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Extrahepatic malignancies are the leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD). Of these cancers, pancreatic cancer is one of the most lethal; however, the link between NAFLD and pancreatic cancer remains unclear. Recently, various research results have been reported on the association between NAFLD and pancreatic cancer, and the results of compiling this information revealed the following. First, the prevalence of pancreatic cancer in patients with NAFLD is at 0.26%. Second, the currently evident pathogenesis includes intrapancreatic risk factors, such as: (1) non‐alcoholic fatty pancreas disease, and (2) intraductal papillary mucinous neoplasm; and extrapancreatic risk factors, such as: (1) insulin resistance and adipocytokines, (2) proinflammatory cytokines, and (3) dysbiosis. Finally, metformin and sodium–glucose cotransporter 2 inhibitors may reduce the risk of pancreatic cancer in diabetes patients with NAFLD. In this review, we summarize the recent evidence on the epidemiology and mechanisms for NAFLD‐related pancreatic cancer. We further discuss the impact of anti‐diabetic medication on pancreatic cancer. [ABSTRACT FROM AUTHOR]

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. 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 FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a serious disease. There are no specific drugs for it, in part because of the lack of effective models to aid drug development. However, it has been shown that three-dimensional organoid culture systems can reproduce the organ structure and maintain the gene expression profile of the original tissue. Therefore, we aimed to construct NAFLD models from liver organoids for pharmacological and mechanism studies. We successfully observed morphological changes in normal liver tissue in mouse liver organoids with positive albumin (ALB) expression and potential for differentiation toward hepatocyte-like cells. The mRNA expression of the hepatocyte markers ALB and hepatocyte nuclear factor 4 alpha increased after liver organoid differentiation. We observed free fatty acid (FFA)-induced lipid accumulation in organoids with significant increases in alanine aminotransferase, aspartate aminotransferase, total bilirubin, and triglyceride levels. Moreover, FFA-induced inflammatory cytokines (interleukin-6, tumor necrosis factor-α, and nitric oxide) and fibrosis indicators (collagen type I α1 and laminin α1) were also increased. In addition, RNA sequencing results showed that the expression of key genes [nucleotide oligomerization domain-like receptor (NLR) family apoptosis inhibitory protein, interferon regulatory factor (IRF) 3, and IRF7] involved in NAFLD metabolic abnormalities and insulin resistance in the NLR signaling pathway was altered after FFA induction of the liver organoids. Finally, we found that JC2-11 and lanifibranor limited the FFA-induced increase in oil-red lipid droplets, liver damage, inflammation, and liver fibrosis. In conclusion, tissue structure, gene expression, and the response of mouse liver organoids to drugs can partially mimic in vivo liver tissue. Liver organoids can successfully construct NAFLD models for drug discovery research. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to evaluate the prevalence of anxiety and depression traits in Italian patients with metabolic dysfunction-associated steatotic liver disease (MASLD), and the possible relation with the severity of liver disease. Methods: Demographic, anthropometric, clinical and laboratory parameters were collected in patients referred to a metabolic unit for a comprehensive evaluation of possible liver disease. Hepatic steatosis and fibrosis were evaluated by surrogate biomarkers. Imaging (controlled attenuation parameter-CAP and vibration-controlled transient elastography-VCTE). Beck depression inventory (BDI) and state-trait anxiety inventory-Y (STAI-Y) were used to define depressive/anxiety states; calorie intake and lifestyle were self-assessed by questionnaires. Results: The whole sample comprised 286 patients (61.9% females; mean age 52.0 years; BMI, 34.6 kg/m2); 223 fulfilled MASLD criteria. BDI and trait anxiety scores were lower in the MASLD cohort, and the prevalence of both moderate/severe depression and severe trait anxiety was reduced compared with non-MASLD cases, despite VCTE-diagnosed fibrosis F3–F4 present in over 15% of cases. However, after correction for demographic and anthropometric confounders, MASLD was not associated with a lower risk of moderate/severe depression or severe anxiety trait (odds ratio, 0.34; 95% confidence interval, 0.12–1.01 and 0.79, 0.27–2.34). Additional adjustment for the severity of fibrosis did not change the results. No differences in state anxiety were observed. Conclusion: The risk of anxiety and depression in MASLD is not different from that generated by diabetes and obesity per se. MASLD patients do not perceive liver disease as a specific source of psychological distress, possibly as a consequence of the unawareness of progressive liver disease. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is considered an independent risk factor for cardiovascular disease (CVD). The overall morbidity and mortality of CVD increase with higher fibrosis stage in NAFLD. Carotid atherosclerosis (CAS) is an important predictor of cardiovascular events. However, the relationship between liver fibrosis degree and the risk of CAS in NAFLD patients remains uncertain. We aimed to investigate the relationship between noninvasive liver fibrosis markers and CAS risk in patients with NAFLD. This study included 3,302 participants with NAFLD. Participants were divided into a CAS group and a non-CAS group based on carotid artery ultrasound results. They were then stratified into quartiles using various noninvasive liver fibrosis markers (fibrosis-4 (FIB-4), modified FIB-4 (mFIB-4), aminotransferase to platelet ratio index (APRI), aminotransferase to alanine aminotransferase ratio (AAR), AAR-to-platelet ratio index (AARPRI), and Forns index) to assess the associations between these markers and the risk of CAS. In the NAFLD population, individuals with CAS exhibited elevated levels of blood pressure, glucose, lipids, and noninvasive liver fibrosis markers (p < 0.001). The higher quartiles of noninvasive liver fibrosis markers, including FIB-4, mFIB-4, AAR, AARPRI, and Forns index, were significantly associated with increased risks of CAS, even after adjusting for multiple CVD risk factors. In individuals with NAFLD, increased noninvasive liver fibrosis markers were independently associated with elevated CAS risk, which may be beneficial in assessing the risk of CVD in individuals with NAFLD. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions Fibroblast growth factor 19 (FGF19) is an intestinal‐derived factor that plays a role in metabolic diseases. We performed a differential study of circulating FGF19 levels and investigated the causal effects of FGF19 on metabolic diseases using Mendelian randomization (MR).Firstly, 958 subjects were included in the physical examination center of affiliated hospital from January 2019 to January 2021. Dividing the subjects into different subgroups to compare FGF19 levels. We conducted a two‐sample MR analysis of genetically predicted circulating FGF19 in relation to alcohol, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available genome‐wide association study summary statistics data.The circulating FGF19 levels in nonalcoholic fatty liver disease (NAFLD) patients were lower than those without NAFLD (P < 0.001). The FGF19 levels in participants with obese were lower than those without obese (P < 0.001). In two‐sample MR analyses, genetically predicted higher circulating FGF19 levels was significantly associated with lower aspartate aminotransferase, γ‐glutamyltransferase, triglycerides, total cholesterol, low‐density lipoprotein, and C‐reactive protein concentrations (P < 0.05) and a negative correlation with cardiovascular disease and cirrhosis whereas a positive association with type 2 diabetes mellitus (P < 0.05).Our study found that circulating FGF19 levels were lower in NAFLD and obese populations. Additionally, our MR research results support the causal effects of FGF19 on improved liver function, lipids, and reduced the occurrence of inflammation, cardiovascular disease, and cirrhosis. We found a positive correlation with diabetes, which may indicate a compensatory increase in regulating above FGF19 resistance states in humans. [ABSTRACT FROM AUTHOR]

Background and Aim: The introduction of the latest nomenclature, metabolic associated steatotic liver disease (MASLD), proposed by the multi‐society without Asian society consensus statement, aims to redefine the diagnostic criteria for metabolic associated fatty liver disease (MAFLD). However, its effect on the epidemiology in Asia remains unclear. Method: We conducted a population‐based cross‐sectional survey on fatty liver disease using multistage stratified random sampling of participants from Guangzhou, a representative area in China (ChiCTR2000033376). Demographic, socioeconomic, lifestyle, and laboratory data were collected. Hepatic steatosis and the severity of fibrosis were assessed using FibroScan. Results: A total of 7388 individuals were recruited, the proportion of which meeting the definitions for nonalcoholic fatty liver disease (NAFLD), MAFLD, and MASLD were 2359 (31.9%), 2666 (36.1%), and 2240 (30.3%), respectively. One hundred and twenty (1.6%) patients had cryptogenic SLD, and 537 (7.3%) patients were diagnosed with MetALD. MASLD did not significantly differ from NAFLD and MAFLD, except that MAFLD patients had a lower proportion of males, hypertension, and diabetes and were less likely to consume tea (P < 0.05). Both cryptogenic SLD and MASLD non‐MAFLD patients exhibited milder hepatic steatosis and a lower frequency of liver injury than NAFLD, MAFLD, or MASLD patients (all P < 0.05). An increased HOMA‐IR (adjusted OR: 1.33, 95% CI: 1.10–2.03) was associated with higher risk of moderate‐to‐severe steatosis for MASLD non‐MAFLD patients, while consuming more cups of tea (P for trend = 0.015) showed inverse associations. Conclusion: Irrespective of terminology used is that fatty liver disease is highly prevalent in the Han Chinese population. Differences in insulin resistance and lifestyle risk factors are associated with redefinition disparities. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Steatotic liver disease is common in people with HIV (PWH). Identifying those with advanced fibrosis (AF, bridging fibrosis or cirrhosis), F3-4, is important. We aimed to examine the performance of FIB-4 and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) in PWH to identify those with AF assessed by liver stiffness measurement (LSM). METHODS: We prospectively collected data on adults participating in 2 National Institute of Health-sponsored HIV NAFLD networks. All had HIV on antiretroviral therapy (ART) ≥6 months with HIV RNA <200 copies/mL. Those with viral hepatitis, other liver disease, excessive alcohol use, or hepatic decompensation were excluded. Vibration-controlled transient elastrography for LSM was performed, and AF defined as ≥11 kPa was compared with FIB-4 and NFS at predefined thresholds (<1.3 and >2.67 for FIB-4 and <-1.455 and >0.675 for NFS). RESULTS: A total of 1,065 participants were analyzed: mean age 51.6 years, 74% male, 28% White, 46% Black, 22% Hispanic, with 34% overweight (body mass index 25-29 kg/m²) and 43% obese (body mass index ≥30 kg/m²). Features of the metabolic syndrome were common: hyperlipidemia 35%, type 2 diabetes 17%, and hypertension 48%. The median CD4+ T-cell count was 666 cells/mm³, 74% had undetectable HIV RNA, and duration of HIV-1 was 17 years with most taking a nucleoside reverse transcriptase inhibitor (92%) and an integrase inhibitor (83%). The mean LSM was 6.3 kPa, and 6.3% had AF. The area under the receiver characteristic curve for FIB-4 and NFS to identify AF were 0.70 and 0.75, respectively. While both had high negative predictive values (97%-98%), the sensitivity at low thresholds and specificity at high thresholds were 64% and 97% for FIB-4 and 80% and 96% for NFS, respectively. Neither FIB-4 nor NFS at either threshold had good positive predictive value to detect AF. DISCUSSION: FIB-4 and NFS have excellent specificity and negative predictive value for detecting AF, and thus can be used as screening tools in PWH to exclude those with AF who do not need further testing (LSM) or referral to hepatologist. [ABSTRACT FROM AUTHOR]

Background: The current study aims to assess cardiovascular risk factors (CVRFs) among diabetic versus nondiabetic nonalcoholic fatty liver disease (NAFLD) patients. NAFLD is the most common hepatic disorder worldwide which is directly associated with diverse CVRFs such as type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS). Materials and Methods: The current cross-sectional population-based study has been conducted on 1031 NAFLD patients. After excluding 340 prediabetes patients, the NAFLD patients were divided into T2DM and normal blood glucose (NBG). Then, CVRFs were compared between the two groups. Results: Out of 691 NAFLD cases included in the study, 337 (48.8%) patients had T2DM. In the T2DM and NBG groups, the body mass index (BMI) was 31.2 ± 4.6 and 29.9 ± 4.3 kg/m2, respectively (P = 0.001). The waist circumference was 102.2 ± 10.2 and 97.6 ± 10.6 cm, respectively (P < 0.001). The systolic blood pressure was 123.3 ± 15.6 and 119.6 ± 13.6 mmHg, respectively (P = 0.043). The triglyceride levels were 191.9 ± 104.7 and 176.5 ± 89.6 mg/dL, respectively (P = 0.042). Generally, these factors were significantly higher among the diabetic patients. Besides, cardiovascular disease (CVD), hypertension, and MS were statistically more prevalent in NAFLD patients with T2DM (P < 0.001) than nondiabetic NAFLD patients. In multiple logistic regression models, the odds ratio of CVD, hypertension, and MS was 2.18, 2.12, and 6.63 for patients with T2DM compared with NBG, respectively. Adjustment was made for age, sex, BMI, smoking, and physical activity. Conclusion: CVRFs were higher in NAFLD patients with T2DM than NAFLD patients with NBG. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) affects over a third of the US population and 25% globally, with current treatments proving ineffective. This study investigates whether manipulating brown adipose tissue (BAT) and beige fat activity by housing C57BL/6J mice at thermoneutral (27 °C) or standard temperatures (22 °C) impacts NAFLD development. Male mice were fed either a chow diet (CHD) or a "fast food" diet (FFD) for 10 weeks. Mice at 27 °C had reduced food intake but increased body weight and plasma leptin levels. FFD-fed mice at 27 °C had greater liver weight (2.6 vs. 1.8 g), triglyceride content (7.6 vs. 3.9 mg/g), and hepatic steatosis compared to those at 22 °C. Gene expression of fatty acid synthase, sterol regulatory element-binding protein 1, and fatty acid translocase CD36 was elevated in FFD-fed mice at 27 °C, but not in CHD-fed mice. Thermoneutral housing also reduced expression of thermogenic markers in BAT and inguinal white adipose tissue (WAT) and caused BAT whitening. In conclusion, thermoneutrality inhibits thermogenic markers and exacerbates NAFLD. Activating BAT or promoting WAT browning via cold exposure or other stimuli may offer a strategy for managing NAFLD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease is the most prevalent chronic liver disease globally and is linked to augmented susceptibility to type 2 diabetes mellitus (DM), cardiovascular disease, and microvascular complications inherent to DM, such as nephropathy, neuropathy, and retinopathy. The fibrosis-4 (FIB-4) scoring system, a noninvasive tool, is useful for predicting the extent of liver fibrosis across diverse pathologies. This study aimed to assess the potential predictive role of FIB-4 scores in microvascular complications associated with diabetes. The medical records of patients with type 2 DM admitted to our endocrinology clinic between February 2019 and December 2020 were retrospectively evaluated. Parameters including demographic attributes, fasting blood glucose, glycated hemoglobin, aspartate aminotransferase, alanine aminotransferase, thrombocyte levels, and microvascular complications were recorded. The FIB-4 score was computed, and patients were categorized based on these scores (<1.3 and ≥ 1.3). The analysis included 312 patients with a median age of 60 (50–68 years); 39.7 % were men. The median duration of diabetes was 10 years (5–20 years), and the median FIB-4 score was 0.93 (0.63–1.34). Neuropathy, nephropathy, and retinopathy were observed in 50.6 %, 31.4 %, and 34 % of the patients, respectively. Although the FIB-4 score did not differ significantly between patients with and without neuropathy or retinopathy, patients with nephropathy exhibited higher FIB-4 scores. Notably, patients with FIB-4 scores ≥ 1.3 demonstrated a significantly higher prevalence of nephropathy. Logistic regression analysis demonstrated that higher FIB-4 scores were significantly associated with an increased risk of nephropathy. The FIB-4 score is a cost-effective and straightforward tool with potential applicability in predicting nephropathy in individuals with type 2 DM. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) constitutes an independent risk factor for the development of coronary heart disease. Low-grade inflammation has been shown to play an important role in the development of atherosclerosis and NAFLD. Free fatty acid receptor 4 (FFAR4/GPR120), which is involved in damping inflammatory reactions, may represent a promising target for the treatment of inflammatory diseases. Our objective was to evaluate the effect of TUG-891, the synthetic agonist of FFAR4/GPR120, on fatty liver in vivo. Methods: The effect of TUG-891 on fatty liver was investigated in apoE−/− mice fed a high-fat diet (HFD), using microscopic, biochemical, molecular, and proteomic methods. Results: Treatment with TUG-891 inhibited the progression of liver steatosis in apoE−/− mice, as evidenced by histological analysis, and reduced the accumulation of TG in the liver. This action was associated with a decrease in plasma AST levels. TUG-891 decreased the expression of liver genes and proteins involved in de novo lipogenesis (Srebp-1c, Fasn and Scd1) and decreased the expression of genes related to oxidation and uptake (Acox1, Ehhadh, Cd36, Fabp1). Furthermore, TUG-891 modified the levels of selected factors related to glucose metabolism (decreased Glut2, Pdk4 and Pklr, and increased G6pdx). Conclusion: Pharmacological stimulation of FFAR4 may represent a promising lead in the search for drugs that inhibit NAFLD. [ABSTRACT FROM AUTHOR]

Purpose: The need to investigate the pathogenesis and treatment of nonalcoholic fatty liver disease (NAFLD) has led to the development of multiple mouse models. The aim of this study was to validate a fast food diet (FFD) mouse model that is introduced as being close to the human disease. Methods: Eight to nine weeks old male and female C57BL/6 J mice were randomly allocated to a FFD group or to a chow diet (CD) group. Every four weeks, mice were weighed, and blood samples were collected for the measurement of glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TGs) and total cholesterol. After 25 weeks, mice were sacrificed, and liver tissue was histologically evaluated. Results: FFD mice gained more weight (p = 0.049) and presented a higher liver-to-body weight ratio (p < 0.001) compared to CD mice. FFD group presented with greater steatosis, hepatocellular ballooning and NAFLD activity score (NAS), whereas lobular inflammation and fibrosis were not significantly different compared to CD. When stratified by sex, NAS was different between FFD and CD groups in both male and female mice. Group by time interaction was significant for weight, ALT and cholesterol, but not for glucose, AST and TGs. Conclusion: FFD mice presented with morphologic and biochemical features of NAFLD and with greater hepatic steatosis, hepatocellular ballooning and NAS, but not lobular inflammation and fibrosis, compared to CD mice. These results only partly validate the FFD mouse model for NAFLD, at least for a 6-month feeding period. [ABSTRACT FROM AUTHOR]

Purpose To explore the relationship between liver fat content (LFC) and nonalcoholic fatty liver disease (NAFLD) and determine the new threshold of LFC to diagnose NAFLD. Methods The data from questionnaire survey, general physical examination, laboratory examination, and image examination were collected. Multivariate regression analysis, receiver operating characteristic curve analysis, smooth curve fitting, and threshold effect analysis were performed using the R software to investigate the relationship between LFC and NAFLD and to identify the new threshold of LFC to diagnose NAFLD. Results The prevalence of NAFLD was 30.42%, with a significantly higher prevalence in men than in women. Regression analyses demonstrated that LFC odds ratio [95% confidence interval (CI)] was 1.28 (95% CI: 1.24–1.31) in fully-adjust model. Analysis of the LFC quartile, with Q1 as a reference, revealed that the odds ratios of NAFLD were 1.47 (95% CI: 1.08–1.99), 2.29 (95% CI: 1.72–3.06), and 10.02 (95% CI: 7.45–13.47) for Q2, Q3, and Q4 groups, respectively. Smooth curve fitting and threshold effect analysis displayed a nonlinear relationship between LFC and NAFLD, and the threshold was 4.5%. The receiver operating characteristic curve indicated that when LFC was 4.5%, the area under curve (95% CI) was 0.80 (0.79–0.82), and the sensitivity and specificity of LFC in diagnosing NAFLD were 0.64% and 0.82%, respectively. Conclusion The relationship between LFC and NAFLD was sigmoidal, with an inflection point of 4.5%. What is already known on this topic At present, there is no standard and uniform threshold for QCT diagnosis of hepatic steatosis, and its threshold is based on MRI. Therefore, this study aimed to explore the correlation between LFC and NAFLD and establish a novel threshold of LFC to diagnose NAFLD. What this study adds This is the first study to report a sigmoidal relationship between LFC and NAFLD with a threshold effect. When LFC was higher than 4.5%, the risk of NAFLD was significantly increased. LFC can be quantified by QCT, which can be a valuable tool for evaluating the NAFLD risk. How this study might affect research, practice, or policy The results of this study have important implications for research, practice, and policy. QCT can be utilized as a noninvasive technique for quantitatively assessing hepatic steatosis, providing a valuable reference for screening, diagnosing, and evaluating the treatment effect of NAFLD. [ABSTRACT FROM AUTHOR]

The aim of this meta‐analysis is to investigate the sources of heterogeneity in randomized clinical trials examining the effects of curcumin supplementation on liver aminotransferases in subjects with nonalcoholic fatty liver disease (NAFLD). We conducted a systematic search of the PubMed, SCOPUS, and Web of Science databases for randomized clinical trials and identified 15 studies (n = 835 subjects). We used random‐effects models with DerSimonian‐Laird methods to analyze the serum levels of alanine aminotransferase and aspartate aminotransferase enzymes. Our results indicate that curcumin did not affect serum alanine aminotransferase, but it did reduce aspartate aminotransferase levels. Notably, both outcomes showed high heterogeneity (p < 0.01). Subgroup analysis revealed that adding piperine to curcumin did not benefit aminotransferase levels in NAFLD patients. Additionally, we found a negative correlation between the duration of the intervention and the relative (mg/kg/day) curcumin dose with the reduction in liver aminotransferases. In summary, the sources of heterogeneity identified in our study are likely attributed to the duration of the intervention and the relative dose of curcumin. Consequently, longer trials utilizing high doses of curcumin could diminish the positive impact of curcumin in reducing serum levels of aminotransferases in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a disorder in which excess fat accumulates in hepatocytes and can lead to serious complications. Oxidative stress is one of the leading causes of NAFLD. Pomegranates are considered antioxidant‐rich fruit. This systematic review study was aimed to investigate the impact of pomegranate on NAFLD. PubMed, Scopus, and Google Scholar databases/search engines (from inception up to July 2023) were searched for interventional studies (human and animal) that examined the effects of supplementation with different parts of pomegranate including fruits, peels, seeds, or flower on NAFLD outcomes. A total of 222 articles were retrieved following the initial search. After excluding duplicates, the title and abstract of 114 articles were screened. Afterward, irrelevant articles were removed and the full texts of the remaining 27 articles were reviewed. Eventually, 19 articles (16 animal and three human interventional studies) that met the inclusion criteria, published between 2009 and 2023, were included in this systematic review. Our study indicates the potential beneficial effects of different parts of pomegranate on the improvement of NAFLD. However, given that the majority of the included articles were animal studies, further investigations in the form of human clinical trials are warranted to suggest a clinical indication of such interventions. [ABSTRACT FROM AUTHOR]

Context The cardiovascular benefits of semaglutide are established; however, its effects on surrogate vascular markers and liver function are not known. Objective To investigate the effects of semaglutide on vascular, endothelial, and liver function in patients with type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD). Methods Overall, 75 consecutive subjects with T2DM and NAFLD were enrolled: 50 patients received semaglutide 1 mg (treatment group) and 25 patients received dipeptidyl peptidase 4 inhibitors (control group). All patients underwent a clinical, vascular, and hepatic examination with Fibroscan elastography at 4 and 12 months after inclusion in the study. Results Treatment with semaglutide resulted in a reduction of Controlled Attenuation Parameter (CAP) score, E fibrosis score, NAFLD fibrosis score, Fibrosis-4 (FIB-4) score and perfused boundary region (PBR) at 4 and at 12 months (P <.05), contrary to controls. Patients treated with semaglutide showed a greater decrease of central systolic blood pressure (SBP) (−6% vs −4%, P =.048 and −11% vs −9%, P =.039), augmentation index (AIx) (−59% vs −52%, P =.041 and −70% vs −57%, P =.022), and pulse wave velocity (PWV) (−6% vs −3.5%, P =.019 and −12% vs −10%, P =.036) at 4 and at 12 months, respectively. In all patients, ΔPWV and ΔPBR were correlated with a corresponding reduction of CAP, E fibrosis, NAFLD fibrosis, and FIB-4 scores. Conclusion Twelve-month treatment with semaglutide simultaneously improves arterial stiffness, endothelial function, and liver steatosis and fibrosis in patients with T2DM and NAFLD. [ABSTRACT FROM AUTHOR]

The purpose of the present clinical trial was to determine the impact of zinc supplementation on serum liver enzymes, steatosis severity, lipid profile, and inflammatory status in overweight or obese children with nonalcoholic steatohepatitis (NASH). This randomized controlled trial was conducted by enrolling 60 children with NASH, aged 10–18 years old. The participants were randomly assigned to two groups that received either 30 mg/day of elemental zinc or placebo for 16 weeks. The severity of liver steatosis was evaluated using liver ultrasonography. Fasting blood samples were collected from each patient at the beginning and after 16 weeks of intervention to measure biochemical parameters. Following a 16-week intervention, zinc supplementation compared with placebo significantly decreased serum alanine aminotransferase (ALT) concentrations and high-sensitivity C-reactive protein and considerably enhanced HDL-cholesterol values. However, zinc intake had no considerable impact on aspartate aminotransferase, the severity of liver steatosis, anthropometric parameters, and other lipid indices versus the placebo group. Overall, zinc supplementation showed a promising impact on serum ALT, HDL-cholesterol, and inflammatory status in overweight or obese children suffering from NASH. Zinc supplementation may be a new strategy for the amelioration of NASH in overweight or obese children. This trial has been registered on the Iranian website for registration of clinical trials with the special ID of IRCT20200531047614N1 (https://www.irct.ir/trial/48543). [ABSTRACT FROM AUTHOR]

Background and Aims: This study examines the relationships between epicardial adipose tissue (EAT), nonalcoholic fatty liver disease (NAFLD), and coronary artery calcium score (CACS) using non‐ECG‐gated CT scans. It aims to determine the effectiveness of EAT measurements and NAFLD as predictors for coronary artery disease (CAD). Methods: This cross‐sectional study was conducted at a specialized center, focusing on individuals who underwent non‐ECG‐gated chest CT scans without contrast. We evaluated EAT thickness and density in three areas: the right atrioventricular groove, the free wall of the right ventricle, and the central area of the right anterior interventricular groove. Additionally, we measured CACS and determined the presence of NAFLD by comparing liver‐to‐spleen density ratios. Statistical analyses, including regression models, were performed using SPSS (version 26). Results: In this study, we enrolled 365 participants, including 203 males with an average age of 47 ± 17.93 years. EAT thickness was 6.28 ± 1.62 mm, and EAT density was −96.07 ± 12.47 Hounsfield units (HU). The mean CACS was 22.27 ± 79.01, and the mean liver density was 50.01 ± 10.76 HU. A significant positive correlation was observed between EAT thickness and CACS (r = 0.208, p < 0.001). EAT density showed a significant negative correlation with CACS (r = −0.155, p = 0.003). No correlation was found between NAFLD and CACS. Univariate logistic regression analysis identified significant predictors of increased CACS, including EAT thickness (OR: 1.803), EAT density (OR: 0.671), diabetes mellitus (DM) (OR: 5.921), and hypertension (HTN) (OR: 7.414). Multivariate analysis confirmed the significance of EAT thickness (OR: 0.682), DM (OR: 3.66), and HTN (OR: 2.79) as predictors of elevated CACS. Conclusion: Our findings demonstrate that increased EAT thickness and decreased density are associated with higher CACS. Also, both DM and HTN significantly contribute to increased CACS. These results support the inclusion of EAT measurements in cardiovascular risk assessment models to enhance diagnostic accuracy. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the immunogenicity of the hepatitis B virus (HBV) vaccine by applying a normal and high-dose hepatitis B virus vaccination program in the mice modeling of non-alcoholic fatty liver disease (NAFLD). NAFLD was induced in mouse livers via diet. At the 10-week mark, both groups were divided into 3 subgroups. While the standard dose vaccination program was applied on days 0, 7, and 21, two high-dose programs were applied: one was applied on days 0 and 7, and the other was applied on days 0, 7, and 21. All mice were euthanized. Blood samples from anti-HB titers; T follicular helper, T follicular regulatory, CD27+, and CD38+ cells; and the liver, spleen, and thymus were taken for histopathologic evaluation. NAFLD subgroups receiving high doses showed higher hepatocyte ballooning scores than normal-dose subgroup. There were differences in CD27+ and CD27+CD38+ cells in animals fed on different diets, without any differences or interactions in terms of vaccine protocols. In the NAFLD group, a negative correlation was observed between anti-HB titers and T helper and CD27+ cells, while a positive correlation was observed with CD38+ cells. NAFLD induced changes in immune parameters in mice, but there was no difference in vaccine efficacy among the applied vaccine protocols. Based on this study's results, high-dose vaccination protocols are not recommended in cases of NAFLD, as they do not enhance efficacy and may lead to increased liver damage. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in patients with diabetes; limited data suggested that statins may reduce the risk of NAFLD progression. This study aimed to examine the association between statins and the development or progression of NAFLD in veterans with diabetes. In a new-user negative control design, we conducted a retrospective propensity score (PS)-matched cohort study of patients with diabetes between 2003 and 2015. After excluding patients with other causes of liver disease, we formed PS using 85 characteristics. The primary outcome was a composite NAFLD progression outcome. Primary analysis examined odds of outcome in PS-matched cohort. Post-hoc analysis included a PS-matched cohort of statin users with intensive lowering of low-density lipoprotein-cholesterol (LDL-C) vs low-intensity lowering. We matched 34,102 pairs from 300,739 statin users and 38,038 non-users. The composite outcome occurred in 8.8% of statin users and 8.6% of non-users (odds ratio (OR) 1.02, 95% confidence interval (95% CI) 0.97–1.08). In the post-hoc analysis, intensive lowering of LDL-C compared to low-intensity showed increased NAFLD progression (OR 1.21, 95% CI 1.13–1.30). This study showed that statin use in patients with diabetes was not associated with decreased or increased risk of NAFLD progression. Intensive LDL-C lowering, compared to low-intensity LDL-C lowering, was associated with an increased risk of NAFLD progression. [ABSTRACT FROM AUTHOR]

Background: GLP-1 receptor agonists (GLP-1 RAs) have been shown to improve glycemic control and insulin sensitivity and reduce body weight in obese patients with type 2 diabetes mellitus (T2D). This trial sought to evaluate the therapeutic effect of oral and subcutaneous semaglutide in NAFLD and its sequelae in obesity and/or T2D. Methods: In an open-labelled intervention study, the sample was 180 patients classified into three parallel groups (1:1:1): group I received oral semaglutide, group II patients received injectable semaglutide, and group III received pioglitazone and/or vitamin E. Patients were evaluated at 6 and 12 months. Results: There was a substantial improvement in lipid profile, liver enzymes, and body mass index, especially in group II. As for HDL, only group II showed a consistent increase at both 6 months (51 ± 4.62 mg/dL) and 12 months (50.08 ± 2.45 mg/dL) compared with baseline (45.6 ± 6.37 mg/dL) (p-value < 0.001). Despite the non-significant difference in NAFLD fibrosis score (NFS) (p-value = 0.45 and 0.63), group II had significantly lower scores of the fibrosis-4 score (FIB-4), liver stiffness measurement (LSM), and controlled attenuation parameter (CAP) at 6 and 12 months (p-value < 0.001). Conclusions: Semaglutide improves lipid profile, liver steatosis, and fibrosis parameters and reduces the BMI in T2D and obese patients with NAFLD. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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]

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]

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]

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]

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]

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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]

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]

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 Aim: We aimed to explore the associations of baseline and cumulative cardiovascular health with nonalcoholic fatty liver disease (NAFLD) development and regression using the new Life's Essential 8 score. Methods: From a health screening database, participants who underwent at least 4 health examinations between 2012 and 2022 were recruited and categorized into two cohorts: (a) the NAFLD development cohort with no history of NAFLD prior to Exam 4 and (b) the NAFLD regression cohort with diagnosed NAFLD prior to Exam 4. The LE8 score was calculated from each component. The outcomes were defined as newly incident NAFLD or regression of existing NAFLD from Exam 4 to the end of follow-up. Results: In the NAFLD development cohort, of 21,844 participants, 3,510 experienced incident NAFLD over a median follow-up of 2.3 years. Compared with the lowest quartile of cumulative LE8, individuals in the highest quartile conferred statistically significant 76% lower odds (hazard ratio [HR] 0.24, 95% confidence interval [CI], 0.21–0.28) of NAFLD incidence, and corresponding values for baseline LE8 were 42% (HR 0.58, 95% CI 0.53–0.65). In the NAFLD regression cohort, of 6,566 participants, 469 experienced NAFLD regression over a median follow-up of 2.4 years. Subjects with the highest quartile of cumulative LE8 had 2.03-fold (95% CI, 1.51–2.74) higher odds of NAFLD regression, and corresponding values for baseline LE8 were 1.61-fold (95% CI, 1.24–2.10). Conclusion: Cumulative ideal cardiovascular health exposure is associated with reduced NAFLD development and increased NAFLD regression. Improving and preserving health behaviors and factors should be emphasized as an important part of NAFLD prevention and intervention strategies. [ABSTRACT FROM AUTHOR]

Background: Although inflammation has been linked to nonalcoholic fatty liver disease (NAFLD), most studies have focused only on a single indicator, leading to inconsistent results. Therefore, a large prospective study that includes a variety of well-documented single and composite indicators of inflammation is needed. This study aimed to thoroughly investigate the potential associations between different systemic inflammatory indicators and NAFLD in the UK Biobank cohort. Methods: After excluding ineligible participants, 378,139 individuals were included in the study. Associations between systemic inflammatory indicators and hepatic steatosis were assessed using multivariate logistic regression. The relationships between systemic inflammatory indicators and nonalcoholic fatty liver disease were analysed using Cox proportional hazards models, and nonlinear associations were investigated using restricted cubic splines. Results: According to the cross-sectional analysis, systemic inflammatory indicators significantly correlated with hepatic steatosis. Over a median followup of 13.9 years, 4,145 individuals developed NAFLD. After sufficient adjustment for confounding factors, CRP levels were found to be nonlinearly positively associated with NAFLD risk (P<0.001), representing the strongest correlation among the tested relationships; lymphocyte count and the LMR showed an L-shaped correlation; monocyte count and neutrophil count showed a linear positive correlation (all P< 0.001); and the NLR, PLR, and SII showed a U-shaped correlation (all P<0.001). Conclusions: Multiple systemic inflammatory indicators are strongly associated with the development of NAFLD, and aggressive systemic inflammation management may have a favourable impact on reducing the burden of NAFLD; further randomized controlled studies are needed. [ABSTRACT FROM AUTHOR]

Background: With the global rise in obesity, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common chronic liver disease. Concurrently, depression is a highly prevalent mental disorder. As the incidence of MASLD and depression continues to increase, a growing body of research indicates a potential association between the two conditions. However, the direction of causality between depression and MASLD remains uncertain. To address this gap, our study utilizes a two-sample Mendelian randomization (MR) approach to explore the bidirectional causal relationship between depression and MASLD. Methods: We extracted single nucleotide polymorphisms (SNPs) associated with depression and MASLD from pooled data of genome-wide association studies (GWAS). A comprehensive assessment of possible causality was also performed. Possible mediating effects of liver enzymes on MASLD were also assessed. Results: A total of three GWAS pooled data on depression as well as GWAS data related to MASLD and GWAS data on four liver enzymes were used in this study. Our findings indicated a strong causal relationship between depression and MASLD (OR, 1.557; 95% CI, 1.097-2.211; P = 0.016). And we found a mediating effect of gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ALT 10% (95% CI: 7% - 13%, P< 0.0002). AST, 4.14% (95% CI: 2.34% - 5.94%, P < 0.05). GGT 0.19% (95% CI: 0.15% - 0.22%, P< 0.000000002). However, we did not find a mediating effect of alkaline phosphatase (ALP). Our inverse MR analysis did not reveal any causal relationship between MASLD and depression. Conclusions: The MR analysis revealed a positive causal relationship between depression and MASLD, while no reverse causal relationship was identified. Liver enzymes may mediate the role between depression and MASLD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is marked by hepatic steatosis accompanied by an inflammatory response. At present, there are no approved therapeutic agents for NAFLD. Dendrobium Huoshanense polysaccharide (DHP), an active ingredient extracted from the stems of Dendrobium Huoshanense, and exerts a protective effect against liver injury. However, the therapeutic effects and mechanisms of action DHP against NAFLD remain unclear. DHP was extracted, characterized, and administered to mice in which NAFLD had been induced with a high-fat and high-fructose drinking (HFHF) diet. Our results showed that DHP used in this research exhibits the characteristic polysaccharide peak with a molecular weight of 179.935 kDa and is composed primarily of Man and Glc in a molar ratio of 68.97:31.03. DHP treatment greatly ameliorated NAFLD by significantly reducing lipid accumulation and the levels of liver function markers in HFHF-induced NAFLD mice, as evidenced by decreased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and total triglyceride (TG). Furthermore, DHP administration reduced hepatic steatosis, as shown by H&E and Oil red O staining. DHP also inhibited the Toll-like receptor 4 (TLR4)/nuclear factor- kappa B (NF-κB) signaling pathway expression, thereby reducing levels of hepatic proinflammatory cytokines. Besides, untargeted metabolomics further indicated that 49 metabolites were affected by DHP. These metabolites are strongly associated the metabolism of glycine, serine, threonine, nicotinate and nicotinamide, and arachidonic acid. In conclusion, DHP has a therapeutic effect against NAFLD, whose underlying mechanism may involve the modulation of TLR4/NF-κB, reduction of inflammation, and regulation of the metabolism of glycine, serine, threonine, nicotinate and nicotinamide metabolism, and arachidonic acid metabolism. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by hepatic steatosis and cardiometabolic risk factors like obesity, type 2 diabetes, and dyslipidemia. Persistent metabolic injury may promote inflammatory processes resulting in metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. Mechanistic insights helped to identify potential drug targets, thereby supporting the development of novel compounds modulating disease drivers. The U.S. Food and Drug Administration has recently approved the thyroid hormone receptor β-selective thyromimetic resmetirom as the first compound to treat MASH and liver fibrosis. This review provides a comprehensive overview of current and potential future pharmacotherapeutic options and their modes of action. Lessons learned from terminated clinical trials are discussed together with the first results of trials investigating novel combinational therapeutic approaches. Approval of resmetirom as the first anti-MASH agent may revolutionize the therapeutic landscape. However, long-term efficacy and safety data for resmetirom are currently lacking. In addition, heterogeneity of MASLD reflects a major challenge to define effective agents. Several lead compounds demonstrated efficacy in reducing obesity and hepatic steatosis, while anti-inflammatory and antifibrotic effects of monotherapy appear less robust. Better mechanistic understanding, exploration of combination therapies, and patient stratification hold great promise for MASLD therapy. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular Carcinoma (HCC) can be classified as one of the most common malignancies worldwide. There is scarcity of the published data on the risk factors for HCC in the Gulf Cooperation Council countries specifically Kuwait. Therefore, this case-control study sought to examine the risk factors associated with HCC in Kuwait. Methods: Fifty-three histopathologically confirmed HCC cases were recruited from the Kuwait Cancer Control Center Registry. One hundred ninety-six controls (1:4 ratio) were selected from medical and/ or surgical outpatient's clinics at all six public hospitals of Kuwait. A structured questionnaire was used to collect the data both from cases and controls through face-to-face interviews. A multivariable logistic regression model was fitted to the case-control data. Adjusted odds ratios (ORadj) and their 95% confidence intervals (CI) were computed using the parameters' estimates of the final model and used for interpretation of the model. Results: The HCC cases compared with the controls were 41.6 times more likely to have had the history of non-alcoholic fatty liver disease (NAFLD) (ORadj = 41.6; 95% CI: 8.9–193.5; p < 0.001). The cases compared with the controls were more likely to have reported the history of heavy alcohol drinking (ORadj = 14.2; 95% CI: 1.2–173.4; p = 0.038). Furthermore, compared with the controls, the HCC cases tended to frequently consume milk and/or milk substitutes (≥ 3 glass/ week) (ORadj = 7.2; 95% CI: 1.2–43.4). Conversely however, there was a significant protective effect if the participants reportedly have had regularly used olive oil in their routine diet as a source of fat (ORadj = 0.17; 95% CI: 0.04–0.80) or regularly used non-steroid anti-inflammatory drugs (NSAIDs) (ORadj = 0.20; 95% CI: 0.05–0.71). Conclusions: This study showed that heavy alcohol consumption, NAFLD history, and excessive consumption of milk/ milk substitutes were associated with a significantly increased HCC risk. Conversely however, regular use of olive oil in the diet as a source of fat or regular use of NSAIDs had a significantly protective effect against HCC risk. Adapting healthy dietary habits and preventing/ treating NAFLD may minimize the HCC risk. Future research with a larger sample size may contemplate validating the results of this study and unraveling additional risk factors contributing to HCC risk. The resultant data may help design and implement evidence-based educational programs for the prevention of HCC in this and other similar settings. [ABSTRACT FROM AUTHOR]