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Background: Although gut microbiota and serum metabolite composition have been observed to be altered in patients with non-alcoholic fatty liver disease (NAFLD), previous observational studies have demonstrated inconsistent results. As this may be influenced by factors such as confounders and reverse causality, we used Mendelian randomization to clarify the causal effect of gut microbiota and blood metabolites on NAFLD. Methods: In this research, we performed a two-step Mendelian randomization analysis by utilizing genome-wide association study (GWAS) data obtained from MiBioGen and UK Biobank. To mitigate potential errors, we employed False Discovery Rate (FDR) correction and linkage unbalanced regression (LDSC) analysis. Sensitivity analyses including cML-MA and bidirectional Mendelian randomization were performed to ensure the robustness of the results. Results: In this study, a total of nine gut microbiota and seven metabolites were found to be significantly associated with NAFLD. MR analysis of the above findings revealed a causal relationship between Ruminococcus2 and cysteine-glutathione disulfide (OR = 1.17, 95%CI = 1.006–1.369, P = 0.041), as well as 3-indoleglyoxylic acid (OR = 1.18, 95%CI = 1.011–1.370, P = 0.036). For each incremental standard deviation in Ruminococcus2 abundance, there was a corresponding 26% reduction in NAFLD risk (OR = 0.74, 95%CI = 0.61–0.89, P = 0.0012), accompanied by a 17% increase in cysteine-glutathione disulfide levels (OR = 1.17, 95%CI = 1.01–1.37, P = 0.041) and an 18% increase in 3-indoleglyoxylic acid levels (OR = 1.18, 95%CI = 0.81-1.00, P = 0.036). The proportion mediated by cysteine-glutathione disulfide is 11.2%, while the proportion mediated by 3-indoleglyoxylic acid is 7.5%. Conclusion: Our study suggests that increased abundance of specific gut microbiota may reduce the risk of developing NAFLD, and this relationship could potentially be mediated through blood metabolites. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the link between triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and nonalcoholic fatty liver disease (NAFLD) and liver fibrosis in American adults. Methods: Information for 6495 participants from the National Health and Nutrition Examination Survey (NHANES) 2017-2020.03 was used for this cross-sectional study. The link between TG/HDL-C ratios and NAFLD and liver fibrosis was assessed by multiple linear regression before evaluating nonlinear correlations based on smoothed curve fitting models. Stratification analysis was then applied to confirm whether the dependent and independent variables displayed a stable association across populations. Results: TG/HDL-C ratios were positively correlated with NAFLD, with higher ratios being linked to increased prevalence of NAFLD. After adjusting for potential confounders, the odds ratios (OR) for NAFLD patients in the fourth TG/HDL-C quartile were 3.61 (95% confidence interval [CI], 2.94-4.38) (P for trend < 0.001) in comparison with those in the first quartile after adjusting for clinical variables. However, no statistical significance was noted for the ratio for liver fibrosis after adjusting for potential confounders (P for trend = 0.07). A nonlinear correlation between TG/HDL-C ratios and NAFLD was observed based on smoothed curve fitting models. However, a nonlinear relationship between the ratios and liver fibrosis was not established. In subgroup analyses, there was an interaction between smoking status and TG/HDL-C ratio in relation to the prevalence of liver fibrosis (P for interaction < 0.001). Conclusions: Among American adults, the TG/HDL-C ratio was noted to be nonlinearly positively associated with the prevalence of NAFLD; however, this relationship was not present in liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) syndrome and nonalcoholic fatty liver disease (NAFLD) have been shown to have a close association in previous studies, but their pathogeneses are unclear. This study explores the molecular mechanisms associated with the pathogenesis of OSA and NAFLD and identifies key predictive genes. Methods: Using the Gene Expression Omnibus (GEO) database, we obtained gene expression profiles GSE38792 for OSA and GSE89632 for NAFLD and related clinical characteristics. Mitochondrial unfolded protein response-related genes (UPRmtRGs) were acquired by collating and collecting UPRmtRGs from the GeneCards database and relevant literature from PubMed. The differentially expressed genes (DEGs) associated with OSA and NAFLD were identified using differential expression analysis. Gene Set Enrichment Analysis (GSEA) was conducted for signaling pathway enrichment analysis of related disease genes. Based on the STRING database, protein-protein interaction (PPI) analysis was performed on differentially co-expressed genes (Co-DEGs), and the Cytoscape software (version 3.9.1) was used to visualize the PPI network model. In addition, the GeneMANIA website was used to predict and construct the functional similar genes of the selected Co-DEGs. Key predictor genes were analyzed using the receiver operating characteristic (ROC) curve. Results: The intersection of differentially expressed genes shared between OSA and NAFLD-related gene expression profiles with UPRmtRGs yielded four Co-DEGs: ASS1, HDAC2, SIRT3, and VEGFA. GSEA obtained the relevant enrichment signaling pathways for OSA and NAFLD. PPI network results showed that all four Co-DEGs interacted (except for ASS1 and HDAC2). Ultimately, key predictor genes were selected in the ROC curve, including HDAC2 (OSA: AUC = 0.812; NAFLD: AUC = 0.729), SIRT3 (OSA: AUC = 0.775; NAFLD: AUC = 0.750), and VEGFA (OSA: AUC = 0.812; NAFLD: AUC = 0.861) (they have a high degree of accuracy in predicting whether a subject will develop two diseases). Conclusion: In this study, four co-expression differential genes for OSA and NAFLD were obtained, and they can predict the occurrence of both diseases. Transcriptional mechanisms involved in OSA and NAFLD interactions may be better understood by exploring these key genes. Simultaneously, this study provides potential diagnostic and therapeutic markers for patients with OSA and NAFLD. [ABSTRACT FROM AUTHOR]

Background: The molecular mechanisms underlying nonalcoholic fatty liver disease (NAFLD) remain to be fully elucidated. Ubiquitin specific protease 13 (USP13) is a critical participant in inflammation-related signaling pathways, which are linked to NAFLD. Herein, the roles of USP13 in NAFLD and the underlying mechanisms were investigated. Methods: L02 cells and mouse primary hepatocytes were subjected to free fatty acid (FFA) to establish an in vitro model reflective of NAFLD. To prepare in vivo model of NAFLD, mice fed a high-fat diet (HFD) for 16 weeks and leptin-deficient (ob/ob) mice were used. USP13 overexpression and knockout (KO) strategies were employed to study the function of USP13 in NAFLD in mice. Results: The expression of USP13 was markedly decreased in both in vitro and in vivo models of NAFLD. USP13 overexpression evidently inhibited lipid accumulation and inflammation in FFA-treated L02 cells in vitro. Consistently, the in vivo experiments showed that USP13 overexpression ameliorated hepatic steatosis and metabolic disorders in HFD-fed mice, while its deficiency led to contrary outcomes. Additionally, inflammation was similarly attenuated by USP13 overexpression and aggravated by its deficiency in HFD-fed mice. Notably, overexpressing of USP13 also markedly alleviated hepatic steatosis and inflammation in ob/ob mice. Mechanistically, USP13 bound to transforming growth factor β-activated kinase 1 (TAK1) and inhibited K63 ubiquitination and phosphorylation of TAK1, thereby dampening downstream inflammatory pathways and promoting insulin signaling pathways. Inhibition of TAK1 activation reversed the exacerbation of NAFLD caused by USP13 deficiency in mice. Conclusions: Our findings indicate the protective role of USP13 in NAFLD progression through its interaction with TAK1 and inhibition the ubiquitination and phosphorylation of TAK1. Targeting the USP13-TAK1 axis emerges as a promising therapeutic strategy for NAFLD treatment. [ABSTRACT FROM AUTHOR]

Chronic liver diseases (CLD) affect 1.5 billion patients worldwide, with dramatically increasing incidence in recent decades. It has been hypothesized that the chronic hyperinflammation associated with CLD may increase the risk of a more severe course of acute pancreatitis (AP). This study aims to investigate the underlying impact of CLD on the outcomes of AP. A systematic search was conducted in Embase, Medline, and Central databases until October 2022. Studies investigating patients with acute pancreatitis and CLD, were included in the meta-analysis. A total of 14,963 articles were screened, of which 36 were eligible to be included. CLD was a risk factor for increased mortality with an odds ratio (OR) of 2.53 (CI 1.30 to 4.93, p = 0.01). Furthermore, renal, cardiac, and respiratory failures were more common in the CLD group, with ORs of 1.92 (CI 1.3 to 2.83, p = 0.01), 2.11 (CI 0.93 to 4.77, p = 0.062) and 1.99 (CI 1.08 to 3.65, p = 0.033), respectively. Moreover, the likelihood of developing Systemic Inflammatory Response Syndrome (SIRS) was significantly higher, with an OR of 1.95 (CI 1.03 to 3.68, p = 0.042). CLD is an important risk factor for worse outcomes in AP pancreatitis, leading to higher mortality and increased rates of local and systemic complications. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the association between the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and the risk and severity of CHD among NAFLD patients. Methods: This retrospective study included 278 patients with NAFLD and chest pain. The TG/HDL-C ratio was calculated and coronary angiography performed. All individuals were divided into NAFLD + CHD and NAFLD groups. The severity of coronary artery stenosis is quantified using the Gensini score based on angiographic results. In NAFLD patients, the association between the TG/HDLC ratio and the risk and severity of CHD was explored. Results: CHD was detected in 139 of 278 patients. Compared to NAFLD group, multivariate logistic regression showed that TG/HDL-C ratio was a risk factor for CHD among NAFLD patients after adjustment for confounding factors with the odds ratio (OR 1.791, 95% CI 1.344-2.386, P<0.001). Further analysis using multivariate logistic regression based on tertiles revealed that, after adjusting for confounding factors, compared to the T1 group, the risk of CHD in the T2 group was 2.17-fold higher (OR, 2.17; 95% CI, 1.07-4.38; P = 0.031). Similarly, the risk of CHD in the T3 group increased by 2.84-fold (OR, 2.84; 95% CI, 1.36-5.94; P = 0.005). The multifactor linear regression analysis showed each 1-unit increase in TG/HDL-C ratio in the NAFLD + CHD group was associated with a 7.75-point increase in Gensini score (b=7.75, 95% CI 5.35-10.15, P<0.001). Conclusion: The TG/HDL-C ratio was positively correlated with CHD risk and reflected coronary atherosclerosis severity in NAFLD patients. [ABSTRACT FROM AUTHOR]

Background: Thyroid hormones (THs) have been found that it is closely associated with the onset and progression of non-alcoholic fatty liver disease (NAFLD). However, the current study could not verify the intrinsic relationship between thyroid hormones and NAFLD, which requires further research. Methods: The searches of studies reported both TH level in serum and NAFLD were performed in PubMed, Web of Science, Cochrane Library, and Embase databases. We combined an overall meta-analysis with a dose-response meta-analysis to assess the correlation and dose-response relationship between thyroid function levels and the risk of NAFLD. Results: Overall, 10 studies were included with a total of 38,425 individuals. We found that the non-linear dose-response model showed that for every 1 ng/dL increase in FT4, the risk of NAFLD was reduced by 10.56% (p=0.003). The odds ratios (ORs) for NAFLD with high free triiodothyronine (FT3) exposure compared to those with low FT3 were 1.580 (95% CI 1.370 to 1.830, I2 = 0.0%, p<0.001) in the overall meta-analysis. The continuous variable meta-analysis indicated that individuals with high levels of TSH (SMD=1.32, 95% CI 0.660 to 1.970, p<0.001) had significantly higher levels of liver fibrosis than those with low levels. Conclusions: Our findings only validate that there is a correlation between the occurrence of NAFLD and abnormal levels of THs, and it is expected that more observational studies will still be conducted in the future to further demonstrate the relationship between thyroid hormones and NAFLD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is currently an important chronic liver disease threatening human life and health. To investigate the risk factors of hepatocellular carcinoma (HCC) associated with nonalcoholic fatty liver disease (NAFLD) by systematic review. We conducted a systematic review and meta-analysis. A systematic search of Chinese and English databases (PubMed, Web of Science, Cochrane Library, China national knowledge infrastructure (CNKI), Wanfang database, and VIP database) was performed until June 30, 2023. Studies were included to investigate the risk factors for HCC in patients with NAFLD. Quality evaluation was performed using the Newcastle-Ottawa Literature Quality Evaluation Scale, and then hazard ratios (HRs) for different influencing factors were combined. We reviewed the results of 12 high-quality cohort studies involving 738,934 patients with NAFLD and 1,480 developed HCC. A meta-analysis based on a random-effects model showed that advanced age (HR = 1.81, 95% CI: 1.51–2.17), male gender (HR = 2.51, 95% CI: 1.67–3.78), hypertension (HR = 1.87, 95% CI: 1.05–3.33), and diabetes (HR = 2.27, 95% CI: 1.63–3.16) were risk factors for HCC in NAFLD, and the differences were statistically significant. However, there was no statistically significant effect of current smoking (HR = 1.45, 95% CI: 0.72–2.92) and dyslipidemia (HR = 1.03, 95% CI: 0.72–1.47) on HCC incidence in this study. Age, sex, hypertension and diabetes are risk factors for HCC in NAFLD patients. Diabetic NAFLD patients have a 2.27-fold increased risk of HCC, and health education and intervention for elderly, male, NAFLD patients with diabetes and hypertension need to be strengthened to promote a reduction in the risk of HCC. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effects of mitogen-inducible gene 6 (MIG6) overexpression on palmitic acid (PA)-induced endoplasmic reticulum stress-associated steatosis in hepatocytes. METHODS: A mouse model of nonalcoholic steatohepatitis was established by feeding twenty C57BL/6J mice a high-fat diet for 26 weeks. The mice were randomly divided into two groups: normal diet control group and high-fat diet group, and their livers were retained for subsequent experiments. The PA was used to induce lipid accumulation in HepG2 cells and AML12 cells, and the cells were divided into two groups: BSA (10% BSA) group and PA (500 μmol/L PA) group. The MIG6 overexpression was induced by transfecting HepG2 and AML12 cells with human and mouse MIG6 overexpression plasmids, respectively. The cells were divided into four groups according to their different treatment conditions: (1) negatiive+BSA group (transfected with negative control plasmid+10% BSA); (2) MIG6+BSA group (transfected with MIG6 overexpression plasmid+10% BSA); (3) negative+PA group (transfected with negative control plasmid+500 μmol/L PA); (4) MIG6+PA group (transfected with MIG6 overexpression plasmid+500 μmol/L PA). Lipid accumulation in hepatocytes was assessed by oil red O staining, and RT-qPCR was used to detect the mRNA expression level of MIG6 in liver tissues. The protein levels of MIG6, lipid synthesis-related molecules fatty acid synthase (FASN) and sterol regulatory element-binding protein 1 (SREBPl), and endoplasmic reticulum stress-related proteins glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) in hepatocytes were detected using Western blot. RESULTS: High-fat diet increased the triglyceride content in the liver tissue of C57BL/6J mice induced lipid accumulation in hepatocytes and suppressed the mRNA expression level of MIG6 (P<0. 01). PA intervention increased the protein levels of lipid synthesis-related molecules such as FASN and SREBP1, and endoplasmic reticulum stress markers GRP78 and CHOP in hepatocytes, but inhibited MIG6 protein levels (P<0. 01). We transfected hepatocytes with MIG6 overexpression plasmid, which significantly increased MIG6 protein levels, decreased GRP78 and CHOP protein levels in hepatocytes (P<0. 01), significantly attenuated PA-induced lipid accumulation in hepatocytes, and down-regulated FASN and SREBP1 protein levels (P<0. 01). These results indicate that MIG6 overexpression inhibited PA-induced endoplasmic reticulum stress and attenuated lipid accumulation in hepatocytes. CONCLUSION: Overexpression of MIG6 inhibits lipid accumulation in hepatocytes by suppressing endoplasmic reticulum stress. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic liver resection (LLR) is rapidly gaining popularity; however, its efficacy for nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) (NAFLD-HCC) has been not evaluated. The purpose of this study was to compare short- and long-term outcomes between LLR and open liver resection (OLR) among patients with NAFLD-HCC. Methods: We used a single-institution database to analyze data for patients who underwent LLR or OLR for NAFLD-HCC from January 2007 to December 2022. We performed propensity score-matching analyses to compare overall postoperative complications, major morbidities, duration of surgery, blood loss, transfusion, length of stay, recurrence, and survival between the two groups. Results: Among 210 eligible patients, 46 pairs were created by propensity score matching. Complication rates were 28% for OLR and 11% for LLR (p = 0.036). There were no significant differences in major morbidities (15% vs. 8.7%, p = 0.522) or duration of surgery (199 min vs. 189 min, p = 0.785). LLR was associated with a lower incidence of blood transfusion (22% vs. 4.4%, p = 0.013), less blood loss (415 vs. 54 mL, p < 0.001), and shorter postoperative hospital stay (9 vs. 6 days, p < 0.001). Differences in recurrence-free survival and overall survival between the two groups were not statistically significant (p = 0.222 and 0.301, respectively). Conclusions: LLR was superior to OLR for NAFLD-HCC in terms of overall postoperative complications, blood loss, blood transfusion, and postoperative length of stay. Moreover, recurrence-free survival and overall survival were comparable between LLR and OLR. Although there is a need for careful LLR candidate selection according to tumor size and location, LLR can be regarded as a preferred treatment for NAFLD-HCC over OLR. [ABSTRACT FROM AUTHOR]

The global prevalence of childhood and adolescent obesity, exacerbated by the coronavirus disease 2019 pandemic, affects school-aged children and preschoolers. Early-onset obesity, which carries a high risk of metabolic complications, may contribute to a lower age at the onset of cardiovascular disease. As metabolic diseases such as diabetes, dyslipidemia, and nonalcoholic fatty liver disease observed in adulthood are increasingly recognized in the pediatric population, there is an emphasis on moving disease susceptibility assessments from adulthood to childhood to enable early detection. However, consensus is lacking regarding the definition of metabolic diseases in children. In response, various indicators such as the pediatric simple metabolic syndrome score, continuous metabolic syndrome score, single-point insulin sensitivity estimator, and fatty liver index have been proposed in several studies. These indicators may aid the early detection of metabolic complications associated with pediatric obesity, although further validation studies are needed. Obesity assessments are shifting in perspective from visual obesity to metabolic health and body composition considerations to fill the gap in health impact assessments. Sarcopenic obesity, defined as the muscle- to-fat ratio, has been proposed in pediatric populations and is associated with metabolic health in children and adolescents. The National Health Screening Program for Children in Korea has expanded but still faces limitations in laboratory testing. These tests facilitate timely intervention by identifying groups at a high risk of metabolic complications. Early detection and intervention through comprehensive health screening are critical for mitigating long-term complications of childhood obesity. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a significant health issue. Emerging research has focused on the role of the gut microbiota in NAFLD, emphasizing the gut-liver axis. This study aimed to identify key research trends and guide future investigations in this evolving area. Methods: This bibliometric study utilized Scopus to analyze global research on the link between the gut microbiota and NAFLD. The method involved a search strategy focusing on relevant keywords in article titles, refined by including only peer-reviewed journal articles. The data analysis included bibliometric indicators such as publication counts and trends, which were visualized using VOSviewer software version 1.6.20 for network and co-occurrence analysis, highlighting key research clusters and emerging topics. Results: Among the 479 publications on the gut microbiota and NAFLD, the majority were original articles (n = 338; 70.56%), followed by reviews (n = 119; 24.84%). The annual publication count increased from 1 in 2010 to 118 in 2022, with a significant growth phase starting in 2017 (R2 = 0.9025, p < 0.001). The research was globally distributed and dominated by China (n = 231; 48.23%) and the United States (n = 90; 18.79%). The University of California, San Diego, led institutional contributions (n = 18; 3.76%). Funding was prominent, with 62.8% of the articles supported, especially by the National Natural Science Foundation of China (n = 118; 24.63%). The average citation count was 43.23, with an h-index of 70 and a citation range of 0 to 1058 per article. Research hotspots shifted their focus post-2020 toward the impact of high-fat diets on NAFLD incidence. Conclusions: This study has effectively mapped the growing body of research on the gut microbiota-NAFLD relationship, revealing a significant increase in publications since 2017. There is significant interest in gut microbiota and NAFLD research, mainly led by China and the United States, with diverse areas of focus. Recently, the field has moved toward exploring the interconnections among diet, lifestyle, and the gut-liver axis. We hypothesize that with advanced technologies, new opportunities for personalized medicine and a holistic understanding of NAFLD will emerge. [ABSTRACT FROM AUTHOR]

Aim Methodology Results Conclusion In this study, we investigated the systemic implications of chronic apical periodontitis (CAP). CAP may contribute to the nonalcoholic fatty liver disease (NAFLD) progression through the gut microbiota and its metabolites, which are related to the degree of fibrosis.Sixteen 7‐week‐old male apolipoprotein E knockout (apoE−/−) mice were randomly divided into two groups: the CAP and Con groups. A CAP model was established by sealing the first‐ and second‐maxillary molars with bacterium‐containing cotton balls. Apical lesions were evaluated by micro‐CT. Histological evaluations of NAFLD were performed using second harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) assays. Additionally, we comprehensively analyzed the gut microbiota using 16S rRNA gene sequencing and explored metabolic profiles by liquid chromatography–mass spectrometry (LC–MS). Immunofluorescence analysis was used to examine the impact of CAP on tight junction proteins and mucin expression. Transcriptome assays have elucidated gene expression alterations in liver tissues.Micro‐CT scans revealed an evident periapical bone loss in the CAP group, and the total collagen percentage was increased (Con, 0.0361 ± 0.00510%, CAP, 0.0589 ± 0.00731%, p < .05). 16S rRNA sequencing revealed reduced diversity and distinct taxonomic enrichment in the CAP group. Metabolomic assessments revealed that differentially enriched metabolites, including D‐galactosamine, were enriched and that 16‐hydroxyhexadecanoic acid and 3‐methylindole were depleted in the CAP group. Immunofluorescence analyses revealed disruptions in tight junction proteins and mucin production, indicating intestinal barrier integrity disruption. Liver transcriptome analysis revealed upregulation of Lpin‐1 expression in the CAP group.This study provides comprehensive evidence of the systemic effects of CAP on liver fibrosis in NAFLD patients by elucidating alterations in the gut microbiota composition and metabolism. [ABSTRACT FROM AUTHOR]

Background: Bile acids (BAs) concentration can affect metabolic improvement caused by bariatric surgery and BA concentrations increase in patients after sleeve gastrectomy (SG). Here, how BAs after SG affect metabolism in nonalcoholic fatty liver disease (NAFLD) was studied. Methods: Mice were given high‐fat diet (HFD) to induce NAFLD and received SG surgery. Hepatic and fecal BA concentrations in mice were detected by liquid chromatography‐tandem mass spectrometry method. BA‐related genes were detected by quantitative real‐time polymerase chain reaction. G protein BA receptor 1 (GPBAR1) expression was identified using western blot analysis. NAFLD mice after SG received GPBAR1 inhibitor Triamterene. The weight of mice and mice liver was detected. Mouse liver tissue was observed by hematoxylin–eosin and Oil Red O staining. Triglyceride (TG), nonesterified fatty acid (NEFA), and cyclic adenosine monophosphate (cAMP) levels in mouse liver tissue were analyzed by metabolic assay and enzyme‐linked immune sorbent assay. Results: SG boosted increase in hepatic total/conjugated BAs and related genes and GPBAR1 expression, and attenuated increase in fecal total BAs/muricholic acid in HFD‐induced mice and increased fecal taurine‐BAs in HFD‐induced mice. Triamterene (72 mg/kg) reversed the inhibitory role of SG in HFD‐induced increase of body weight, lipid accumulation, inflammatory cell infiltration, and increase of hepatic weight and TG/NEFA content, and counteracted the positive role of SG in HFD‐induced increase of hepatic cAMP concentration in mice. Conclusions: BAs improve metabolism via activating GPBAR1 to increase cAMP in NAFLD mice after SG. [ABSTRACT FROM AUTHOR]

The primary catalyst for nonalcoholic fatty liver disease (NAFLD) is widely recognized as the induction of lipotoxicity in hepatocytes by an excess of fatty acids. In China, Penthorum chinense Pursh (PcP) is commonly employed as a functional food due to its known hepatoprotective properties. The present study aimed to investigate the influence of PcP extract on in vivo and in vitro models of NAFLD. We found that PcP extract can attenuate palmitic acid (PA)‐induced lipotoxicity in HepG2 cells. PA was observed to trigger pyroptosis, as indicated by the increased expression of NLRP3 and GSDMD/N, activation of Caspase‐1, and subsequent release of IL‐1β and IL‐18. However, these changes were reversed after PcP was administered. Furthermore, the application of an NLRP3 agonist inhibited the protective effects of PcP on lipotoxicity, indicating that PcP decreased lipotoxicity by inhibiting the NLRP3/Caspase‐1/GSDMD pathway. Ultimately, we established a rat model of NAFLD through the administration of a high‐fat diet (HFD), followed by the oral delivery of PcP extracts. The results demonstrated that the administration of PcP extract effectively decreased dyslipidemia and hepatic steatosis, which coincided with a decrease in hepatic pyroptosis through modulation of the NLRP3/Caspase‐1/GSDMD pathway in liver tissues. Overall, our findings provide insight into the mechanism by which PcP extracts alleviate hepatic steatosis, highlighting the potential significance of modulating the NLRP3/Caspase‐1/GSDMD pathway in the context of pyroptosis. [ABSTRACT FROM AUTHOR]

Purpose: The prevalence of nonalcoholic steatohepatitis (NASH) is increasing with the increasing prevalence of childhood obesity. Although NASH has a high risk of progression to liver fibrosis and cirrhosis, few studies have reported noninvasive markers for predicting hepatic fibrosis in children. This study aimed to evaluate and compare the diagnostic accuracies of serologic biomarkers and scoring systems for hepatic fibrosis in obese children with NASH. Methods: A total of 96 children were diagnosed with NASH based on liver biopsy findings and divided into two groups according to the degree of liver fibrosis: mild (stage 0-1) or advanced (stage 2-4). Clinical and laboratory parameters and serum levels of hyaluronic acid and type IV collagen were measured. The aspartate aminotransferase/platelet ratio index (APRI) and fibrosis-4 (FIB-4) score were calculated. Results: Among the noninvasive markers, only serum type IV collagen level and FIB-4 were significantly different between the two groups. The area under the receiver operating curve of each biomarker and scoring system was 0.80 (95% confidence interval [CI]: 0.70-0.90) for type IV collagen at an optimal cutoff of 148 ng/mL (sensitivity 69.8%, specificity 84.6%), followed by 0.69 (95% CI: 0.57-0.83) for APRI, 0.68 (95% CI: 0.56-0.80) for FIB-4, and 0.65 (95% CI: 0.53-0.77) for hyaluronic acid. Conclusion: Type IV collagen as a single noninvasive serologic biomarker for hepatic fibrosis and FIB-4 as a hepatic fibrosis score are beneficial in predicting advanced hepatic fibrosis and determining proper diagnosis and treatment strategies before fibrosis progresses in obese children with NASH. [ABSTRACT FROM AUTHOR]

To systematically summarize the published literature on the genetic variants associated with nonalcoholic fatty liver disease (NAFLD). Literature from Web of Science, PubMed, and Embase between January 1980 and September 2022 was systematically searched. Meta-analyses of the genetic variants were conducted using at least five data sources. The epidemiologic credibility of the significant associations was graded using the Venice criteria. Based on literature screening, 399 eligible studies were included, comprising 381 candidate gene association, 16 genome-wide association, and 2 whole-exome sequencing studies. We identified 465 genetic variants in 173 genes in candidate gene association studies, and 25 genetic variants in 17 genes were included in the meta-analysis. The meta-analysis identified 11 variants in 10 genes that were significantly associated with NAFLD, with cumulative epidemiological evidence of an association graded as strong for two variants in two genes (HFE, TNF), moderate for four variants in three genes (TM6SF2, GCKR, and ADIPOQ), and weak for five variants in five genes (MBOAT7, PEMT, PNPLA3, LEPR, and MTHFR). This study identified six variants in five genes that had moderate to strong evidence of an association with NAFLD, which may help understand the genetic architecture of NAFLD risk. [ABSTRACT FROM AUTHOR]

Purpose: There is a strong association between metabolic dysfunction–associated steatotic liver disease (MASLD) and obesity which are both important risk factors for cardiovascular diseases (CVDs). The current study aimed to assess the association of MBS with different CVDs in patients with MASLD. Materials and Methods: The National Inpatient Sample (NIS) database from 2016 to 2020 were analyzed by using ICD-10 codes. A propensity score matching in a 1:1 ratio was done to match the MBS and non-MBS groups. Results: After weighted analysis, 1,124,155 and 68,215 patients were included in non-MBS and MBS groups, respectively. MBS was associated with significantly lower risk of hospitalization for coronary artery disease (OR 0.633 (0.569–0.703), p value < 0.001), acute myocardial infarction (OR 0.606 (0.523–0.701), p value < 0.001), percutaneous coronary intervention (OR 0.578 (0.489–0.682), p value < 0.001), and thrombolysis (OR 0.765 (0.589–0.993), p value = 0.044) compared to the non-MBS group in patients with MASLD. Furthermore, MBS was associated with 52% reduced risk of hospitalization for hemorrhagic stroke in patients with MASLD (OR 0.481, 95% CI 0.337–0.686, p value < 0.001). However, ischemic stroke was not significant between the two groups (OR 1.108 (0.905–1.356), p value = 0.322). In addition, MBS was associated with 63% and 60% reduced risk of hospitalization for heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) in patients with MASLD (OR 0.373, 95% CI 0.300–0.465 and OR 0.405, 95% CI 0.325–0.504, p value < 0.001 for both), respectively. Conclusion: The current study showed that MBS is significantly associated with a reduced risk of hospitalization for CVD in patients with MASLD. [ABSTRACT FROM AUTHOR]

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Introduction and Objectives: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH) and, ultimately, cirrhosis. Clostridioides difficile is the most common nosocomial cause of diarrhea and is associated with worse clinical outcomes in other liver diseases, including cirrhosis, but has not been extensively evaluated in concomitant NAFLD/NASH. Materials and Methods: We conducted a retrospective cohort study using the National Inpatient Sample database from 2015 to 2017. Patients with a diagnosis of CDI, NAFLD, and NASH were identified using International Classification of Diseases (Tenth Revision) codes. The outcomes of our study include length of stay, hospitalization cost, mortality, and predictors of mortality. Results: The CDI and NASH cohort had a higher degree of comorbidity burden and prevalence of peptic ulcer disease, congestive heart failure, diabetes mellitus, and cirrhosis. Patients with NASH and CDI had a significantly higher mortality rate compared to the CDI only cohort (mortality, 7.11 % vs. 6.36 %; P = 0.042). Patients with CDI and NASH were at increased risk for liver-related complications, acute kidney injury, and septic shock (P < 0.001) compared to patients with CDI only. Older age, intestinal complications, pneumonia, sepsis and septic shock, and liver failure conferred an increased risk of mortality among the CDI and NASH cohort. Conclusions: Patients with NASH had a higher rate of liver-related complications, progression to septic shock, and mortality rate following CDI infection compared to the CDI only cohort. [ABSTRACT FROM AUTHOR]

Background: Although nonalcoholic fatty liver disease (NAFLD) commonly occurs in overweight or obese individuals, it is increasingly being identified in the lean population. The association between lean and an increased risk of all-cause mortality among patients with NAFLD remains controversial. We aimed to perform a systematic review and meta-analysis of the literature to evaluate this association and compare the long-term outcomes of lean NAFLD patients and non-lean NAFLD patients. Methods: For this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang, and Chinese Biomedical Literature Database (CBM) from inception to October 15, 2021, for relevant original research articles without any language restrictions. Our primary outcome was to compare the all-cause mortality in lean NAFLD patients and non-lean NAFLD patients by qualitative synthesis. Relative risks (RRs) and corresponding 95% confidential intervals (CIs) were pooled with a random effect model. Heterogeneity was evaluated using I-squared (I²) statistics while publication bias was determined using Egger's tests. Subgroup and sensitivity analyses were performed. As for secondary outcomes, we estimated total, cardiovascular, and liver-related mortality, as well as the incidence of diabetes, hypertension, cirrhosis, and cancer in lean and non-lean individuals with NAFLD by quantitative synthesis. Person-years of follow-up were used as the denominator to estimate the mortality and incidence. Results: We identified 12 studies (n = 26,329), 7 of which (n = 7924) were used to evaluate the risk of all-cause mortality between lean and non-lean NAFLD patients. Lean patients with NAFLD were found to be at an elevated risk of death compared to non-lean patients (RR = 1.39, 95% CI 1.08–1.82, heterogeneity: I² = 43%). Among the lean NAFLD population, all-cause mortality was 13.3 (95% CI: 6.7–26.1) per 1000 person-years, 3.6 (95% CI: 1.0–11.7) for liver-related mortality, and 7.7 (95% CI: 6.4–9.2) for cardiovascular-related mortality. The incidence of new-onset diabetes was 13.7 (95% CI 8·2–22.7) per 1000 person-years, new-onset hypertension was 56.1 (95% CI: 40.2–77.9), cirrhosis was 2.3 (95% CI: 1.0–5.0), and cancer was 25.7 (95% CI: 20.3–32.4). Conclusions: Lean patients with NAFLD had a higher risk of all-cause death than non-lean patients. Body mass index (BMI) should not be used as a criterion to determine whether further observation and therapy of patients with NAFLD are warranted. [ABSTRACT FROM AUTHOR]

Background: We aimed to characterize the relationship between the serum 25-hydroxyvitamin D concentration and the circulating lipid concentrations of patients with NAFLD in the Hulunbuir region of China. Methods: One hundred fifty-six patients, who were diagnosed with NAFLD in the Physical Examination Department of the Second Clinical College of Inner Mongolia University for the Nationalities between January 2021 and March 2023, were recruited as NAFLD group, and 160 healthy people were recruited as a control group during the same period. The serum 25(OH)VitD, TBIL, TG, TC, LDL-C, HDL-C, AST, ALT, GGT, and FPG activities of the participants were measured, and hepatic ultrasonography was performed. Results: The BMI of the NAFLD group was higher than of the control group (p < 0.05). The serum 25(OH)VitD3 (p < 0.05) and the HDL-C concentrations of the NAFLD group were lower than those of the normal control group. However, the AST (p < 0.05), ALT (p < 0.05), and GGT (p < 0.05) activities, and the serum TG (p < 0.05), TC (p < 0.05), LDL-C (p < 0.05), and the fasting glucose (p < 0.05) concentrations of the NAFLD group were higher than those of the normal control group. The serum 25(OH)VitD3 concentrations of the NAFLD group significantly correlated negatively with BMI (r = -0.302, p < 0.01), TG (r = -0.221, p < 0.05), and fasting glucose (r = -0.236, p < 0.05). The BMI, TG, and fasting glucose of vitamin D-deficient participants were higher than of the participants with adequate or insufficient levels of vitamin D (p < 0.05). Finally, the BMI of vitamin D-deficient participants was higher than of those with an adequate vitamin D status (p < 0.05). Conclusions: A deficiency of 25(OH)VitD is more common in people from the Hulunbuir region of China than elsewhere. In addition, the vitamin D status is significantly associated with NAFLD; as the serum vitamin D concentration decreases, patients with NAFLD show greater dyslipidemia and hyperglycemia and a higher BMI. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) poses an emerging threat topublic health. Nonalcoholic steatohepatitis (NASH) is reported to be the most rapidly rising cause of hepatocellular carcinoma in the western world. Recently, a new term has been proposed: metabolic dysfunction-associated steatotic liver disease (MASLD). The introduction of this new terminology has sparked a debate about the interchangeability of these terms. The pathogenesis of NAFLD/MASLD is thought to be multifactorial, involving both genetic and environmental factors. Among these factors, alterations in gut microbiota and gut dysbiosis have recently garnered significant attention. In this context, this review will further discuss the gut–liver axis, which refers to the bidirectional interaction between the human gut microbiota and the liver. Additionally, the therapeutic potential of probiotics, particularly next-generation probiotics and genetically engineered bacteria, will be explored. Moreover, the role of prebiotics, synbiotics, postbiotics, and phages as well as fecal microbiota transplantation will be analyzed. Particularly for lean patients with NAFLD/MASLD, who have limited treatment options, approaches that modify the diversity and composition of the gut microbiota may hold promise. However, due to ongoing safety concerns with approaches that modulate gut microbiota, further large-scale studies are necessary to better assess their efficacy and safety in treating NAFLD/MASLD. [ABSTRACT FROM AUTHOR]

Background and aimsNonalcoholic fatty liver disease (NAFLD) has reached pandemic proportions. Early detection can identify at-risk patients who can be linked to hepatology care. The vibration-controlled transient elastography (VCTE) controlled attenuation parameter (CAP) is biopsy validated to diagnose hepatic steatosis (HS). We aimed to develop a novel clinical predictive algorithm for HS using the CAP score at a Veterans' Affairs hospital.MethodsWe identified 403 patients in the Greater Los Angeles VA Healthcare System with valid VCTEs during 1/2018-6/2020. Patients with alcohol-associated liver disease, genotype 3 hepatitis C, any malignancies, or liver transplantation were excluded. Linear regression was used to identify predictors of NAFLD. To identify a CAP threshold for HS detection, receiver operating characteristic analysis was applied using liver biopsy, MRI, and ultrasound as the gold standards.ResultsThe cohort was racially/ethnically diverse (26% Black/African American; 20% Hispanic). Significant positive predictors of elevated CAP score included diabetes, cholesterol, triglycerides, BMI, and self-identifying as Hispanic. Our predictions of CAP scores using this model strongly correlated (r = 0.61, p

Background & aimsPrevious studies have shown a potential association between nonalcoholic fatty liver disease (NAFLD) and some immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA), but this association has not been analyzed systematically. Therefore, we aimed to perform a systematic review and meta-analysis to ascertain a pooled prevalence estimate of NAFLD among patients with RA to fill this gap in knowledge.MethodsWe conducted a literature search in PubMed, Embase, Web of Science, Scopus, and ProQuest, for observational studies published from inception to August 31, 2022, which reported prevalence of NAFLD in 100 or more adult (age, ≥18 y) patients with RA. To be included, NAFLD diagnosis was based on either imaging or histologic assessment. The results were presented as pooled prevalence, odds ratio, and 95% CI. The I2 statistic was used to measure the heterogeneity between studies.ResultsThis systematic review included 9 eligible studies derived from 4 continents comprising 2178 patients (78.8% women) with RA. The pooled prevalence of NAFLD was 35.3% (95% CI, 19.9-50.6; I2 = 98.6%; P < .001) in patients with RA. All studies used ultrasound for the diagnosis of NAFLD, except for 1 study that used transient elastography. The pooled prevalence of NAFLD in men with RA was significantly higher than in women with RA (35.2%; 95% CI, 24.0-46.5 compared with 22.2%; 95% CI, 17.9-26.58; P for interaction = .048). Each 1-unit increase in body mass index was associated directly with a 24% increased risk of NAFLD in RA patients (adjusted odds ratio, 1.24; 95% CI, 1.17-1.31; I2 = 0.0%; P = .518).ConclusionsBased on this meta-analysis, 1 in 3 patients with RA had NAFLD, which appears comparable with its overall prevalence among the general population. Clinicians should actively screen for NAFLD in patients with RA.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder. Its pathogenesis is multifactorial, and different pathogenic mechanisms cause differences in its course and outcomes at different clinical stages. This study evaluated serum levels of alpha-fetoprotein (AFP), lipids, and liver enzymes in Sudanese patients with NAFLD. Methods and Results: This study was conducted at the Advance Diagnostic Center, Bihari Hospital, Khartoum State, Sudan, from September 2021 to November 2022. A total of 80 participants (56 women and 24 men) were divided into two groups: The study group included 40 patients diagnosed with NAFLD, and the control group comprised 40 healthy individuals. All patients underwent an ultrasound examination. The serum levels of AST, ALT, triglycerides (TG), and total cholesterol (TC) were measured using a spectrophotometric method, while AFP levels were assessed using an enzyme-linked immunosorbent assay (ELISA). Our study revealed a significant increase in the levels of AST, ALT, TG, and AFP in NAFLD patients compared to the control group (P

Abstract Background Increasing evidences suggest that nonalcoholic fatty liver disease (NAFLD) is associated with neuropsychiatric disorders. Nevertheless, whether there were causal associations between them remained vague. A causal association between neuropsychiatric disorders and NAFLD was investigated in this study. Methods We assessed the published genome-wide association study summary statistics for NAFLD, seven mental disorder-related diseases and six central nervous system dysfunction-related diseases. The causal relationships were first assessed using two-sample and multivariable Mendelian randomization (MR). Then, sensitivity analyses were performed, followed by a reverse MR analysis to determine whether reverse causality is possible. Finally, we performed replication analyses and combined the findings from the above studies. Results Our meta-analysis results showed NAFLD significantly increased the risk of anxiety disorders (OR = 1.016, 95% CI = 1.010–1.021, P value

Abstract Muscle quality index (MQI) is a novel indicator reflecting the quality of skeletal muscles. The association between MQI and the development of advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) is unknown. We investigated the association of low MQI with advanced fibrosis among adults with NAFLD using a nationally representative sample of the US population. Adults with NAFLD who participated in the National Health and Nutrition Examination Survey (NHANES) 2011–2014 were included. Sex-specific standard was used to define low and extremely low MQI. Univariate and multivariate logistic regressions were used to assess the association between MQI level and advanced fibrosis. In the study, 3758 participants with NAFLD were included. The prevalence of low and extremely low MQI was 11.7% (95% CI 10.4–13.0%) and 2.2% (95% CI 1.6–2.8%), respectively. Among these participants, 96 were assessed to have advanced fibrosis. Individuals with low [(odds ratio (OR) 2.45, 95% confidence interval (CI) 1.22–4.91)] and extremely low MQI (OR 10.48, 95% CI 3.20–34.27) were associated with advanced fibrosis in multivariable analysis. A linear trend relationship was also observed between MQI level and the risk of advanced fibrosis (P trend = 0.001). Subgroup and sensitivity analyses yielded similar results to the main analyses. Decreased MQI is highly prevalent, and is associated with an increased risk of advanced fibrosis in adult US population with NAFLD.

Abstract Nonalcoholic fatty liver disease (NAFLD) is expanding as a global health problem with approximately 25% of the world's population affected by it. Dietary modification is one of the most important strategies for preventing NAFLD. The association between nutrient density and the Healthy Eating Index 2015 (HEI2015) with NAFLD demonstrates that nutrient density is an independent predictor of NAFLD in Iranian adults [fully adjusted model: OR (95% CI)tertile3vs.1: 0.68 (0.54–0.85), P for trend = 0.001]. However, a favorable association between NAFDL and diet quality (HEI 2015) is more pronounced in participants with abdominal obesity [fully adjusted model: OR (95% CI)tertile3vs.1: 0.63 (0.41–0.98), P for trend = 0.03]. Based on the gender-stratified path analysis, diet quality indirectly through Waist-to-Height Ratio (WHtR), C-reactive protein (CRP), and metabolic syndrome in women, and men through WHtR, hemoglobin A1c (HBA1c), CRP, and metabolic syndrome affects NAFLD. Nutrient density directly and indirectly in women through WHtR, CRP, and metabolic syndrome, and in men indirectly through WHtR, hemoglobin A1c, and metabolic syndrome negatively affect NAFLD. Hence, in these subjects; we can provide early dietary intervention and education to prevent progression to NAFLD.

Abstract Given the global high prevalence of MASLD and its poor CVD prognosis, it is essential to perform risk stratification for MASLD patients. The specific impact of High Sensitivity Troponins (hs-cTn ) on mortality in MASLD patients remains unexplored. The NHANES databases from 1999 to 2004, which include data on high-sensitivity cardiac troponin (hs-cTn) levels and comorbidities, were linked with the most recent mortality dataset. Myocardial injury was determined using the 99th upper reference limits (URL) for hs-cTn. Our study included 3460 MASLD patients. The mean follow-up duration was 192 months, during which 1074 (23%) MASLD participants died from all-cause mortality, and 363 (7.3%) died from CVD mortality. Our findings indicate that MASLD patients with elevated levels of hs-cTnT (> 99th URL) exhibit increased risks of all-cause mortality [adjusted hazard ratio (aHR) = 1.93] and CVD mortality (aHR = 2.4). Similar results were observed for hs-cTnI, where the aHRs for all-cause mortality and CVD mortality were 2.03 and 2.97, respectively. Furthermore, we identified a nonlinear dose-response relationship between hs-cTn levels and the risk of mortality (P for nonlinearity

Abstract Background There is a contradiction in the use of microbiota-therapies, including probiotics, prebiotics, and synbiotics, to improve the condition of patients with nonalcoholic fatty liver disease (NAFLD). The aim of this review was to evaluate the effect of microbiota-therapy on liver injury, inflammation, and lipid levels in individuals with NAFLD. Methods Using Pubmed, Embase, Cochrane Library, and Web of Science databases were searched for articles on the use of prebiotic, probiotic, or synbiotic for the treatment of patients with NAFLD up to March 2024. Results Thirty-four studies involving 12,682 individuals were included. Meta-analysis indicated that probiotic, prebiotic, and synbiotic supplementation significantly improved liver injury (hepatic fibrosis, SMD = -0.31; 95% CI: -0.53, -0.09; aspartate aminotransferase, SMD = -0.35; 95% CI: -0.55, -0.15; alanine aminotransferase, SMD = -0.48; 95% CI: -0.71, -0.25; alkaline phosphatase, SMD = -0.81; 95% CI: -1.55, -0.08), lipid profiles (triglycerides, SMD = -0.22; 95% CI: -0.43, -0.02), and inflammatory factors (high-density lipoprotein, SMD = -0.47; 95% CI: -0.88, -0.06; tumour necrosis factor alpha, SMD = -0.86 95% CI: -1.56, -0.56). Conclusion Overall, supplementation with probiotic, prebiotic, or synbiotic had a positive effect on reducing liver enzymes, lipid profiles, and inflammatory cytokines in patients with NAFLD.

Xuebing Zhang,1 Lianjie Wang,1 Ge Wang,1 Jiayue Li,1 Yiming Mu,2 Shidong Wang,1 Xiaoran Li1 1Department of Endocrinology, Dongzhimen Hospital Beijing University of Chinese Medicine, Beijing 100700, People’s Republic of China; 2Department of Endocrinology, First Medical Centre of Chinese PLA General Hospital, Beijing 100853, People’s Republic of ChinaCorrespondence: Shidong Wang; Xiaoran Li, Email A2082@bucm.edu.cn; 466187309@qq.comBackground: Nonalcoholic fatty liver disease (NAFLD) has become a major global health burden, which increases the risk of extra-hepatic complications such as type 2 diabetes mellitus (T2DM), dyslipidemia, metabolic syndrome (MetS), and cardiovascular disease (CVD). However, NAFLD remains underappreciated and underdiagnosed. Our study aimed to explore the prevalence of NAFLD and the association between NAFLD and CVD events among adults aged 40 and older in Northern China.Methods: This study was conducted in the Shijingshan district of Beijing, China from November 2011 to August 2012. A total of 18891 subjects were recruited in the study. The information including demographical information, lifestyle, previous history of diabetes, hypertension, dyslipidemia, CVD, and liver disease were gathered. Data on physical examination, blood lipid profile, fasting blood glucose, and 2-hour blood glucose were recorded. Determination of MetS was according to T2DM guideline of Chinese Diabetes Society (2020 edition). The association between CVD and NAFLD was evaluated by multivariate logistic regression.Results: The prevalence of NAFLD was 15.2%. After adjustment for age, smoking status, alcohol intake, WC, hypertension, dyslipidemia and hyperglycemia, the odds ratios (ORs) of CVD in men were 1.622 (95%CI: 1.345– 1.957) and 1.990 (95%CI: 1.709– 2.316) in women with NAFLD, compared with the subjects without NAFLD.Conclusions: NAFLD is independently associated with increased risk of CVD development.Keywords: nonalcoholic fatty liver disease, metabolic syndrome, cardiovascular disease, middle-aged and elderly, Chinese

Abstract Background We aimed to investigate the post-cessation T2DM risk in male NAFLD and NAFLD-free smokers in a 7-year cohort study. Methods The study population was male adults who underwent annual health checkups in a 7-year cohort study. Recent quitters were categorized into four groups based on their weight gain during follow-up:

Abstract Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, and it is characterized by a series of fatty liver diseases that can lead to severe liver disease. Although no therapeutic drug has been approved as an effective therapy for NAFLD to date, dietary changes and physical activity are thought to be the cornerstone of NAFLD management. For this reason, some articles are available to analyze the studies done so far using various modifications of intermittent fasting (IF) among animals and patients with NAFLD. Data from preclinical and clinical trials suggested that IF positively impacts inflammatory and metabolic markers in both animals and humans. Inflammation and oxidative stress are the major risk factors involved in the pathogenesis of NAFLD. IF has been shown to have positive benefits in alleviating metabolic disorders, promoting the browning of white tissue, resetting circadian rhythm, and activating autophagy of cells. This review is intended to provide a detailed synopsis of the protocols, potential mechanisms of action, and supporting evidence for IF in NAFLD. We will highlight what is currently known about IF approaches in NAFLD treatments in clinical populations with mechanism insight from animal studies, and the safety concerns in certain patient groups. Graphical Abstract The protocols of intermittent fasting (IF) are various. Data from trials suggested that IF positively impacts both humans and animals. IF has been shown to have potential treatments for nonalcoholic fatty liver disease.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver ailment worldwide, in which nonpharmacological strategies have a considerable role in the treatment. Probiotic supplementation as well as physical exercise can improve cardiometabolic parameters, but further research is needed to determine the effects of combined treatment versus exercise alone in managing NAFLD-associated biomarkers, primarily liver enzymes, lipid markers, and insulin resistance. Objectives This systematic review and meta-analysis aimed to evaluate the effects of probiotic supplementation, combined with exercise versus exercise alone, on liver enzymes and cardiometabolic markers in patients with NAFLD. Methods A systematic review and meta-analysis of randomized clinical trials was performed by searching PubMed, Scopus, and Web of Science databases up to April 2024. The search was restricted to articles published in the English language and human studies. Random effects models were used to calculate weighted mean differences (WMD). Results Pooled estimates (9 studies, 615 patients, intervention durations ranging from 8 to 48 weeks) revealed that probiotics plus exercise decreased aspartate transaminase (AST) [WMD=-5.64 U/L, p = 0.02], gamma-glutamyl transferase (GGT) [WMD=-7.09 U/L, p = 0.004], low-density lipoprotein (LDL) [WMD=-8.98 mg/dL, p = 0.03], total cholesterol (TC) [WMD=-16.97 mg/dL, p = 0.01], and homeostatic model assessment for insulin resistance (HOMA-IR) [WMD=-0.94, p = 0.005] significantly more than exercise only. However, probiotics plus exercise did not significantly change high-density lipoprotein (HDL) [WMD = 0.07 mg/dL, p = 0.9], fasting insulin [WMD=-1.47 µIU/mL, p = 0.4] or fasting blood glucose (FBG) [WMD=-1.57 mg/dL, p = 0.3] compared with exercise only. While not statistically significant, there were clinically relevant reductions in alanine aminotransferase (ALT) [WMD=-6.78 U/L, p = 0.1], triglycerides (TG) [WMD=-21.84 mg/dL, p = 0.1], and body weight (BW) [WMD=-1.45 kg, p = 0.5] for probiotics plus exercise compared with exercise only. The included studies exhibited significant heterogeneity for AST (I2 = 78.99%, p = 0.001), GGT (I2 = 73.87%, p = 0.004), LDL (I2 = 62.78%, p = 0.02), TC (I2 = 72.41%, p = 0.003), HOMA-IR (I2 = 93.86%, p = 0.001), HDL (I2 = 0.00%, p = 0.9), FBG (I2 = 66.30%, p = 0.01), ALT (I2 = 88.08%, p = 0.001), and TG (I2 = 85.46%, p = 0.001). There was no significant heterogeneity among the included studies for BW (I2 = 0.00%, p = 0.9). Conclusion Probiotic supplementation combined with exercise training elicited better results compared to exercise alone on liver enzymes, lipid profile, and insulin resistance in patients with NAFLD. Systematic Review Registration PROSPERO registration number CRD42023424290.

Abstract Background Although gut microbiota and serum metabolite composition have been observed to be altered in patients with non-alcoholic fatty liver disease (NAFLD), previous observational studies have demonstrated inconsistent results. As this may be influenced by factors such as confounders and reverse causality, we used Mendelian randomization to clarify the causal effect of gut microbiota and blood metabolites on NAFLD. Methods In this research, we performed a two-step Mendelian randomization analysis by utilizing genome-wide association study (GWAS) data obtained from MiBioGen and UK Biobank. To mitigate potential errors, we employed False Discovery Rate (FDR) correction and linkage unbalanced regression (LDSC) analysis. Sensitivity analyses including cML-MA and bidirectional Mendelian randomization were performed to ensure the robustness of the results. Results In this study, a total of nine gut microbiota and seven metabolites were found to be significantly associated with NAFLD. MR analysis of the above findings revealed a causal relationship between Ruminococcus2 and cysteine-glutathione disulfide (OR = 1.17, 95%CI = 1.006–1.369, P = 0.041), as well as 3-indoleglyoxylic acid (OR = 1.18, 95%CI = 1.011–1.370, P = 0.036). For each incremental standard deviation in Ruminococcus2 abundance, there was a corresponding 26% reduction in NAFLD risk (OR = 0.74, 95%CI = 0.61–0.89, P = 0.0012), accompanied by a 17% increase in cysteine-glutathione disulfide levels (OR = 1.17, 95%CI = 1.01–1.37, P = 0.041) and an 18% increase in 3-indoleglyoxylic acid levels (OR = 1.18, 95%CI = 0.81-1.00, P = 0.036). The proportion mediated by cysteine-glutathione disulfide is 11.2%, while the proportion mediated by 3-indoleglyoxylic acid is 7.5%. Conclusion Our study suggests that increased abundance of specific gut microbiota may reduce the risk of developing NAFLD, and this relationship could potentially be mediated through blood metabolites.

Abstract The primary catalyst for nonalcoholic fatty liver disease (NAFLD) is widely recognized as the induction of lipotoxicity in hepatocytes by an excess of fatty acids. In China, Penthorum chinense Pursh (PcP) is commonly employed as a functional food due to its known hepatoprotective properties. The present study aimed to investigate the influence of PcP extract on in vivo and in vitro models of NAFLD. We found that PcP extract can attenuate palmitic acid (PA)‐induced lipotoxicity in HepG2 cells. PA was observed to trigger pyroptosis, as indicated by the increased expression of NLRP3 and GSDMD/N, activation of Caspase‐1, and subsequent release of IL‐1β and IL‐18. However, these changes were reversed after PcP was administered. Furthermore, the application of an NLRP3 agonist inhibited the protective effects of PcP on lipotoxicity, indicating that PcP decreased lipotoxicity by inhibiting the NLRP3/Caspase‐1/GSDMD pathway. Ultimately, we established a rat model of NAFLD through the administration of a high‐fat diet (HFD), followed by the oral delivery of PcP extracts. The results demonstrated that the administration of PcP extract effectively decreased dyslipidemia and hepatic steatosis, which coincided with a decrease in hepatic pyroptosis through modulation of the NLRP3/Caspase‐1/GSDMD pathway in liver tissues. Overall, our findings provide insight into the mechanism by which PcP extracts alleviate hepatic steatosis, highlighting the potential significance of modulating the NLRP3/Caspase‐1/GSDMD pathway in the context of pyroptosis.

Abstract Chronic liver diseases (CLD) affect 1.5 billion patients worldwide, with dramatically increasing incidence in recent decades. It has been hypothesized that the chronic hyperinflammation associated with CLD may increase the risk of a more severe course of acute pancreatitis (AP). This study aims to investigate the underlying impact of CLD on the outcomes of AP. A systematic search was conducted in Embase, Medline, and Central databases until October 2022. Studies investigating patients with acute pancreatitis and CLD, were included in the meta-analysis. A total of 14,963 articles were screened, of which 36 were eligible to be included. CLD was a risk factor for increased mortality with an odds ratio (OR) of 2.53 (CI 1.30 to 4.93, p = 0.01). Furthermore, renal, cardiac, and respiratory failures were more common in the CLD group, with ORs of 1.92 (CI 1.3 to 2.83, p = 0.01), 2.11 (CI 0.93 to 4.77, p = 0.062) and 1.99 (CI 1.08 to 3.65, p = 0.033), respectively. Moreover, the likelihood of developing Systemic Inflammatory Response Syndrome (SIRS) was significantly higher, with an OR of 1.95 (CI 1.03 to 3.68, p = 0.042). CLD is an important risk factor for worse outcomes in AP pancreatitis, leading to higher mortality and increased rates of local and systemic complications.

Abstract Background The molecular mechanisms underlying nonalcoholic fatty liver disease (NAFLD) remain to be fully elucidated. Ubiquitin specific protease 13 (USP13) is a critical participant in inflammation-related signaling pathways, which are linked to NAFLD. Herein, the roles of USP13 in NAFLD and the underlying mechanisms were investigated. Methods L02 cells and mouse primary hepatocytes were subjected to free fatty acid (FFA) to establish an in vitro model reflective of NAFLD. To prepare in vivo model of NAFLD, mice fed a high-fat diet (HFD) for 16 weeks and leptin-deficient (ob/ob) mice were used. USP13 overexpression and knockout (KO) strategies were employed to study the function of USP13 in NAFLD in mice. Results The expression of USP13 was markedly decreased in both in vitro and in vivo models of NAFLD. USP13 overexpression evidently inhibited lipid accumulation and inflammation in FFA-treated L02 cells in vitro. Consistently, the in vivo experiments showed that USP13 overexpression ameliorated hepatic steatosis and metabolic disorders in HFD-fed mice, while its deficiency led to contrary outcomes. Additionally, inflammation was similarly attenuated by USP13 overexpression and aggravated by its deficiency in HFD-fed mice. Notably, overexpressing of USP13 also markedly alleviated hepatic steatosis and inflammation in ob/ob mice. Mechanistically, USP13 bound to transforming growth factor β-activated kinase 1 (TAK1) and inhibited K63 ubiquitination and phosphorylation of TAK1, thereby dampening downstream inflammatory pathways and promoting insulin signaling pathways. Inhibition of TAK1 activation reversed the exacerbation of NAFLD caused by USP13 deficiency in mice. Conclusions Our findings indicate the protective role of USP13 in NAFLD progression through its interaction with TAK1 and inhibition the ubiquitination and phosphorylation of TAK1. Targeting the USP13-TAK1 axis emerges as a promising therapeutic strategy for NAFLD treatment.

Abstract Theabrownin (TB), which is derived from Pu‐erh tea and previously recognized as an intestinal farnesoid X receptor (FXR) antagonist, is known to have favorable effects on metabolic diseases such as hyperlipidemia and obesity. However, the mechanisms underlying the beneficial effects of TB in nonalcoholic fatty liver disease (NAFLD) require further exploration. This study aimed to use an NAFLD mouse model to evaluate changes in hepatic steatosis via the intestinal FXR–ceramide (Cer) axis following treatment with TB. The results indicated that TB alleviated hepatic steatosis and reduced total Cer levels in NAFLD mice. In particular, the levels of Cer(d18:1/16:0) in the intestine and liver were significantly reduced, which is considered to play a vital role in aggravating NAFLD. Furthermore, the transcriptional expression of Cer synthetase was markedly downregulated following treatment with TB or FXR antagonist, but this expression was reversed following treatment with a specific intestinal FXR agonist. These results indicate that TB alleviates NAFLD by reducing Cer levels via the inhibition of the intestinal FXR–Cer synthetase pathway.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a significant health issue. Emerging research has focused on the role of the gut microbiota in NAFLD, emphasizing the gut-liver axis. This study aimed to identify key research trends and guide future investigations in this evolving area. Methods This bibliometric study utilized Scopus to analyze global research on the link between the gut microbiota and NAFLD. The method involved a search strategy focusing on relevant keywords in article titles, refined by including only peer-reviewed journal articles. The data analysis included bibliometric indicators such as publication counts and trends, which were visualized using VOSviewer software version 1.6.20 for network and co-occurrence analysis, highlighting key research clusters and emerging topics. Results Among the 479 publications on the gut microbiota and NAFLD, the majority were original articles (n = 338; 70.56%), followed by reviews (n = 119; 24.84%). The annual publication count increased from 1 in 2010 to 118 in 2022, with a significant growth phase starting in 2017 (R2 = 0.9025, p

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. NAFLD leads to liver fibrosis and hepatocellular carcinoma, and it also has systemic effects associated with metabolic diseases, cardiovascular diseases, chronic kidney disease, and malignant tumors. Therefore, it is important to diagnose NAFLD early to prevent these adverse effects. Methods The GSE89632 dataset was downloaded from the Gene Expression Omnibus database, and then the optimal genes were screened from the data cohort using lasso and Support Vector Machine Recursive Feature Elimination (SVM-RFE). The ROC values of the optimal genes for the diagnosis of NAFLD were calculated. The relationship between optimal genes and immune cells was determined using the DECONVOLUTION algorithm CIBERSORT. Finally, the specificity and sensitivity of the diagnostic genes were verified by detecting the expression of the diagnostic genes in blood samples from 320 NAFLD patients and liver samples from 12 mice. Results Through machine learning we identified FOSB, GPAT3, RGCC and RNF43 were the key diagnostic genes for NAFLD, and they were further demonstrated by a receiver operating characteristic curve analysis. We found that the combined diagnosis of the four genes identified NAFLD samples well from normal samples (AUC = 0.997). FOSB, GPAT3, RGCC and RNF43 were strongly associated with immune cell infiltration. We also experimentally examined the expression of these genes in NAFLD patients and NAFLD mice, and the results showed that these genes are highly specific and sensitive. Conclusions Data from both clinical and animal studies demonstrate the high sensitivity, specificity and safety of FOSB, GPAT3, RGCC and RNF43 for the diagnosis of NAFLD. The relationship between diagnostic key genes and immune cell infiltration may help to understand the development of NAFLD. The study was reviewed and approved by Ethics Committee of Tianjin Second People’s Hospital in 2021 (ChiCTR1900024415).

BackgroundNonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are independent risk factors for cardiovascular disease (CVD).AimsTo examine the clinical utility of liver fat quantification for determining CVD risk among a well-phenotyped cohort of patients with T2DM.MethodsThis was a cross-sectional analysis of a prospective cohort of adults aged ≥50 with T2DM. Liver fat was quantified with magnetic resonance imaging proton-density-fat-fraction (MRI-PDFF), an advanced imaging-based biomarker. Patients were stratified into a higher liver fat group (MRI-PDFF ≥ 14.6%), and a lower liver fat group (MRI-PDFF

Despite many recent studies on non-alcoholic fatty liver disease (NAFLD) therapeutics, the optimal treatment has yet to be determined. In this unfinished project, we combined secondary metabolites (SMs) from the gut microbiota (GM) and Hordeum vulgare (HV) to investigate their combinatorial effects via network pharmacology (NP). Additionally, we analyzed GM or barley – signalling pathways – targets – metabolites (GBSTMs) in combinatorial perspectives (HV, and GM). A total of 31 key targets were analysed via a protein-protein interaction (PPI) network, and JUN was identified as the uppermost target in NAFLD. On a bubble plot, we revealed that apelin signalling pathway, which had the lowest enrichment factor antagonize NAFLD. Holistically, we scrutinized GBSTM to identify key components (GM, signalling pathways, targets, and metabolites) associated with the Apelin signalling pathway. Consequently, we found that the primary GMs (Eubacterium limosum, Eggerthella sp. SDG-2, Alistipes indistinctus YIT 12060, Odoribacter laneus YIT 12061, Paraprevotella clara YIT 11840, Paraprevotella xylaniphila YIT 11841) to ameliorate NAFLD. The molecular docking test (MDT) suggested that tryptanthrin-JUN is an agonist, conversely, dihydroglycitein-HDAC5, 1,3-diphenylpropan-2-ol-NOS1, and (10[(Acetyloxy)methyl]-9-anthryl)methyl acetate-NOS2, which are antagonistic conformers in the apelin signalling pathway. Overall, these results suggest that combination therapy could be an effective strategy for treating NAFLD.

Background Nonalcoholic fatty liver disease (NAFLD) is a common digestive system disease, which is often diagnosed by imaging methods in clinical work. At present, there is a lack of research on the effectiveness evaluation of imaging diagnostic methods with histology as the gold standard. Objective To study the consistency of imaging and histological diagnosis of NAFLD, and to analyze the influencing factors of gallstone disease (GD) complicated with NAFLD. Methods From January 2021 to July 2022, 53 patients with GD who underwent simple cholecystectomy and liver biopsy were selected from the Department of Hepatobiliary surgery, Nanjing Hospital affiliated to Nanjing University of traditional Chinese Medicine. The demographic characteristics, BMI, systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the subjects were collected, and the laboratory indexes, imaging and histological results were collected. The consistency of imaging and histological diagnosis of NAFLD was evaluated by Kappa consistency test. According to the histological diagnostic criteria, the subjects were divided into NAFLD group (n=15) and non-NAFLD group (n=38). Multivariate Logistic regression analysis was used to explore the influencing factors of NAFLD in patients with GD. Results The imaging detection rate of NAFLD in GD patients was 20.7% (11/53), which was lower than that of histology (28.3%) (15/53) (Kappa=0.404, P=0.001). The sensitivity of imaging diagnosis was 60.0% (9/15), the specificity was 94.7% (36/38), and the rate of missed diagnosis was 40.0% (6/15). There were 8 cases of nonalcoholic fatty liver (NAFL), 7 cases of nonalcoholic steatohepatitis (NASH) and no NASH associated cirrhosis in 15 patients with histological manifestation of NAFLD. The proportion of fibrosis in the NASH group was higher than that in the NAFL group. There were significant differences in the levels of BMI, SBP, fasting blood glucose (FPG) and aspartate aminotransferase (AST) between NAFLD group and non-NAFLD group (P