of oroxylin A and unravel its molecular mechanisms in mitigating high-fat diet (HFD)-induced NAFLD in murine models. Wild-type (WT) and nuclear factor erythroid 2-related factor 2 knockout (Nrf2-/-) mice were administered a HFD to generate in vivo models, while free fatty acids-treated HepG2 cells served as the in vitro model. To investigate the effects of oroxylin A, serum and liver biochemical markers, hepatic histology, lipid metabolism, and oxidative stress were assessed in a NAFLD mouse model. The underlying mechanisms of oroxylin A were further explored through Western blotting, immunohistochemistry, and immunofluorescence analysis. Oroxylin A mitigated hepatic steatosis and injury by reducing liver index, AST, ALT, TG, and TC levels, improving histology, and restoring lipid metabolism. Glucose and insulin tolerance tests demonstrated improved glucose homeostasis and insulin sensitivity. Moreover, oroxylin A suppressed inflammation, apoptosis, and fibrosis, while enhancing antioxidant defenses, and improving mitochondrial function. Mechanistically, oroxylin A activated the Keap1/Nrf2/GPX4/SLC7A11 axis, upregulating Nrf2 and HO-1. These effects were abolished in Nrf2-/- mice. In vitro results were consistent, and molecular docking, dynamics simulations, and CETSA confirmed its direct Keap1 binding. Oroxylin A protects against NAFLD by modulating the Nrf2 pathway, reducing oxidative stress and ferroptosis, making it a promising candidate for clinical NAFLD therapy.

Non-alcoholic fatty liver disease (NAFLD) affects more than a quarter of the global population and has become the world's number one chronic liver disease, seriously jeopardizing public life and health. Despite the new terminology of metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed, the mechanisms underlying the heterogeneity across BMI stratification in non-alcoholic fatty liver disease (NAFLD) remain unclear. The aim of this study was to reveal the differences in metabolic and fibrotic characteristics between lean (BMI < 23 kg/m2) and non-lean NAFLD in an Asian population.

The current study collected NAFLD patients from the physical examination population. Patients were divided into two groups by BMI to compare their clinical parameters, including lean (BMI < 23 kg/m2) and non-lean (BMI ≥ 23 kg/m2) and fibrosis subgroups (with a threshold of LSM = 8 kPa) and analyzed for risk factors by logistic regression models.

Of the 11,577 NAFLD patients who participated in the study, there were 916 lean and 10,661 non-lean. The non-lean group was younger than the lean group (median age 50 vs. 52 years, P < 0.001) and had a significantly higher prevalence of hypertension (28.0% vs. 18.3%), diabetes mellitus (10.1% vs. 6.1%), and liver fibrosis (9.1% vs. 5.1%) (all P < 0.001). Analysis of metabolic indexes showed that TyG, TyG-BMI, TG/HDL-C and APRI were higher in the non-lean group (all P < 0.001). Gender stratification revealed that ALT was significantly higher in the male non-lean group, while HDL-C was lower in the female non-lean group (1.35 vs. 1.47 mmol/L). Multiple regression suggested that the risk of fibrosis was independently associated with CAP values and fasting glucose, BMI, direct bilirubin, globulin, and age in the non-lean group, whereas the risk was mainly driven by GGT and ALP in the lean group.

Non-lean NAFLD patients showed more significant metabolic disturbances and risk of liver fibrosis. Although metabolic indicators (TyG, FIB-4) have limited predictive value for liver fibrosis, they are strongly associated with metabolic risk in MASLD.

This study sought to investigate the independent and synergistic impacts of fasting blood glucose (FBG) and serum uric acid (SUA) levels on non-alcoholic fatty liver disease (NAFLD) in participants with and without type 2 diabetes mellitus (T2DM).

A total of 12,430 participants (mean age: 54.34 ± 15.23, 34.34% female) were enrolled through the Health Screening Center of Tianjin Medical University General Hospital. FBG was classified as < 6 mmol/L, 6-7 mmol/L, and ≥ 7 mmol/L. SUA was classified into two categories: normal SUA and hyperuricemia (SUA level ≥ 420 µmol/L for men, ≥ 360 µmol/L for women). T2DM was ascertained through self-reported data. The diagnosis of NAFLD is established via abdominal ultrasound imaging. Logistic regression models and interaction effect models are used for data analysis.

Of the 12,430 participants, 4846 (38.99%) were diagnosed with NAFLD. In comparison to individuals with FBG < 6 mmol/L and no self-reported T2DM, those with FBG ≥ 7 mmol/L and no self-reported T2DM exhibited the highest prevalence of NAFLD (odds ratio [OR] 2.91, 95% CI 2.16-3.93) following multi-adjusted analysis. In the joint effect analysis of FBG and SUA, FBG ≥ 7 mmol/L and hyperuricemia were linked to a greater prevalence of NAFLD compared to FBG < 6 mmol/L and normal SUA, both in individuals with self-reported T2DM (OR 2.92, 95% CI 1.68-5.05) and those without self-reported T2DM (OR 7.87, 95% CI 3.57-17.34). An additive interaction existed between FBG and SUA regarding NAFLD in individuals without self-reported T2DM (AP 0.488, 95% CI: 0.068-0.909, P = 0.02).

Elevated FBG levels are associated with NAFLD irrespective of self-reported T2DM status. The concomitant elevation of FBG and SUA levels exhibits a significant correlation with NAFLD, particularly in individuals lacking self-reported T2DM.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a significant public health concern. However, the relationship between MAFLD and different types of respiratory diseases is not yet fully understood. In UK Biobank prospective cohort, 11 types of respiratory diseases were identified according to the ICD-10 codes. Cox regression was used to determine the association between MASLD and respiratory disease risk. A total of 393,416 subjects with an average age of 56.6 years were included, MASLD patients account for 34.9%. After fully adjustment for confounding factors, 9 out of 11 respiratory diseases were significantly associated with MASLD, including influenza (hazard ratio (HR): 1.294), pneumonia (HR: 1.258), chronic lower respiratory diseases (HR: 1.297), asthma (HR: 1.222), lung diseases due to external agents (HR: 1.190), interstitial lung diseases (HR: 1.336), diseases of the pleura (HR: 1.175), pulmonary embolism (HR: 1.225), lung and bronchus cancer (HR: 1.212) and respiratory system death (HR: 1.108) (P < 0.05 for all). The risk of respiratory diseases increases with the severity of MASLD assessed by fibrosis score. The relationship between the MASLD phenotype and respiratory diseases is independent of polygenic risk scores and four related risk alleles. These findings emphasize the value of comprehensive prevention of respiratory diseases by targeting MASLD.

Fatty liver disease is often associated with renal impairment in many patients. Early detection and prompt intervention are crucial for improving patient quality of life and reducing mortality rates. This study aimed to develop and validate a nomogram for detecting the risk of Chronic Kidney Disease (CKD) comorbidity in adults with Nonalcoholic Fatty Liver Disease (NAFLD) in the United States.

From the NHANES (2017‒2020) database, the authors enrolled 2848 NAFLD participants, of whom 633 also had CKD. The authors employed the Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate logistic regression to identify variables with predictive value. The overlapping features were selected to construct a predictive model, which was presented as a nomogram. The effectiveness of the nomogram was evaluated using Receiver Operating Characteristic (ROC) curves, calibration plots, and decision curve analysis.

Six indicators were included in the model: age, systolic blood pressure, serum albumin, high-sensitivity C-reactive protein, total cholesterol, and triglycerides. The area under the curve of the nomogram for predicting CKD in the training set was 0.772, with a 95 % Confidence Interval (95 % CI) of 0.746 to 0.797. In the validation set, the area under the curve was 0.722, with a 95 % CI of 0.680 to 0.763. The calibration curve analyses demonstrated that the prediction outcomes of the model aligned well with the actual outcomes, indicating good clinical applicability.

The nomogram demonstrated excellent performance and has the potential to serve as an auxiliary tool for detecting CKD in NAFLD patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty-liver disease, is an important and rising health issue with a link with atherosclerotic cardiovascular (CV) disease (CVD), affecting ∼25-30 % of the adults in the general population; in patients with diabetes, its prevalence culminates to ∼70 %; its evolutive form, nonalcoholic steatohepatitis, is estimated to be the main cause of liver transplantation in the future. MASLD is a multisystem disease that affects, besides the liver, extra-hepatic organs and regulatory pathways; it raises the risk of type 2 diabetes mellitus (T2D), CVD, and chronic kidney disease; the disease may also progress to hepatocellular carcinoma. Its diagnosis requires hepatic steatosis and at least one cardiometabolic risk factor and the exclusion of both significant alcohol consumption and other competing causes of chronic liver disease. Beyond CV events, associated metabolic comorbidities comprise obesity (∼50 %), T2D (∼20 %), hyperlipidemia (∼70 %), hypertension (∼40 %), and metabolic syndrome (∼40 %). Among the various clinical events, CV events mostly determine prognosis as they are the leading cause of death in these patients. Regarding management, statins exert beneficial effects in improving liver injury; silybin, derived from Silybum marianum, has some protective effects; lifestyle modification, such as weight loss, dietary changes, physical exercise, and abstention from alcohol use combined with optimal management of comorbidities are most helpful. Bariatric surgery may be an option in persons with MASLD and obesity. Adults with non-cirrhotic MASLD and significant liver fibrosis may be candidates for targeted treatment with resmetirom, which has histological efficacy on steatohepatitis and fibrosis with an acceptable safety and tolerability profile, whereas, no MASLD-targeted pharmacotherapy can be beneficial in the cirrhotic stage, whereby other measures may include metabolic drugs, nutritional counseling, surveillance for portal hypertension and hepatocellular carcinoma, and finally, liver transplantation in decompensated cirrhosis.

Metabolic-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition globally, characterized by suboptimal treatment outcomes. Traditional therapies often fail to address the multifaceted pathogenesis of MAFLD, which involves lipid metabolism, inflammation, and gut-liver axis dysregulation. JiGuCao Capsule formula (JCF), a patented Chinese medicine, has demonstrated clinical efficacy in liver disease treatment, indicating its potential as a new therapeutic option for MAFLD.

This study aimed to investigate the therapeutic effects and underlying mechanisms of JCF in treating MAFLD, particularly focusing on its impact on liver pathology, intestinal health, and gut microbiota composition.

A MAFLD mouse model was developed by administering a high-fat diet and 5% fructose water for 16 weeks. At week 8, mice exhibited significant steatosis, inflammation, and insulin resistance. Fifty mice were allocated into two groups: the normal diet (ND) group with 19 mice and the high-fat feed diet (HFD) group with 31 mice. Seven mice from each group were sacrificed at week 8 for serological and histopathological assessments. The remaining mice were allocated into ND (n = 6), HFD (n = 6), HFD + JCFL (human equivalent dose,780 mg/kg, n = 6), HFD + JCFH (threefold the human equivalent dose, 2340 mg/kg, n = 6), HFD + Polyene Phosphatidylcholine (PPC) (human equivalent dose,177.84 mg/kg, n = 6) and ND+ JCF (human equivalent dose,780 mg/kg, n = 6) groups. Daily gavage started at week 9. At week 16, after fasting, body weight and liver condition were recorded, and mice were euthanized with pentobarbital sodium. Mouse tissues and feces were collected for histopathological, molecular biological, and multi-omics analyses.

JCF effectively slowed MAFLD progression in mice by decreasing hepatic lipid accumulation and inflammation. Treatment with JCF significantly reduced hepatic triglycerides and inflammatory markers, including TNF-α and IL-6. JCF enhanced lipid metabolism, repaired the intestinal barrier, and lowered inflammatory cytokines in the intestines, as indicated by reduced serum LPS and restored tight junction proteins expression, such as claudin-1 and occludin. Fecal microbiota analysis indicated that JCF treatment elevated Lactobacillus levels and reduced Colidextribacter levels, correlating with enhanced metabolic profiles. The primary bioactive compounds identified in JCF responsible for these therapeutic effects were betulinic acid, cholic acid, deoxycholic acid, oleanolic acid, and pectolinarigenin. Transcriptomic analysis showed that JCF regulated key pathways involved in lipid metabolism, including the pparγ-cd36 axis and modulation of ox-LDL levels. The results indicate that JCF effectively mitigates MAFLD by influencing the gut-liver axis and lipid metabolism.

JCF alleviates MAFLD by modulating the gut-liver axis and lipid metabolism. Its effects involve improving gut barrier function, regulating microbiota, and targeting the pparγ-cd36 axis. Active compounds like betulinic acid support its therapeutic potential. JCF shows promise as a novel treatment for MAFLD, with further clinical studies needed.

Μetabolic dysfunction-associated steatotic liver disease (MASLD) comprises a heterogeneous condition in the presence of steatotic liver. There can be a hierarchy of metabolic risk factors contributing to the severity of metabolic dysfunction and, thereby, the associated risk of both liver and extrahepatic outcomes, but the precise ranking and combination of metabolic syndrome (MetS) traits that convey the highest risk of major adverse liver outcomes and extrahepatic disease complications remains uncertain. Insulin resistance, low-grade inflammation, atherogenic dyslipidaemia and hypertension are key to the mechanisms of liver and extrahepatic complications. The liver is pivotal in MetS progression as it regulates lipoprotein metabolism and secretes substances that affect insulin sensitivity and inflammation. MASLD affects the kidneys, heart and the vascular system, contributing to hypertension and oxidative stress. To address the global health burden of MASLD, intensified by obesity and type 2 diabetes mellitus epidemics, a holistic, multidisciplinary approach is essential. This approach should focus on both liver disease management and cardiometabolic risk factors. This Review examines the link between metabolic dysfunction and liver dysfunction and extrahepatic disease outcomes, the diverse mechanisms in MASLD due to metabolic dysfunction, and a comprehensive, personalized management model for patients with MASLD.

Metabolism associated fatty liver disease (MAFLD) has emerged as a growing global health challenge with limited effective treatments. Research on nuclear receptors offers promising new therapeutic avenues for MAFLD. The liver X receptor (LXR) has gained attention for its roles in tumors and metabolic and inflammatory diseases; However, its effects on MAFLD treatment remain a subject of debate. This review explores the therapeutic role of LXRα in MAFLD, focusing on its functions in the intestine, hepatic and adipose tissue, and summarizes recent advancements in LXRα ligands over the past five years. In the intestine, LXRα activation enhances the efflux of non-biliary cholesterol and reduces inflammation in the gut-liver axis by regulating intestinal high-density lipoprotein synthesis and its interaction with lipopolysaccharide. In the liver, LXRα activation facilitates cholesterol transport, influences hepatic lipid synthesis, and exerts anti-inflammatory effects. In adipose tissue, LXRα helps delay MAFLD progression by managing lipid autophagy and insulin resistance. Ligands that modulate LXRα transcriptional activity show considerable promise for MAFLD treatment.

PNPLA3 rs738409 variant is a risk factor for onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess its global prevalence, clinical and histological characteristics, and long-term outcomes in patients with MASLD.

PubMed and Embase databases were searched until December 30, 2023, for observational studies on PNPLA3 genotyped adults with MASLD. Proportions were pooled using a generalized linear mixed model with Clopper-Pearson intervals. Continuous and dichotomous variables were analyzed using the DerSimonian-Laird method. International Prospective Register of Systematic Reviews registration number: CRD42023449838.

A total of 109 studies involving 118,302 individuals with MASLD were identified. The overall minor allele frequency of the G allele [MAF(G)] at PNPLA3 was 0.45 (95% confidence interval [CI]: 0.43; 0.48) with high heterogeneity (I2 = 98%). The highest MAF(G) was found in Latin America (0.63) and the lowest in Europe (0.38). No African countries were identified. Carriers of the PNPLA3 variant had reduced adiposity, altered fat metabolism, and worse liver damage/histology than noncarriers. There was significant heterogeneity in the clinical/histological analyses (I2 > 50%). Only the PNPLA3 GG genotype was associated with higher mortality and liver-related events with no heterogeneity (I2 = 0%). Metaregressions showed the influence of adiposity, age, diabetes mellitus, and glucose on some PNPLA3 expression parameters. Overall, there was a moderate risk of bias in the included studies.

This study reveals the global pattern of PNPLA3 and its clinical, histological, and outcome implications in MASLD. Patients with MASLD and PNPLA3 variant have different clinical features and worse liver severity, and only PNPLA3 GG has a higher risk of mortality and liver outcomes. Our findings highlight the importance of PNPLA3 genotyping in clinical trials and advocate for personalized medicine approaches.

Inhibiting de novo lipogenesis (DNL) in hepatocytes is a promising strategy for treating metabolic fatty liver diseases. ACLY, a key enzyme in the DNL pathway, has become a therapeutic target for non-alcoholic fatty liver disease (NAFLD). However, its inhibition shows mixed outcomes, depending on interventions and diets. Evidence suggests ACLY inhibition activates the ACSS2-mediated acetate metabolism and the subsequent DNL, though potential mechanisms and possible consequences remain unclear. This study found that targeting hepatic ACLY with AAV8-shRNA failed to improve NAFLD in mice fed a high-fat, high-fructose diet. Instead, it worsened inflammation and liver injury. ACLY inhibition conditionally upregulated DNL enzymes, but consistently activated the ACSS2-acetyl-CoA pathway and suppressed fatty acid oxidation. Further, ACLY inhibition led to polyunsaturated fatty acid accumulation, triggering mitochondrial dysfunction. The resulting ROS redirected carbon flux into acetate, activating the ACSS2-acetyl-CoA pathway, which promoted lipid biosynthesis and exacerbated mitochondrial dysfunction-a vicious cycle that fueled inflammation and liver damage. Dual inhibition of ACLY and ACSS2 broke this cycle by reducing hepatic acetyl-CoA flux, suppressing DNL, enhancing fatty acid oxidation via PPAR-α activation, and improving mitochondrial function. This combined targeting strategy reduced lipid accumulation, alleviated inflammation, and normalized aminotransferase levels, effectively reversing NAFLD progression.

Extracellular vesicles (EVs) are cell-produced, membrane-surrounded vesicles that harbour the biological features of donor cells. In the current study, we are the first to isolate and characterize EVs isolated from human precision-cut liver slices (PCLS), obtained from both healthy and metabolic dysfunction-associated steatohepatitis (MASH) cirrhotic livers. PCLS derived from patients can faithfully represent disease conditions in humans. EVs were isolated from human PCLS after incubating in normal medium or modified medium that mimics the pathophysiological environment of metabolic dysfunction associated liver disease (MASLD). MASH PCLS produced higher amounts of EVs compared to healthy PCLS (p < 0.001). Mass spectrometry revealed that around 300 proteins were significantly different in EVs derived from MASH PCLS versus healthy PCLS (FDR < 0.05), irrespective of the type of medium. Significantly changed EV proteins were largely involved in signalling receptor binding function and showed potential in promoting fibrosis. In the liver, these ligand-associated receptors are highly expressed in hepatic stellate cells, and the MASH EVs functionally promoted the activation of hepatic stellate cells. Furthermore, the amounts of EpCAM and ITGA3 in EVs were positively associated with the progression of MASLD, which suggests the use of liver-derived EVs as potential biomarkers for MASLD. Characterization of EVs derived from human PCLS may assist future studies in investigating the pathogenesis and identifying liver-specific EVs as biomarkers of MASLD.

The Dietary Approaches to Stop Hypertension (DASH) diet has long been recommended for the management of hypertension, while it may provide other metabolic benefits. This study aimed to analyze the association between the DASH diet and nonalcoholic fatty liver disease (NAFLD) risk through a systematic review and meta-analysis. We hypothesized that the adherence to DASH diet is inversely associated with NAFLD risk. PubMed, Web of Science, Scopus, and Google Scholar were searched to find relevant publications up to September 2024. We included observational studies evaluating the association between the DASH diet score and the risk of NAFLD. Pooling effect sizes was conducted using a random effects model to determine the odd ratio (OR) of incident NAFLD associated with the DASH diet. Eight studies with a total of 120937 participants were included in the meta-analysis. The pooled OR for NAFLD in the highest score of the DASH diet vs. lowest score was 0.78 (95% CI: 0.70-0.86, P < .001), indicating a significant inverse association between the DASH diet and NAFLD risk. The result was stable to sensitivity analysis. A significant heterogeneity was observed between studies (I2=62.7%, P = .009). Overall, this meta-analysis showed that individuals with the highest score of the DASH diet were 22% less likely to have NAFLD in comparison to those with the lowest score of the DASH diet, independent of body mass index. Further high-quality prospective studies are needed to confirm the protective effect of the DASH diet on NAFLD.

This study aimed to investigate the relationship between lung function and metabolic dysfunction-associated steatotic liver disease (MASLD), and the potential mediating role of type 2 diabetes.

Data from the 2007 to 2012 National Health and Nutrition Examination Survey were used. Logistic regression analysis was employed to assess the association between lung function parameters [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), FEV 1 /FVC] and MASLD prevalence while exploring type 2 diabetes mediation. Further analyses included linkage disequilibrium score regression, Mendelian randomization, and meta-analysis to examine the causal relationship between lung function and MASLD, considering type 2 diabetes mediation.

The results showed that higher FVC and FEV 1 levels were associated with decreased MASLD risk, with type 2 diabetes partially mediating this relationship. Genetic analyses supported a causal link between lung function and MASLD, with type 2 diabetes acting as an intermediary. However, no significant association was found between FEV 1 /FVC and MASLD.

The study identified a causal relationship between lung function and MASLD, with type 2 diabetes playing a partial mediating role.

To gain more light on the effects of resveratrol and pterostilbene in the hepatic metabolic modifications in an in vivo model of diet-induced hepatic steatosis, and to explore their relationships with gut microbiota by untargeted metabolomics and metagenomics. Rats were divided into five groups receiving either a standard diet or a high-fat high-fructose (HFHF) diet supplemented or not with pterostilbene (15 or 30 mg/kg body weight/day; PT15 or PT30 groups, respectively) or resveratrol (30 mg/kg body weight/day; RSV30 group). Supplementation with the stilbenes reduced the hepatic steatosis induced by the HFHF diet. After the metabolomics study, 27 differentially expressed metabolites showed variable importance in projection scores > 1 and could be considered as potential biomarkers. Therefore, based on the pathway enrichment analysis, "riboflavin metabolism" and "nicotinate and nicotinamide metabolism" revealed significant enrichment. Further, riboflavin showed positive correlations to Eubacterium and Faecalibacterium, and negative correlations to Lactobacillus and Oscillospira genera. Nicotinamide mononucleotide was only positively correlated to the Ralstonia genus. The untargeted metabolomics approach showed that the actions of resveratrol or pterostilbene on the prevention of liver steatosis are mediated by specific mechanisms of action. Particularly, pterostilbene, but not resveratrol, is suggested to significantly enrich riboflavin or nicotinate and nicotinamide metabolic pathways.

Endothelial-to-mesenchymal transition (EndMT) has emerged as a key process contributing to the pathology of non-alcoholic fatty liver disease (NAFLD). Thus, identifying EndMT inhibitors may help impede NAFLD progression.

Our research aims to identify potent natural EndMT inhibitors and explore their therapeutic potential and mechanisms of action in NAFLD.

A natural compound library was employed to screen potential EndMT inhibitors. High-fat diet (HFD)-induced ApoE-/- mice and free fatty acid (FFA)-treated human hepatic sinusoidal endothelial cells (HHSECs) were employed as animal and cellular models of NAFLD. EndMT was evaluated by western blotting, qRT-PCR, immunofluorescence staining, tube formation, wound healing, and transwell assays. LC-MS/MS was applied to screen for altered secreted proteins during EndMT. Molecular docking, CETSA, and SPR assays were employed to validate the combination of xanthotoxin with TGFβR2.

Xanthotoxin was identified as a novel EndMT inhibitor. Further investigation revealed that xanthotoxin ameliorates NAFLD in ApoE-/- mice. By inhibiting EndMT, xanthotoxin improves endothelial dysfunction, reduces the pro-NAFLD factor ANGPTL2 secretion, and increases the anti-NAFLD factor SOD2 secretion, thus reducing hepatocyte steatosis, inflammation, and hepatic stellate cell fibrosis. Additional studies demonstrated that xanthotoxin binds to TGFβR2 and acts as its antagonist to block EndMT. In mice, EC-specific overexpression of TGFβR2 negated xanthotoxin's therapeutic impact on NAFLD.

This study reveals for the first time that xanthotoxin attenuates NAFLD by acting as a TGFβR2 antagonist to inhibit EndMT. These findings highlight the significant therapeutic potential of xanthotoxin in NAFLD treatment.

Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of hepatic disorders characterized by excessive lipid accumulation in the liver with a global prevalence rate of 30%. Despite their increasing prevalence, current therapeutic interventions remain suboptimal, constrained by substantial adverse effects and prohibitive treatment costs. Through an anti-lipid droplet (LD) accumulation screening platform, over 3000 methanolic extracts of Formosan plants were evaluated. Among them, the leaf extract of Syzygium simile demonstrated significant inhibitory activity of 40% at 25 μg/mL, emerging as the most promising species. Through bioassay-guided fractionation, 20 compounds were isolated from the n-hexane layer of the leaves, including nine new compounds [simisyzygins C-G (1-5, respectively) and simicadinenes A-D (6-9, respectively)] and 11 known compounds. These new compounds possess unique carbon skeletons characterized as flavonoid-sesquiterpenoid hybrids. Their structures were elucidated by the analysis of spectroscopic data. The structures of 1, 4, 5, and 11 were further confirmed by single-crystal X-ray diffraction analysis. Syzygioblane B (11) demonstrated the most potent inhibition of LD accumulation in Huh7 cells, achieving a 64.1% reduction at 40 μM with dose-dependency (5-40 μM) and no observable cytotoxicity. This is the first phytochemical and biological investigation of S. simile that highlights its potential as a promising botanical drug candidate for treating LD accumulation-related diseases.

Nonalcoholic steatohepatitis (NASH) has become a leading cause of liver fibrosis and hepatocellular carcinoma; however, there are no efficient drugs for NASH therapy. Acetyl-CoA carboxylase (ACC) is a crucial enzyme regulating lipid metabolism that is considered as a potential target for NASH treatment. Allosteric inhibitors target nonfunctional sites, which tend to be highly variable in protein families; thus, allosteric inhibitors are explored as an important source of drug candidates. Herein, several hotspot residues are initially identified by utilizing molecular dynamic simulation, MM-GBSA calculation, and alanine mutation. Then, focusing on the interaction with hotspot residues, several cyclobutane-based ACC allosteric inhibitors are designed, synthesized, and biologically evaluated. Among them, B1 demonstrates potent ACC inhibitory activity in vitro, a higher distribution in liver than in other tissues, and a potent therapeutic effect for NASH in vivo, making it a promising candidate for the treatment of NASH.