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Background: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing with obesity, and it is believed that the ongoing low-grade inflammation in obesity and alterations in the enterohepatic axis contributing this process. This study aimed to determine the role of fecal calprotectin (FC) as inflammatory biomarker in obesity and NAFLD., Methods: Between November 2022-August 2023, 31 obese and 10 healthy adolescents aged between 10 and 18 years enrolled in this prospective controlled study. Body mass index higher than 2 standard deviation is considered as obesity. Obese adolescents were divided into two subgroups: obese adolescents (n = 11) and Obese + NAFLD group (n = 20). NAFLD diagnosis was made with biochemical analysis or ultrasonography. FC levels and laboratory parameters analyzed in study group, while only FC samples taken from control group. Anthropometric and laboratory parameters were compared between groups. This study was registered in ClinicalTrials.gov (NCT06229184)., Results: The median (IQR P25-75) FC levels in the obese + NAFLD, obese and the healthy controls were 136.23 (43.36-332.04), 61.77 (29.70-285.92) and 38.95 (27.59-50.52) µg/g feces, respectively (p = 0.018). Subgroup analyses revealed that the significant difference was between the obese + NAFLD group and the control group (p = 0.02), while no significant differences were observed between the control and obese groups, or between the obese and obese + NAFLD groups. FC positivity rates were 20% (n = 2) in the control group, 54.5% (n = 6) in the obese group, and 75% (n = 15) in the Obese + NAFLD group (p = 0.018)., Conclusions: FC is significantly higher in obese adolescents compared to healthy peers, but no significant difference was observed between obese and obese + NAFLD groups. Further studies needed on this subject., Trial Registration: This trial is registered in ClinicalTrials.gov (Trial registration number [ClinicalTrials.gov ID] NCT06229184)., Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted under the Helsinki Declaration and approved by the local institutional review board. All participants were informed about the study and written informed consent was obtained. Consent to publish: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

With the global epidemic trend of obesity, non-alcoholic fatty liver disease (NAFLD) has become a significant cause of chronic liver disease, seriously affecting human health. Medium-chain triglycerides (MCT) with a fatty acid chain length varying between 6 and 10 carbon atoms (most sources from coconut and palm kernel oils), which exhibited activities to improve lipid metabolism, prevent cardiovascular diseases, and enhance immunity. However, the efficacy differences and potential mechanisms between MCT and traditional long-chain vegetable oils (palm oil, PA; high oleic peanut oil, OA) in obesity-induced NAFLD were still unclear. The present study treated obesity-induced NAFLD mice with different dietary lipids for 16 weeks. The results showed that MCT supplements significantly improved abnormal elevation of weight gain and blood lipids and reduced hepatic lipid accumulation to a greater extent than PA and OA. Furthermore, bile acid profiling results indicated that MCT significantly changed the composition of bile acids in the liver, reduced the concentrations of cholic acid (CA), deoxycholic acid (DCA), β-muricholic acid (β-MCA), and ursodeoxycholic acid (UDCA) and increased the concentrations of chenodeoxycholic Acid (CDCA), taurochenodeoxycholic acid （TCDCA), hyodeoxycholic acid (HDCA), and taurohyodeoxycholic acid (THDCA). Mechanistically, MCT supplement upregulated FXR signal and inhibited the expression of key genes for triglyceride synthesis in the liver, thereby reducing hepatic lipid accumulation. In summary, MCT exerted a superior effect on PA and OA in improving obesity-induced NAFLD. These results provided new evidence for the application of MCT in treating NAFLD., (© 2024 Institute of Food Technologists.)

Background: Pediatric non-alcoholic fatty liver disease (NAFLD) is a chronic steatosis of the liver associated with energy metabolism in children and adolescents, failure to intervene promptly can elevate the risk of developing hepatocellular carcinoma. Therefore, this study aimed to understand the underlying mechanism of pediatric NAFLD and investigate potential biomarkers and therapeutic targets., Methods: We investigated genes using the GSE185051 data set related to energy metabolism from the GeneCards database, constructed protein-protein interaction network, identified hub genes and established networks representing interactions between these hub genes and miRNA, RNA-binding proteins, transcription factors, and drugs. Subsequently, we performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis, Gene Set Enrichment Analysis (GSEA), and immune infiltration analysis., Results: Our analysis identified 9 hub genes through the PPI network. The target molecules were identified through the interaction network between hub genes and miRNAs, RNA-binding proteins, transcription factors, and drugs. GO analysis revealed that hub genes were associated with oxidative stress responses and other pathways. KEGG analysis highlighted their involvement in pathways such as insulin resistance, among others. GSEA revealed that hub genes were highly enriched in pathways related to Omega-9 fatty acid synthesis, among others. Immune infiltration analysis suggested that mast cells and T follicular helper cells play significant roles in the pathogenesis of NAFLD., Conclusion: We identified the hub genes in pediatric NAFLD closely related to energy metabolism. These findings offer the potential for identifying potential novel diagnostic biomarkers, and establishing therapeutic targets for pediatric NAFLD., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no competing interests. Ethical approval: This study does not contain any studies with human participants or animals performed by any of the authors., (© 2024. The Author(s).)

Background and Aim: This study aimed to investigate the relationship between advanced lung cancer inflammation index (ALI) and non-alcoholic fatty liver disease (NAFLD) and advanced liver fibrosis (AF)., Methods: A total of 5642 individuals from the National Health and Nutrition Examination Survey (NHANES) between 2017 and 2020 were examined. Limited cubic spline regression model, and weighted logistic regression were employed to determine if ALI levels were related to the prevalence of NAFLD and AF. Additionally, a mediating analysis was conducted to investigate the role of lipid biomarkers, such as total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), in the effects of ALI on the prevalence of NAFLD and AF., Results: After adjusting for potential confounders, a significant positive association was found between ALI with NAFLD and AF prevalence. Compared with those in ALI Tertile 1, participants in Tertile 3 had higher odds of NAFLD prevalence (odds ratio [OR]: 3.16; 95% confidence interval [CI]: 2.52-3.97) and AF (OR: 3.17; 95% CI: 2.30-4.36). Participants in both Tertile 2 and Tertile 3 had lower odds of developing AF (P for trend = 0.005). Moreover, we discovered a nonlinear association between ALI and NAFLD. An inflection point of 74.25 for NAFLD was identified through a two-segment linear regression model. Moreover, TC and HDL-C levels mediated the association between ALI and NAFLD by 10.2% and 4.2%, respectively (both P < 0.001)., Conclusion: Our findings suggest that higher ALI levels are positively associated with an increased prevalence of NAFLD and AF, partly mediated by lipid biomarkers., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The relationship between depression and severe non-alcoholic fatty liver disease (NAFLD) has not been clearly defined. We conducted a longitudinal cohort study and a two-sample Mendelian randomization (MR) analysis to assess the association of depression with severe NAFLD risk. We used individual data from the UK Biobank study with 481,181 participants, and summary data from published genome-wide association studies. The association between depression and severe NAFLD was assessed using Cox proportional hazards regression analysis. Two-sample MR for depression with NAFLD was conducted, the principal analysis employed the inverse variance weighted (IVW) approach. In the observational study, after a median follow-up of 13.46 years, 4,563 participants had severe NAFLD. In multivariable-adjusted model, participants with depression had an increased risk of severe NAFLD (hazards ratio:1.21, 95% confidence interval (CI):1.09-1.34), as compared to those without depression. In subgroup analyses, the association between depression and severe NAFLD risk was generally observed across different subgroups. For the MR, result also showed that genetically predicted depression was causally associated with a higher risk of NAFLD (odds ratio:1.55, 95%CI:1.10-2.19) in IVW. Our study revealed a prospective association of depression with severe NAFLD, thus potentially necessitating clinical monitoring of individuals with depression for severe NAFLD., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethical approval The UK Biobank study has approval from the North West Multi-centre Research Ethics Committee, all methods were performed in accordance with the relevant guidelines and regulations, and all participants provided written informed consent. As our MR study was based on publicly available data, no additional ethical approval or consent was required., (© 2024. The Author(s).)

Non-alcoholic fatty liver disease (NAFLD), a metabolic-associated fatty liver disease, has become the most common chronic liver disease worldwide. Recently, the discovery of cuproptosis, a newly identified mode of cell death, further highlighted the importance of copper in maintaining metabolic homeostasis. An increasing number of studies have confirmed that liver copper metabolism is closely related to the pathogenesis of NAFLD. However, the relationship between NAFLD and copper metabolism, especially cuproptosis, remains unclear. In this review, we aim to summarize the current understanding of copper metabolism and its dysregulation, particularly the role of copper metabolism dysregulation in the pathogenesis of NAFLD. More importantly, this review emphasizes potential gene-targeted therapeutic strategies, challenges and the future of cuproptosis-related genes in the treatment of NAFLD. This review aims to provide innovative therapeutic strategies for NAFLD., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Dietary interventions and increased physical activity are the cornerstones for management of the paediatric non-alcoholic fatty liver disease (NAFLD). Though, no specific diet has been proven superior, Indo-Mediterranean diet (IMD) has shown promise in adult literature. Thus, we aimed to compare the effect of IMD and a standard calorie-restricted diet (CRD) in Indian overweight children and adolescents with biopsy-proven NAFLD., Methods: Thirty-nine consecutive biopsy-proven NAFLD children between the ages of 8 and 18 years were randomized into either IMD or CRD for 180 days, and various parameters were evaluated at baseline and then after 180 days (NCT05073588)., Results: A total of 34 subjects (18 in IMD and 16 in CRD group) completed the study. There was a significantly higher decrease in controlled attenuation parameter (CAP) values (as a marker of hepatic steatosis; on transient elastography) (95% CI: 4.2-73.4, p = 0.042), weight (95% CI: 0.75-5.5, p = 0.046) and body mass index (BMI) (95% CI: 0.21-2.05, p = 0.014) (but not in Pediatric NAFLD Fibrosis Index or PNFI; as a marker of hepatic fibrosis) in IMD group compared to the CRD group. Liver stiffness measurement, serum cholesterol and low-density lipoprotein levels and HOMA-IR decreased only in the IMD group (p < 0.001). Our statistical model showed that delta-Weight was the only independent variable associated with delta-CAP., Conclusion: Both IMD and CRD can improve the various anthropometric, clinical, imaging and biochemical parameters but IMD was superior to CRD in terms of reducing CAP values and weight/BMI over 180 days in overweight/obese NAFLD children., (© 2024 World Obesity Federation.)

The global incidence of pediatric non-alcoholic fatty liver disease (NAFLD) is rising, and it is linked to various potentially dangerous complications such as cardiovascular complications, particularly atrial fibrillation (AF). Atrial electromechanical conduction delay (EMD) has been reported as an early predictor for AF development. This study aimed to explore the link between NAFLD and the increased risk of AF development. This cross-sectional study was performed on 100 newly diagnosed NAFLD children (aged 14-18 years) as the patient group and 100 healthy individuals as a control group. Transthoracic echocardiography and simultaneous electrocardiography (ECG) recording were employed to estimate atrial electromechanical properties. EMD values were calculated for the inter-atrial, left intra-atrial, and right intra-atrial. Our results showed that pediatric patients with NAFLD exhibited significantly prolonged EMD values in the left and right intra-atrial as well as in inter-atrial regions compared to the control group (P = 0.03, P < 0.001, P < 0.01, respectively). Conclusion: Children with NAFLD show atrial electromechanical alterations that may presage AF in adulthood., (© 2024. The Author(s).)

Aim: This study aimed to investigate the mechanisms through which diosgenin inhibits the pathogenesis of non-alcoholic fatty liver disease, focusing particularly on ferroptosis-related pathways and its reliance on nuclear factor erythroid 2-related factor 2., Materials and Methods: Using a rat model, we showed diosgenin's efficacy in reducing lipid deposition throughout the body and examined its impact on ferroptosis-related gene expression in vivo. Moreover, in vitro experiments using human hepatocellular liver carcinoma cell line cells were conducted to assess oxidative stress and ferroptosis levels., Results: Diosgenin decreased lipid accumulation and steatosis; lowered serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, glutamic pyruvic transaminase and glutamic oxaloacetic transaminase; reduced interleukin-1β and tumour necrosis factor-α; diosgenin decreased malondialdehyde levels; and increased serum superoxide dismutase levels in a rat model of high-fat diet-induced non-alcoholic fatty liver disease. Diosgenin upregulated the expression of nuclear factor erythroid 2-related factor 2 and its downstream ferroptosis-related genes to inhibit ferroptosis in the livers of rats with non-alcoholic fatty liver disease. Diosgenin decreased reactive oxygen species levels and enhanced the expression of ferroptosis-related genes in human hepatocellular liver carcinoma cells induced by free fatty acids, with its effects being dependent on nuclear factor erythroid 2-related factor 2., Conclusions: This study highlights the potential of diosgenin from Dioscoreaceae plants in mitigating oxidative stress and ferroptosis levels through nuclear factor erythroid 2-related factor 2 regulation, offering novel insights into the treatment of non-alcoholic fatty liver disease and other metabolic disorders through traditional Chinese medicine., (© 2024 John Wiley & Sons Ltd.)

Purpose: To evaluate comprehensive bone health among young Indian women, including bone mass, microarchitecture, and turnover, in relation to their non-alcoholic fatty liver disease (NAFLD) status., Methods: This cross-sectional study (May 2018-November 2019) recruited women with a history of gestational diabetes mellitus (GDM) and normoglycemia in their index pregnancy, who were at least 6 months postpartum. All participants underwent abdominal ultrasonography for determination of NAFLD status (grades 2 and 3: severe NAFLD) and transient elastography (FibroScan) for hepatic fibrosis (LSM >6 kPa). Bone mass was assessed by DXA, bone microarchitecture with trabecular bone score {TBS} (low TBS ≤ 1.310) and bone turnover with markers of bone formation (osteocalcin and P1NP), and resorption (CTX)., Results: Bone mineral density (BMD) at femoral neck (p = 0.026) and total hip (p = 0.007) was significantly higher among women with NAFLD (n = 170) compared to those without (n = 124). There was no significant difference in bone turnover markers between the two groups. The presence of NAFLD [adjusted OR: 1.82 (1.07, 3.11)] was associated with low TBS, with a greater strength of association among women with severe NAFLD [adjusted OR: 2.97 (1.12, 7.88)]. However, these associations were attenuated and no longer significant after additionally adjusting for BMI. Women with NAFLD and hepatic fibrosis manifested significantly higher BMD at lumbar spine, femoral neck, and total hip (p < 0.001 for all) and significantly lower bone turnover markers (osteocalcin, p = 0.009 and CTX, p = 0.029), however, the association with low TBS was not observed., Conclusion: Among young Indian women, NAFLD is associated with increased bone mass and impaired bone microarchitecture, and hepatic fibrosis with increased bone mass and reduced bone turnover., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This study aimed to elucidate the mechanism of oleuropein (OLE) ameliorates non-alcoholic fatty liver disease (NAFLD) and its underlying mechanisms., Results: Male C57BL/6J mice were fed either a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.03% (w/w) OLE for 16 weeks. OLE supplementation decreased body weight and liver weight, improved serum lipid profiles, and ameliorated HFD-induced hepatic dysfunction. Liver metabolomics analysis revealed that OLE increased the levels of nicotinamide, tauroursodeoxycholic acid, taurine, and docosahexaenoic acid, which were beneficial for lipid homeostasis and inflammation regulation. OLE exerted its protective effects by activating peroxisome proliferator-activated receptor alpha (PPARα), a key transcription factor that regulates fibroblast growth factor 21 (FGF21) expression and modulates lipid oxidation, lipogenesis and inflammation pathways. Importantly, OLE supplementation did not significantly affect body weight or liver weight in PPARα knockout (PPARα KO) mice, indicating that PPARα is essential for OLE-mediated NAFLD prevention., Conclusion: Our results suggest that OLE alleviates NAFLD in mice by activating PPARα and modulating liver metabolites. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Non-alcoholic fatty liver disease (NAFLD) is a liver disease without approved treatment. Oxymatrine (OMT) has protective effects in various liver diseases. We aimed to investigate the roles and mechanisms of OMT in NAFLD. NAFLD models were established using high-fat and high-sucrose diet-fed rats and oleic acid (OA)-stimulated hepatocytes, respectively. Then, OMT was used to treat the NAFLD models, with metformin as a positive control. Liver damage, lipid accumulation and hepatic lipid profile of NAFLD rats were assessed. Peroxisome proliferator activated receptor alpha (PPARα), sirtuin 1 (Sirt1)/adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway- and fatty acid oxidation (acyl-CoA oxidase 1 and carnitine palmitoyltransferase 1A)-associated proteins were measured both in vivo and in vitro. Furthermore, hepatocytes were transfected with si-Sirt1 and oe-PPARα to verify the mechanisms of OMT in NAFLD. NAFLD rats supplemented with OMT displayed reduced liver damage and lipid accumulation. After OMT intervention, the liver lipid profile of NAFLD rats was changed greatly, most of the top differentially expressed lipid metabolites were triglyceride, moreover, diacylglycerol content was decreased in NAFLD rats. OMT activated the Sirt1/AMPK pathway and PPARα, and upregulated acyl-CoA oxidase 1 and carnitine palmitoyltransferase 1A expressions in NAFLD models. In vitro, OMT enhanced viability, and improved lipid accumulation in OA-stimulated hepatocytes. However, the protective functions of OMT in OA-exposed hepatocytes were offset by Sirt1 knockdown, while PPARα overexpression further counteracted the effects of Sirt1 knockdown. OMT could relieve NAFLD by promoting Sirt1/AMPK pathway- and PPARα-mediated hepatic fatty acid oxidation, indicating that OMT is a potential approach for NAFLD treatment., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Testosterone deficiency is linked to an increased prevalence of non-alcoholic fatty liver disease (NAFLD), although the mechanisms underlying this association are not fully understood. Ferroptosis, a regulated cell death pathway driven by iron-dependent lipid peroxidation, has been suggested to play a role in NAFLD pathogenesis. Since testosterone deficiency is associated with lipid disorders and iron deposition, we hepothesize that ferroptosis may be involved in the pathogenesis of diet-induced NAFLD exacerbated by testosterone deficiency., Methods: Apolipoprotein E (APOE -/- ) mice were subjected to sham surgery or bilateral castration and subsequently fed a high-fat diet for 16 weeks. Liver gene expression was analyzed using RNA sequencing. Additional assessments included blood analysis, histological staining, measurement of iron and antioxidant enzyme levels, quantitative real-time PCR, Western blotting, and electron microscopy. The effects of testosterone on ferroptosis induced by free fatty acids (FFAs) and Erastin were further investigated in HepG2 cells in vitro., Results: Testosterone deficiency resulted in increased hepatic lipid accumulation and macrovesicular steatosis in high-fat diet-fed APOE -/- mice, accompanied by hepatic inflammation, fibrosis, and elevated liver enzyme levels. Transcriptomic analysis revealed that testosterone deficiency affects ferroptosis and circadian rhythm-related signaling pathways. Castrated APOE -/- mice exhibited significantly higher hepatic iron deposition, lipid peroxidation, and expression of key ferroptosis-related proteins, along with decreased Brain and muscle ARNT-like gene 1 (BMAL1) protein expression. In vitro, testosterone treatment reduced lipid and iron accumulation and lipid peroxidation in HepG2 cells subjected to FFAs and Erastin. Moreover, BMAL1 knockdown negated the protective effects of testosterone against ferroptosis in hepatocytes., Conclusion: Our study demonstrated that testosterone deficiency exacerbates NAFLD induced by a high-fat diet by promoting hepatocyte ferroptosis through modulation of the circadian protein BMAL1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Mitochondrial dynamics plays a crucial role in the occurrence and development of non-alcoholic fatty liver diseases (NAFLD). SENP1, a SUMO-specific protease, catalyzes protein de-SUMOylation and involves in various physiological and pathological processes. However, the exact role of SENP1 in NAFLD remains unclear. Therefore, we investigated the regulatory role of SENP1 in mitochondrial dynamics during the progression of NAFLD. In the study, the NAFLD in vivo model induced by high fat diet (HFD) and in vitro model induced by free fatty acids (FFA) were established to investigate the role and underlying mechanism of SENP1 through detecting mitochondrial morphology and dynamics. Our results showed that the down-regulation of SENP1 expression and the mitochondrial dynamics dysregulation occurred in the NAFLD, evidenced as mitochondrial fragmentation, up-regulation of p-Drp1 ser616 and down-regulation of MFN2, OPA1. However, over-expression of SENP1 significantly alleviated the NAFLD, rectified the mitochondrial dynamics disorder, reduced Cyt-c release and ROS levels induced by FFA or HFD; moreover, the over-expression of SENP1 also reduced the SUMOylation levels of Drp1 and prevented the Drp1 translocation to mitochondria. Our findings suggest that the possible mechanisms of SENP1 were through rectifying the mitochondrial dynamics disorder, reducing Cyt-c release and ROS-mediated oxidative stress. The findings would provide a novel target for the prevention and treatment of NALFD., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study evaluated the ability of the triglyceride (TG) to high-density lipoprotein cholesterol (TG/HDL-C) ratio to identify individuals at risk of type 2 diabetes mellitus (T2DM) in the non-alcoholic fatty liver disease (NAFLD) population. We retrospectively studied 4,769 patients with NAFLD from the Affiliated Hospital of Hangzhou Normal University (2020-2023). Binary logistic regression models were used to evaluate the association between the TG/HDL-C ratio and lipid parameters with T2DM. TG/HDL-C ratio was positively associated with T2DM in patients with NAFLD, with an odds ratio (OR) of 2.72 (95% confidence interval, 2.23-3.31, p < 0.001) for T2DM in the highest TG/HDL-C ratio quartile compared with the lowest one after adjusting for known confounders. The OR for the TG/HDL-C ratio had a stronger predictive value than those of TG, total cholesterol, HDL-C, and low-density lipoprotein cholesterol, indicating that the TG/HDL-C ratio could be a better discriminator of T2DM. The TG/HDL-C ratio better identifies potential risks of T2DM in individuals with NAFLD than individual lipid parameters. Therefore, clinicians should pay attention to individuals with high TG and low HDL-C levels during T2DM risk assessment in NAFLD cohorts., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition that is strongly linked to gut microbiota imbalance and chronic inflammation. This study aims to explore the preventive effects of dihydromyricetin (DHM) on NAFLD by modulating the intestinal flora and the TLR4/NF-κB signaling pathway. Fifty male C57BL/6J mice were randomly assigned to five groups: a normal control group, a model group, and three DHM treatment groups receiving low (500 mg/kg), medium (750 mg/kg), and high doses (1,000 mg/kg). NAFLD was induced using a high-fat diet, and DHM was administered for 8 weeks. ELISA measured serum levels of LPS, IL-1β, and TNF-α, while Western Blot assessed liver expression of TLR4 and NF-κB p65. Changes in intestinal flora composition were analyzed using high-throughput 16S rRNA sequencing. The results showed that DHM treatment significantly reduced serum levels of LPS, IL-1β, and TNF-α, decreasing the liver expression of TLR4 and NF-κB p65. Intestinal flora analysis indicated a notable increase in beneficial bacteria, especially in the medium and high-dose groups. DHM treatment also significantly improved liver pathology, reducing fat deposition and inflammatory cell infiltration. In conclusion, DHM effectively prevents the progression of NAFLD by improving gut microbiota balance and suppressing inflammatory signaling pathways.

Nonalcoholic fatty liver disease (NAFLD) has rapidly emerged as the most prevalent chronic liver disease globally, representing a significant and escalating public health challenge. Meconopsis integrifolia (Maxim.) Franch, a traditional Tibetan medicinal herb used for treating hepatitis, remains largely unexplored regarding its therapeutic potential and active components in combating NAFLD. This study first evaluated the in vitro lipid accumulation inhibitory activity of different extraction fractions of M. integrifolia using a HepG2 cell steatosis model. The ethyl acetate fraction was found to significantly reduce triglyceride (TG) and low-density lipoprotein (LDL) levels, inhibit lipid droplet deposition in HepG2 cells, and promote lipid metabolism balance through modulation of the AMPK/SREPB-1c/PPAR-α signaling pathway. Further analysis utilizing chromatographic techniques and nuclear magnetic resonance spectroscopy (NMR) led to the isolation of 13 compounds from the active ethyl acetate fraction. Notably, compounds 6 , 9 , 10 , 11 , 12 , and 13 were identified for the first time from this Tibetan herb. In vitro activity assays and molecular docking analyses further confirmed that the compounds Luteolin ( 1 ), Quercetin 3- O -[2‴, 6‴- O -diacetyl-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside] ( 6 ), and Quercetin 3- O -[2‴- O -acetyl-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside] ( 8 ) are potential key components responsible for the NAFLD-ameliorating effects of M. integrifolia . This study highlights the therapeutic potential of M. integrifolia in treating NAFLD and provides a foundation for its further development and application, underscoring its significance in the advanced utilization of traditional Tibetan medicine.

Objective: This study investigated copper (Cu) status in relation to abdominal obesity indices and liver function in patients with non-alcoholic fatty liver disease (NAFLD). This case-control study was carried out on 80 overweight/obese patients with NAFLD and 80 apparently healthy age, sex, and body mass index (BMI)-matched controls. A validated and reliable 168-item semi-quantitative food frequency questionnaire was completed for each subject and fasting serum levels of liver aminotransferases, ferritin, Cu and ceruloplasmin were assessed., Results: Mean intakes of energy and carbophydrate were significantly lower in patients with NAFLD than the control group while mean protein intake was highre (p < 0.05). Although mean Cu intake was greater in cases than controls, low dietary intake of Cu was found in 7.5% and 32.5% of the cases and controls, respectively. Apart from serum levels of liver aminotransferases (p < 0.001) and ferritin (p = 0.010), no significant differences were found in serum levels of Cu and ceruloplasmin. Serum and dietary Cu were positively correlated with obesity indices and serum ceruloplasmin was correlated with waist to height ratio and ferritin only in cases (p < 0.05). Low Cu intake (< 0.95 mg/day) was more likely to increase the odds of NAFLD (p for trend = 0.002), after adjusting for potential confounders., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of Tabriz University of Medical Science. The study protocol obtained approval from the Ethics Committee of Tabriz University of Medical Science (IR.TBZMED.REC.1399.176). Informed written consent was obtained from all participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Aims: Acquired resistance to thyroid hormone appears to exist in the general population. We aimed to evaluate the association between indices of thyroid hormone sensitivity and non-alcoholic fatty liver disease (NAFLD), and made stratified analyses by diabetic status., Methods: We included 26,413 participants from a health screening program and 8,246 hospitalized patients with type 2 diabetes. Thyroid Feedback Quantile-based Index (TFQI), thyroid stimulating hormone index (TSHI) and thyrotroph thyroxine resistance index (TT4RI) were calculated. Advanced fibrosis risk was determined using the FIB-4 score. Multivariate logistic regression analysis was performed., Results: TFQI was associated with an increased risk of NAFLD in patients with diabetes (fourth quartile vs. first quartile: odds ratio [OR]=1.39 and 1.82 in hospitalized and non-hospitalized patients, respectively, both P<0.001) but not non-diabetic participants (OR=0.94, P=0.40). Further adjustment for the homeostasis model assessment of insulin resistance generated similar findings in diabetes (OR=1.27, P=0.025). The TFQI-associated NAFLD risk increase in diabetic patients was confined to NAFLD with low probability of advanced fibrosis (OR 1.42, P=0.001), but not those with intermediate-to-high probability (OR=0.86, P=0.23). Also, TFQI was associated with a significantly lower risk for advanced fibrosis in the diabetic at-risk patients (OR=0.62, P=0.005) but not those non-diabetic at-risk participants, independent of the presence of NAFLD. The association was less significant for TT4RI and TSHI., Conclusions: Impaired sensitivity to thyroid hormone was associated with an increased risk of developing NAFLD but a reduced risk of advanced fibrosis limited to diabetic individuals. Our findings suggest stratified studies of NAFLD based on diabetic status are needed in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Liu, Wang, Han, Yan, Xiang, Shen and Feng.)

Background: A body of evidence has suggested bidirectional relationships among gallstone disease (GSD), non-alcoholic fatty liver disease (NAFLD), and kidney stone disease (KSD). However, the results are inconsistent, and studies on this topic in China are relatively few. Our goal is to explore the bidirectional associations among these three diseases through a multicenter study, systematic review, and meta-analysis., Aim: To explore the bidirectional associations among these three diseases through a multicenter study, systematic review, and meta-analysis. The results may help to investigate the etiology of these diseases and shed light on the individualized prevention of these three diseases., Methods: Subjects who participated in physical examinations in Beijing, Tianjin, Chongqing in China were recruited. Multivariable logistic regression was employed to explore the bidirectional relationships among GSD, KSD, and NAFLD. Systematic review and meta-analysis were initiated to confirm the epidemiologic evidence from previous observational studies. Furthermore, trial sequential analysis (TSA) was conducted to evaluate whether the evidence was sufficient and conclusive., Results: Significant bidirectional associations were detected among the three diseases, independent of potential confounding factors. The pooled results of the systematic review and meta-analysis also corroborated the aforementioned results. The combined evidence from the multicenter study and meta-analysis was significant [pooled odds ratio (OR) = 1.42, 95%CI: 1.16-1.75, KSD → GSD; pooled OR = 1.48, 95%CI: 1.31-1.67, GSD → KSD; pooled OR = 1.31, 95%CI: 1.17-1.47, GSD → NAFLD; pooled OR = 1.37, 95%CI: 1.26-1.50, NAFLD → GSD; pooled OR = 1.28, 95%CI: 1.08-1.51, NAFLD → KSD; pooled OR = 1.21, 95%CI: 1.16-1.25, KSD → NAFLD]. TSA indicated that the evidence was sufficient and conclusive., Conclusion: The present study presents relatively sufficient evidence for the positive bidirectional associations among GSD, KSD, and NAFLD. The results may provide clues for investigating the etiology of these three diseases and offer a guideline for identifying high-risk patients., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest with the information presented., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

This article delved into the comprehensive study by Jiang et al , which meticulously examined the bidirectional relationships among gallstone disease, non-alcoholic fatty liver disease, and kidney stone disease through a multicenter study, systematic review, and meta-analysis. The study provides significant evidence supporting these associations, offering valuable insights into the etiology and potential prevention strategies for these interconnected conditions. The clinical significance of these bidirectional relationships is profound, as they underscore the importance of recognizing these conditions not only as isolated diseases but as part of a complex network that can influence each other. These results highlight the critical need for thorough screening and personalized prevention strategies for individuals with these interconnected conditions. Explicit implications for prevention strategies and early screening practices are crucial, as they can lead to early detection and intervention, significantly altering disease progression and outcomes. Furthermore, identifying potential therapeutic targets within these shared pathways may enhance treatment efficacy and patient outcomes, making this research highly relevant to clinical practice. By comprehending the common pathophysiological mechanisms and applying specific interventions, healthcare professionals can greatly enhance patient care and lessen the impact of these widespread diseases on global health., Competing Interests: Conflict-of-interest statement: The author reports no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The wide application of copper oxide nanoparticles (CuO NPs) in various fields such as medicine, food, agriculture, and animal husbandry can result in direct or indirect oral exposure of CuO NPs to the human body. Therefore, the research on the biosafety of CuO NPs is crucially important. However, previous research mainly concentrated on CuO NPs-induced oxidative stress, rather than the dysregulation of metabolic homeostasis. Our current finding indicates that CuO NPs can enter the systemic circulation and accumulate in the liver by being adopted by the colon and disrupting the intestinal barrier. Subsequently, CuO NPs can impair bile acid (BA) homeostasis through increased reabsorption of bile acids (BAs), ultimately leading to non-alcoholic fatty liver disease (NAFLD). Additionally, the direct stimulation from CuO NPs, damage to the gut barrier, and disruption of BA homeostasis can also disrupt microbial homeostasis in the intestines, including alterations in the composition and biological functions of gut microbiota, thereby triggering NAFLD. These findings deepen our understanding of the biosafety of CuO NPs and provide evidence for their role in disrupting physiological homeostasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome associated with obesity and type 2 diabetes mellitus. Currently, there are no effective drugs to treat NAFLD. Palmitoleic acid (PA) has demonstrated therapeutic potential in managing various metabolic diseases and inflammation. Although ferroptosis is known to play a critical role in the NAFLD development, it remains unclear whether PA can alleviate NAFLD by inhibiting ferroptosis., Methods: Thirty C57BL/6 mice were divided into three groups: standard diet, high-fat diet (HFD), and HFD with PA. The experiment lasted 16 weeks., Results: PA alleviated liver injury, hepatitis, and dyslipidemia in HFD-induced NAFLD mice. It improved insulin resistance, downregulated genes and proteins related to fat synthesis, and upregulated genes and proteins linked to lipolysis and fat oxidation. Mechanistically, bioinformatics enrichment revealed the involvement of ferroptosis in NAFLD. PA mitigated oxidative stress and reduced liver iron content in NAFLD. It downregulated acyl-CoA synthetase long-chain family member 4 (ACSL4) expression while upregulating glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression, thereby inhibiting ferroptosis., Conclusion: PA exerts a protective effect against liver lipotoxicity by inhibiting lipid metabolism-mediated ferroptosis. These findings provide new insights into preventive and therapeutic strategies for the pathological processes of NAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally. Growing data suggests that smoking plays an important role in the evolution of NAFLD. CDGSH iron sulfur domain 3 (CISD3) regulates critical biological activities. However, its role in nicotine-associated NAFLD and its underlying mechanisms have not been elucidated. Mice were given a high-fat diet for 10 weeks to induce the development of NAFLD. The results revealed that in mice with NAFLD, nicotine treatment resulted in reduced CISD3 expression, leading to mitochondrial dysfunction and impaired β-oxidation. Notably, exacerbation of hepatic steatosis and inflammatory injury was observed. Furthermore, Cisd3-knockout exacerbated lipid accumulation, aggravating oxidative stress and apoptosis. In conclusion, these results contribute to our knowledge of the function of CISD3 in nicotine-associated NAFLD, revealing the possibility of using CISD3 as a potential molecular target for treating NAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To verify the prevalence and factors associated with Non-Alcoholic Fatty Liver Disease (NAFLD) among women with Polycystic Ovary Syndrome (PCOS)., Methods: A cross-sectional study was conducted with 53 patients with PCOS. The diagnosis of PCOS followed the Rotterdam criteria. The diagnosis of NAFLD was made through US showing hepatic steatosis, excluding significant alcohol consumption and chronic liver disease. The following variables were compared between the groups of women with and without NAFLD: age, race, anthropometric data, blood pressure levels, liver enzymes, glycemic and lipid profiles, total testosterone, presence of hirsutism, and metabolic syndrome (MS). Variables were compared between the groups using T-test, Mann-Whitney, and Chi-square tests., Results: Among 53 patients with PCOS, 50.9% had NAFLD. The NAFLD group had higher weight (p=0.003), BMI (p=0.001), waist circumference (p≤0.001), fasting glucose (p=0.021), HbA1C% (p=0.028), triglycerides (p=0.023), AST (p=0.004), ALT (p=0.001), higher prevalence of MS (p=0.004), and lower levels of HDL cholesterol (p=0.043). The other variables did not differ between the groups. Both groups were predominantly of caucasian race, and there was no significant difference in age., Conclusion: The prevalence of NAFLD among patients with PCOS was 50.9%. Metabolic and hepatic enzyme abnormalities were more prevalent in this group compared to the group without the disease. Obesity tripled the prevalence of NAFLD., Competing Interests: Conflicts to interest: none to declare., (© 2024. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved.)

Background: The triglyceride-glucose (TyG) index and related parameters, as well as the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), have been developed as insulin resistance markers to identify individuals at risk for non-alcoholic fatty liver disease (NAFLD). However, its use for predicting NAFLD in patients with type 2 diabetes mellitus (T2DM) remains unclear. In this study, we aimed to observe the performance of insulin resistance indices in diagnosing NAFLD combined with T2DM and to compare their diagnostic values in clinical practice., Patients and Methods: Overall, 268 patients with T2DM from the Endocrinology Department of Jiangsu Provincial Hospital of Traditional Chinese Medicine were enrolled in this study and divided into two groups: an NAFLD group (T2DM with NAFLD) and a T2DM group (T2DM without NAFLD). General information and blood indicators of the participants were collected, and insulin resistance indices were calculated based on these data. Receiver operating characteristic (ROC) analysis was conducted to calculate the area under the curve (AUC) for insulin resistance-related indices, aiming to assess their ability to discriminate between T2DM patients with and without NAFLD., Results: ROC analysis revealed that among the five insulin resistance-related indices, four parameters (TyG, TyG-body mass index [BMI], TyG-waist circumference [WC], and TyG- (waist-hip ratio [WHR]) exhibited high predictive performance for identifying NAFLD, except for HOMA-IR (AUCs:0.710,0.738,0.737 and 0.730, respectivly). TyG-BMI demonstrated superior predictive value, especially in males. For males, the AUC for TyG-BMI was 0.764 (95% confidence interval [CI] 0.691-0.827). The sensitivity and specificity for male NAFLD were 90.32% and 47.89%, respectively. Moreover, in the Generalized linear regression models, there were positive associations of TyG, TyG-BMI, TyG-WC, TyG-WHR, and HOMA-IR with controlled attenuation parameter (CAP), with β values of 21.30, 0.745, 0.247, and 2.549 (all P < 0.001), respectively., Conclusion: TyG-BMI is a promising predictor of NAFLD combined with T2DM, particularly in lean male patients., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol was approved by the Ethics Committee of Jiangsu Province Hospital of Traditional Chinese Medicine, with a waiver of informed consent. All methods were conducted in accordance with relevant guidelines and regulations. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background/aims: Mesenchymal stem cells (MSCs) have shown promising therapeutic potential in treating liver diseases, such as non-alcoholic fatty liver disease (NAFLD). Genetic modification has been employed to enhance the characteristics of MSCs for more effective disease treatment. Here, we present findings on human adipose-derived MSCs with Atg5 deficiency, investigating their therapeutic impact and the associated mechanisms in NAFLD., Methods: In vitro, lentiviral transduction was employed to downregulate Atg5 or HGF in human adipose-derived MSCs using short hairpin RNA (shRNA). Subsequently, experiments were conducted to evaluate cell senescence, proliferation, cell cycle, apoptosis, and other pertinent aspects. In vivo, a non-alcoholic fatty liver mouse model was established by feeding them a high-fat diet (HFD), and the effects of MSCs transplantation were assessed through serological, biochemical, and pathological analyses., Results: Our research findings indicate that Atg5-deficient MSCs display heightened proliferative activity. Subsequent co-culturing of MSCs with hepatocytes and the transplantation of Atg5-deficient MSCs into NAFLD mouse models demonstrated their ability to effectively reduce lipid accumulation in the NAFLD disease model by modulating the AMPKα/mTOR/S6K/Srebp1 pathway. Furthermore, we observed that Atg5 deficiency enhances the secretion of hepatocyte growth factor (HGF) by promoting recycling endosome (RE) production. Lastly, our study revealed that 3-MA-primed MSCs can improve the characteristics of NAFLD by boosting the secretion of HGF., Conclusions: Our research findings suggest that Atg5-deficient MSCs protect against NAFLD by accelerating HGF secretion. This indicates that Atg5 gene-modified MSCs may represent a promising strategy for treating NAFLD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of hepatic and extrahepatic cancers, in particular those linked to obesity. In people with chronic liver disease, aspirin may confer protection against hepatocellular carcinoma (HCC). We explore the potential chemoprotective effect of aspirin/other anti-platelet agents on obesity-related cancers, including HCC in people with NAFLD., Methods: We performed a retrospective cohort study of anonymised electronic medical records using the TriNetX network (Cambridge, MA, USA), a global federated database. We identified adults aged 18 or over with a diagnosis of NAFLD, prior to commencing antiplatelet agents. Two groups were created: antiplatelet (1) versus no antiplatelet use (2). We propensity score matched for nine variables. Antiplatelet use was defined as aspirin, ticagrelor, cangrelor, clopidogrel or prasugrel use for at least 1 year. The outcomes of interest were incidence of HCC and other obesity-related cancers. Follow-up was for 5 years. We performed subgroup analyses on aspirin users only and stratified findings for sex and age. Sensitivity analysis was conducted on individuals with 3- and 5-year aspirin exposure., Results: Post matching, there were 42,192 people per group. Antiplatelet use in people with NAFLD was associated with statistically significant reduction in all obesity-related cancers (HR 0.71, 95% CI 0.65-0.78, p < 0.001) and individually for HCC (HR 0.52, 95% CI 0.40-0.68, p < 0.001), breast carcinoma (HR 0.78, 95% CI 0.66-0.92, p = 0.003), pancreatic carcinoma (HR 0.61, 95% CI 0.47-0.78, p < 0.001) and colorectal carcinoma (HR 0.68, 95% CI 0.56-0.84, p < 0.001). For women, there was a significant reduction in risk of ovarian carcinoma (HR 0.75, 95% CI 0.57-0.98, p = 0.034). Aspirin monotherapy was similarly associated with reduced incidence of HCC (HR 0.46, 95% CI 0.32-0.64, p < 0.001) and all obesity-related cancers (HR 0.71, 95% CI, 0.56-0.90, p = 0.004), with benefits observed in males (HR 0.71, 95% CI 0.56-0.90, p = 0.004), females (HR 0.77, 95% CI 0.67-0.88, p < 0.001) and in older (HR 0.72, 95% CI 0.63-0.82, p < 0.001) but not younger people (HR 0.78, 95% CI 0.60-1.03, p = 0.589)., Conclusions: Aspirin/antiplatelet agents may have a role in primary cancer prevention in people living with NAFLD., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: MA receives funding and salary contribution from the Novo Nordisk UK research foundation. DJC has received investigator-initiated grants from Astra Zeneca and Novo Nordisk and support for education from Perspectum. GHI is an employee of TriNetX LLC. UA has received honoraria from Eli Lilly, Procter & Gamble, Viatris, Grunenthal and Sanofi for educational meetings and funding for attendance to an educational meeting from Diiachi Sankyo. UA has also received investigator-led funding by Procter & Gamble and is a council member of the Royal Society of Medicine’s Vascular, Lipid & Metabolic Medicine Section., (© 2024. The Author(s).)

Non-alcoholic fatty liver disease (NAFLD) is a progressive condition, advancing from simple hepatic lipid accumulation to inflammation, fibrosis, and increased risk of mortality. This study explores the therapeutic efficacy of bioactive peptides PIISVYWK (P1) and FSVVPSPK (P2) in ameliorating NAFLD in both oleic acid-treated HepG2 cells and high-fat diet (HFD)-induced mice. Our findings demonstrated that P1 and P2 significantly reduced hepatic fat deposition, enhanced lipolysis by promoting the release of free glycerol and free fatty acids, and suppressed key de novo lipogenesis-related proteins, including peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α (C/EBPα), sterol regulatory element-binding protein 1 (SREBP-1), and fatty acid synthase (FAS). Furthermore, both peptides stimulated fatty acid oxidation via phosphorylation of AMP-activated protein kinase (AMPK) and hormone-sensitive lipase (HSL). Notably, reductions in body and liver weight, along with improved cholesterol profiles and liver function markers (alanine transaminase and aspartate aminotransferase), were observed in HFD mice. Additionally, P1 and P2 significantly attenuated the production of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in both in vitro and in vivo models. Collectively, these results highlight the potent therapeutic potential of P1 and P2 in mitigating NAFLD progression, offering a promising intervention for this increasingly prevalent metabolic disorder., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD), a prevalent chronic liver disease, is marked by excessive lipid deposition in the liver without alcohol abuse. Scapharca subcrenatum, a major Chinese farmed bivalve, yields S. subcrenatum polysaccharide (TGP), an active substance with known biological activity. Previous studies revealed TGP's significant regulatory effect on a high-fat diet (HFD)-induced NAFLD in mice. However, the precise mechanisms, particularly involving gut microbiota, remain unclear. In the current study, an antibiotic-treated mouse model was established to determine the mechanistic role of the gut microbiota in the observed anti-obesity effects of TGP. In addition, 16S rRNA genomic and metagenome-derived taxonomic analyses were performed to assess the gut microbial populations. The results showed that TGP selectively enhanced the number of the eosinophilic bacterium Lactobacillus johnsonii, which was reduced in HFD mice. Of note, the oral administration of L. johnsonii formulations to HFD mice alleviated NAFLD, and this was related to regulating lipid metabolism and the accumulation of lipids in the liver. Therefore, the current study uncovered a potential pathway for developing NAFLD treatment strategies based on the interaction between TGP and the gut microbiota., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The Angiopoietin-like 4 (ANGPTL4) and ETS Variant Transcription Factor 4 (ETV4) are involved in the metabolic transition and carcinogenesis in the liver. However, the role of ETV4 in the development of non-alcoholic fatty liver disease (NAFLD) is currently unknown. Our study reveals that ETV4 expression was upregulated in the diet-induced non-alcoholic fatty liver disease, and plays a critical role in the dysregulated lipid metabolism. We demonstrate a mechanism by which ANGPTL4 regulates lipid homeostasis via involving the AMPK/ETV4 axis. Transient knockdown of ETV4 abolished the ANGPTL4-induced expression of Srebp1c, Acc and Fasn. Insulin treatment potentially increased the physical association of ETV4 with SREBP1, and promotes nuclear translocation and transcriptional activity of SREBP1. In addition, we show that combined therapy with omega-3 fatty acids and diacylglycerol O-acyltransferase inhibitor 1 (DGAT1) inhibitor (A-922500) counteracted the ANGPTL4-ETV4 axis-induced lipogenesis in vitro, and in vivo in obese mice via activation of GPR120-βarrestin2-AMPK pathway. Finally, we demonstrate that targeted pharmacologic therapy using GalNac-ETV4 siRNA that specifically inhibits ETV4 gene expression in the liver protects against diet-induced NAFLD, obesity and dyslipidemia. Hence, our study reveal previously unrecognized role of ETV4 in the NAFLD, and provides rationale targeting ETV4 to treat NAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally, with a complex and contentious pathogenesis. Caveolin-1 (CAV1) is an important regulator of liver function and can mitigate liver injury by scavenging reactive oxygen species (ROS). Evidence suggests that NOX4 is a source of ROS production, that oxidative stress and ferroptosis are closely related, and that both are involved in the onset and progression of NAFLD. However, whether CAV1 attenuates liver injury in NAFLD caused by high-fat diet via the NOX4/ROS/GPX4 pathway remains unclear. An in vivo fatty liver model was established by feeding mice with a high-fat diet for 16 weeks. In addition, an in vitro fatty liver model was established by incubating AML-12 cells with free fatty acids for 24 h using an in vitro culture method. In our study, it was observed that a high-fat diet induces mitochondrial damage and worsens oxidative stress in NAFLD. This diet also hinders GPX4 expression, leading to an escalation of ferroptosis and lipid accumulation. To counteract these effects, intraperitoneal administration of CSD peptide in mice attenuated the high-fat diet-induced liver mitochondrial damage and ferroptosis. Likewise, overexpression of CAV1 resulted in an increase in GPX4 expression and a reduction in levels of ROS-mediated iron metamorphosis, thus mitigating the progression of the disease. However, the effects of CAV1 on GPX4-mediated ferroptosis and lipid deposition could be reversed by CAV1 small interfering RNA (SiRNA). Finally, NOX4 inhibitor (GLX351322) treatment increased CAV1 siRNA-mediated GPX4 expression and decreased the level of ROS-mediated ferroptosis. These findings suggest a potential mechanism underlying the protective role of CAV1 against high-fat diet-induced hepatotoxicity in NAFLD, shedding new light on the interplay between CAV1, GPX4, and ferroptosis in liver pathology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To evaluate the diagnostic value of the FibroScan-AST (FAST) score, non-alcoholic fatty liver fibrosis score (NFS), FibroScan, and liver fibrosis index (FIB-4) for identifying fibrotic non-alcoholic steatohepatitis (NASH) in patients with chronic hepatitis B (CHB) with metabolic dysfunction-associated fatty liver disease (MAFLD)., Methods: All patients with CHB and MAFLD who underwent liver biopsy at the Zhenjiang Third Hospital affiliated with Jiangsu University between August 2010 and December 2022 were included in the analysis. The diagnostic accuracy of FAST, NFS, FibroScan, and FIB-4 for diagnosing NASH and liver fibrosis were evaluated based on the area under the receiver-operating characteristic curve (AUC)., Results: A total of 156 patients with CHB combined with MAFLD were included, including 69 with NASH and fibrosis stage 2 or higher (NASH+ F  ≥ 2), and 16 with NASH and cirrhosis (NASH+F4). The AUC of FAST, NFS, liver stiffness measurement (LSM), and FIB-4 for diagnosing NASH+ F  ≥ 2 was 0.739 ( p  < 0.001), 0.643 ( p  = 0.006), 0.754 ( p  < 0.001), and 0.665 ( p  = 0.003), respectively. The specificity of FAST, NFS, LSM, and FIB-4 was 67%, 51.8%, 78.6% and 76.8%, respectively, and the sensitivity was 75%, 78.6%, 67.9%, and 53.6%, respectively. No significant differences were found between groups. The AUC of FAST, NFS, LSM, and FIB-4 for diagnosing NASH+F4 was 0.650 ( p  = 0.038), 0.725 ( p  = 0.001), 0.851 ( p  < 0.001), and 0.560 ( p  = 0.533), respectively. The specificity of the FAST, NFS, LSM, and FIB-4 was 55.9%, 50.0%, 71.6%, and 75.5%, respectively and the sensitivity was 80.0%, 100%, 100%, and 50.0%, respectively. The differences between AUCs of FIB-4 and FAST compared with LSM were 0.291 and 0.201, respectively ( p  < 0.05)., Conclusion: In patients with CHB combined with MAFLD, FAST did not have better accuracy than NFS and FIB-4 for predicting fibrotic NASH, whereas LSM had better accuracy than FAST and FIB-4.

Background: Obesity is a significant risk factor for the progression of non-alcoholic fatty liver disease (NAFLD). However, a convenient and efficacious non-invasive test for monitoring NAFLD progression in patients with obesity is currently lacking. This study aims to investigate the associations between CT-based body composition and the progression of biopsy-proven NAFLD in patients with obesity., Methods: Liver biopsy was conducted in patients with obesity, and the progression of NAFLD was evaluated by the NAFLD activity score (NAS). Body composition was assessed through abdominal computed tomography (CT) scans., Results: A total of 602 patients with an average age of 31.65 (±9.33) years old were included, comprising 217 male patients and 385 female patients. The wall skeletal muscle index (SMI), total SMI, and visceral fat index (VFI) were positively correlated with NAS in both male and female patients. Multivariate regression analysis demonstrated significant associations between high liver steatosis and wall SMI (HR: 1.60, 95% CI: 1.12 to 2.30), total SMI (HR: 1.50, 95% CI: 1.02 to 2.08), VSI (HR: 2.16, 95% CI: 1.48 to 3.14), visceral fat to muscle ratio (HR: 1.51, 95% CI: 1.05 to 2.18), and visceral to subcutaneous fat ratio (HR: 1.51, 95% CI: 1.07 to 2.12). Non-alcoholic steatohepatitis (NASH) was significantly associated with wall SMI (HR: 1.52, 95% CI: 1.06 to 2.19) and VSI (HR: 1.50, 95% CI: 1.03 to 2.17). Liver fibrosis ≥ F2 was significantly associated with psoas muscle index (HR: 0.64, 95% CI: 0.44 to 0.93) and psoas skeletal muscle density (HR: 0.61, 95% CI: 0.41 to 0.89)., Conclusions: Our study suggested that certain CT-based body composition indicators, notably high VFI, were significantly associated with the progression of NAFLD in patients with obesity. Great attentions and timely managements should be given to these patients with body composition characteristics associated with the risk of NAFLD progression., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Non-alcoholic fatty liver disease (NAFLD) is a metabolically stressed liver injury closely related to insulin resistance and genetic susceptibility and has become the leading chronic liver disease in China., Purpose: To analyze the effectiveness of five Chinese patent medicines used alone or in combination with western medications (WM) for NAFLD using Bayesian network meta-analysis., Methods: Searches were conducted in Embase, Cochrane Library, PubMed, CNKI, Wanfang Database, VIP, and SinoMed for randomized controlled trials (RCTs) on Danning tablets, Huazhi Rougan granules, Dangfei Liganning capsules, Kezhi capsules, and Qianggan capsules, either alone or in combination with WM for NAFLD, up to January 10, 2024. This study was screened based on pre-designed inclusion and exclusion criteria, and the risk of bias was evaluated using the Cochrane ROB2 tool. The primary outcome was clinical efficacy rate, while secondary outcomes included levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Triglycerides (TG), and Low-density lipoprotein cholesterol (LDL-C). These data will be analyzed using WinBUGS 1.4.3 and then visualized using Stata 14.0 software., Results: A total of 77 RCTs involving 7770 patients were included. The results indicated that Huazhi Rougan granules combined with WM (OR = 0.13, 95 % CI 0.05 ∼ 0.26) had a SUCRA probability value of 81.7 %, ranked first in clinical efficacy and significantly improved blood lipids levels including TG, High-density Lipoprotein Cholesterol (HDL-C), and LDL-C, Total cholesterol (TC). For the Chinese patent medicines alone, Danning tablets led with a 75.3 % clinical efficacy rate. Huazhi Rougan granules significantly increased levels of ALT (96.2 %) and AST (MD = -14.48, 95 % CI -23.38 ∼ -5.32). Dangfei Liganning capsules demonstrated significant efficacy in improving TG (73.1 %) and TC (83 %) levels., Conclusion: In the treatment of NAFLD, the combination of Huazhi Rougan granules and WM demonstrated significant clinical effectiveness and improvement in blood lipid profiles. For different outcome indicators, Danning tablets used alone showed the highest clinical efficacy, while significant improvement in liver function indicators was best achieved with Huazhi Rugan granules used alone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objective: The objective of this study was to thoroughly investigate the clinical value of triglyceride glucose-body mass index (TyG-BMI) in patients diagnosed with non-alcoholic fatty liver disease (NAFLD). Specifically, we aimed to determine its association with non-alcoholic steatohepatitis (NASH) and the progression of liver fibrosis., Methods: The study included 393 patients diagnosed with NAFLD after liver biopsy. The patients were divided into two distinct cohorts: a training cohort ( N  = 320) and a validation cohort ( N  = 73). The training cohort was further divided into four groups based on TyG-BMI quartiles. The clinical characteristics of the patients in each group were compared in detail, and the association between TyG-BMI and NASH, NAFLD Activity Score (NAS) ≥ 4, at-risk NASH, significant fibrosis, advanced fibrosis, and cirrhosis was analyzed using multiple models. Additionally, we generated receiver operating characteristic (ROC) curves to evaluate the predictive ability of TyG-BMI for NASH and fibrosis staging in patients with NAFLD., Results: Patients with higher TyG-BMI values had a significantly higher prevalence of NASH, NAS ≥ 4, at-risk NASH, significant fibrosis, advanced fibrosis, and cirrhosis (all p  < .05). TyG-BMI was an independent predictor of these diseases in both unadjusted and adjusted models (all p  < .05). ROC curve analysis further revealed the excellent performance of TyG-BMI in predicting NASH, NAS ≥ 4, at-risk NASH, significant fibrosis, advanced fibrosis, and cirrhosis. The validation cohort yielded analogous results. Furthermore, we constructed three multivariate models of TyG-BMI in conjunction with elastography metrics, which demonstrated elevated diagnostic AUC values of 0.782, 0.792, 0.794, 0.785, 0.834, and 0.845, respectively., Conclusion: This study confirms a significant association between insulin resistance and NAFLD, including at-risk NASH and fibrosis staging, as assessed using the TyG-BMI index. TyG-BMI and its associated multivariate models can be valuable noninvasive indicators for NAFLD diagnosis, risk stratification, and disease course monitoring.

Purpose: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. This study focused on assessing the predictive significance of NAFLD for recurrent stroke and transient ischemic attack (TIA) risk to determine the value of NAFLD., Method: This study included 742 participants (mean age: 64.26 ± 9.42 years, 497 males) with carotid atherosclerosis who underwent carotid CT angiography (CTA) between January 2013 and December 2021 in this retrospective study. NAFLD was diagnosed by non-enhanced abdominal CT. The clinical endpoint was a recurrent ischemic stroke or TIA. Cox proportional hazards and Kaplan-Meier analysis assessed whether NAFLD was associated with the endpoint. We accessed the predictive values of NAFLD, clinical, plaque characteristics, and combined model by the C statistics. The predictive performance of the combined model was assessed by receiver operating characteristic curve (ROC) analysis., Results: A total of 742 participants (mean age: 64.26 ± 9.42 years, 497 males) were included. During 2.9 years of follow-up (interquartile range, 2.1-3.9), 166 patients reached the clinical endpoint. Multivariable cox analyses showed NAFLD was associated with recurrent stroke or TIA in all groups (all P<0.05). Patients with NAFLD had a lower event-free survival (EFS) rate than those without NAFLD (P<0.05). The combined model, including NAFLD, clinical data and plaque features, showed the best performance in predicting the clinical endpoint (AUC=0.79)., Conclusions: NAFLD contributes to the prediction of recurrent ischemic stroke or TIA. NAFLD may be a novel imaging marker that offers a new perspective on preventing cardiovascular disease in the clinic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with its incidence increasing in parallel with the global prevalence of obesity and type 2 diabetes mellitus. Despite our steadily increasing knowledge of its pathogenesis, there is as yet no available pharmacotherapy specifically tailored for NAFLD. To define the appropriate management, it is important to clarify the context in which the disease appears. In the case of concurrent metabolic comorbidities, NAFLD patients are treated by targeting these comorbidities, such as diabetes and obesity. Thus, GLP-1 analogs, PPAR, and SGLT2 inhibitors have recently become central to the treatment of NAFLD. In parallel, randomized trials are being conducted to explore new agents targeting known pathways involved in NAFLD progression. However, there is an imperative need to intensify the effort to design new, safe drugs with biopsy-proven efficacy. Of note, the main target of the pharmacotherapy should be directed to the regression of fibrotic NASH, as this histologic stage has been correlated with increased overall as well as liver-related morbidity and mortality. Herein we discuss the drugs currently at the forefront of NAFLD treatment., (© 2024. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Background: Lean individuals with non-alcohol fatty liver disease (NAFLD) often have normal body size but abnormal visceral fat. Therefore, an alternative to body mass index should be considered for prediction of lean-NAFLD. This study aimed to use representative visceral fat links with other laboratory parameters using the least absolute shrinkage and selection operator (LASSO) method to construct a predictive model for lean-NAFLD., Methods: This retrospective cross-sectional analysis enrolled 2325 subjects with BMI < 24 kg/m 2 from medical records of 51,271 examinees who underwent a routine health check-up. They were randomly divided into training and validation cohorts at a ratio of 1:1. The LASSO-derived prediction model used LASSO regression to select 23 clinical and laboratory factors. The discrimination and calibration abilities were evaluated using the Hosmer-Lemeshow test and calibration curves. The performance of the LASSO model was compared with the fatty liver index (FLI) model., Results: The LASSO-derived model included four variables-visceral fat, triglyceride levels, HDL-C-C levels, and waist hip ratio-and demonstrated superior performance in predicting lean-NAFLD with high discriminatory ability (AUC, 0.8416; 95% CI: 0.811-0.872) that was comparable with the FLI model. Using a cut-off of 0.1484, moderate sensitivity (75.69%) and specificity (79.86%), as well as high negative predictive value (95.9%), were achieved in the LASSO model. In addition, with normal WC subgroup analysis, the LASSO model exhibits a trend of higher accuracy compared to FLI (cut-off 15.45)., Conclusions: We developed a LASSO-derived predictive model with the potential for use as an alternative tool for predicting lean-NAFLD in clinical settings.

Aims: Heart failure (HF) and non-alcoholic fatty liver disease (NAFLD) are significant global health issues with a complex interrelationship. This study investigates their shared biomarkers and causal relationships using bioinformatics and Mendelian randomization (MR) approaches., Methods: We analysed NAFLD and HF datasets from the Gene Expression Omnibus (GEO). The GSE126848 dataset included 57 liver biopsy samples [14 healthy individuals, 12 obese subjects, 15 NAFL patients and 16 non-alcoholic steatohepatitis (NASH) patients]. The GSE24807 dataset comprised 12 NASH samples and 5 healthy controls. The GSE57338 dataset included 313 cardiac muscle samples [177 HF patients (95 ischaemic heart disease patients and 82 idiopathic dilated cardiomyopathy patients) and 136 healthy controls]. The GSE84796 dataset consisted of 10 end-stage HF patients and 7 healthy hearts procured from organ donors. We identified differentially expressed genes (DEGs) and constructed a protein-protein interaction (PPI) network. Functional pathways were elucidated through enrichment analyses using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneMANIA annotation. Single nucleotide polymorphism (SNP) data for HF and NAFLD were sourced from genome-wide association studies (GWAS). The HF dataset included 486 160 samples (14 262 experimental and 471 898 control), and the NAFLD dataset comprised 377 988 samples (4761 experimental and 373 227 control). MR analysis investigates the causal interrelations., Results: Our analysis revealed 4032 DEGs from GSE126848 and 286 DEGs from GSE57338. The top 10 hub genes (CD163, VSIG4, CXCL10, FCER1G, FPR1, C1QB, CCR1, C1orf162, MRC1 and CD38) were significantly enriched in immune response, calcium ion concentration regulation and positive regulation of monocyte chemotaxis. CIBERSORT analysis indicated associations between these hub genes and natural killer (NK) cells and macrophages. Transcription factor (TF) target prediction for CD38, CXCL10 and CCR1 highlighted related TFs. A two-sample MR analysis confirmed a bidirectional causal relationship between NAFLD and HF. The main method [inverse variance weighted (IVW)] demonstrated a significant positive causal relationship between NAFLD and HF [P = 0.037; odds ratio (OR) = 1.024; 95% confidence interval (CI): 1.001 to 1.048]. Similarly, HF was associated with an increase in the risk of NAFLD (P < 0.001; OR = 1.117; 95% CI: 1.053 to 1.185)., Conclusions: Our findings reveal novel molecular signatures common to NAFLD and HF and confirm their bidirectional causality, highlighting the potential for targeted therapeutic interventions and prompting further investigation into their intricate relationship., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)