Nonalcoholic Fatty Liver Disease Research Articles

Evolving epidemiology of NAFLD in South Korea: incidence, prevalence, progression, and healthcare implications from 2010 to 2022.

Non-alcoholic fatty liver disease (NAFLD), now the most common chronic liver worldwide, has become a significant public health concern. This study aims to analyze the evolving epidemiology of NAFLD in South Korea. We utilized claim data from the Korean National Health Insurance Service from 2010 to 2022 to analyze NAFLD's incidence, prevalence, and progression. From 2010 to 2022, the incidence and prevalence rates of NAFLD each increased from 1.87% to 4.47% and from 10.49% to 17.13%, respectively. The differences in prevalence rates between urban and rural areas were minimal in 2012 and 2022, yet both areas showed significant increases in the prevalence of NAFLD over the decade. The NAFLD group had a higher prevalence of comorbidities compared to the control group, and the most common comorbid condition was hypertension. Moreover, the ten-year incidence rates of malignancy, heart disease, and stroke in the NAFLD group were 13.42%, 15.72%, and 8.36%, respectively, which were significantly higher than those in the control group. The incidence rates of cirrhosis and hepatocellular carcinoma in NAFLD over 10 years were 2.22% and 0.77%, respectively. The total medical costs of NAFLD patients more than doubled over ten years and were all significantly higher than those of the control group. A significant increase in NAFLD prevalence and its impact on healthcare utilization was observed in South Korea. With NAFLD leading to serious liver diseases and increased healthcare costs, integrated care strategies that include both medical treatment and lifestyle modifications are essential.

Nuciferine Alleviates High-Fat Diet- and ApoE-/--Induced Hepatic Steatosis and Ferroptosis in NAFLD Mice via the PPARα Signaling Pathway.

Nonalcoholic fatty liver disease (NAFLD) causes significant global mortality and healthcare costs with no recommended pharmacological intervention for clinical management. Nuciferine (Nuc) is an alkaloid with aromatic rings, abundantly found in Nelumbo nucifera Gaertn. In this study, we explored the protective mechanisms of Nuc against hepatic steatosis and ferroptosis in NAFLD. High-fat diet (HFD) and healthy male ApoE-/- mice were used to induce NAFLD and a hypercholesterolemia model. Nuc was administered to the mice for four consecutive weeks from the ninth week. Various assessments, including histopathology, RNA sequencing, lipid metabolism, and ferroptosis-related protein expression, showed that Nuc alleviated hepatic steatosis and ferroptosis. We further showed that Nuc improves fatty acid accumulation and ferroptosis through the PPARα signaling pathway in mice and RSL3-treated AML-12 cells. The PPARα inhibitor GW6471 blocked Nuc's protective effects, leading to excess accumulation of iron ions. Thus, Nuc may be a potential therapeutic agent for NAFLD.

Validation of serum non-invasive tests of liver fibrosis as prognostic markers of clinical outcomes in people with fatty liver disease in Australia.

The validity of non-invasive tests (NITs) of liver fibrosis for the prediction of liver and mortality outcomes in an Australian cohort is unknown. We aimed to verify the utility of available NITs to predict overall and cause-specific mortality and major adverse liver outcome (MALO). This was an analysis from the Crossroads 1 clinic sub-study of a randomly sampled adult cohort from regional Australia between 2001 and 2003. Baseline variables included demographic details, anthropometry, health and lifestyle data, and laboratory tests. Non-alcoholic fatty liver disease (NAFLD) and metabolic-(dysfunction) associated fatty liver disease (MAFLD) were defined by fatty liver index≥60 and other accepted criteria. Outcomes were defined by the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes for linked hospitalization and death registry data. Available serum-based NITs were analyzed as predictors of overall, cardiovascular disease-related, and cancer-related mortality and MALO in those with fatty liver disease (FLD). In total, 1324 and 1444 participants were included for NAFLD and MAFLD analysis (prevalence 35.4% and 40.7%, respectively). There were 298 deaths (89 cardiovascular disease-related and 98 cancer-related) and 24 MALO over a median 19.7years of follow-up time. In both forms of FLD, fibrosis-4 index, Steatosis-Associated Fibrosis Estimator score, and Forns fibrosis score consistently had the highest area under the receiver operating characteristic curve (AUROC) for overall and cause-specific mortality, with AUROC>0.70 for each outcome. However, all had poor discriminatory ability for determining MALO in each FLD. Several liver fibrosis NITs perform similarly reasonably well in predicting the risk of mortality outcomes in those with FLD but are poorly discriminatory for MALO prediction.

Clinical significance of serum FGF21 levels in diagnosing nonalcoholic fatty liver disease early

The endogenous FGF21 level is a potential target for diagnosing NAFLD. This study aimed to assess the clinical utility of FGF21 in diagnosing NAFLD and provide new ideas for predicting and preventing NAFLD. A total of 193 patients diagnosed with NAFLD based on diagnostic criteria and 64 healthy individuals were included in the NAFLD and non-NAFLD groups, respectively. Data on the participant names, sex, age, height, weight, blood pressure, serum FGF21 levels, liver function enzyme (AST, ALT, ALP, and GGT) levels, lipid profile (TC, TG, HDL-C, and LDL-C) indicators, and blood glucose levels were collected. The data were statistically analyzed to assess the correlations between serum FGF21 levels and related biochemical markers in NAFLD patients. The areas under the receiver operating characteristic curves (AUCs) of serum FGF21, lipids (TG + TC + HDL + LDL), and FGF21 combined with lipids for the diagnosis of NAFLD were compared. Compared with the non-NAFLD group, the NAFLD group presented significantly higher levels of FGF21. Serum FGF21 levels in the NAFLD group were positively correlated with the TG, TC, and LDL-C levels (P < 0.05). The area under the receiver operating characteristic curve (AUC) of serum FGF21 for the diagnosis of NAFLD was 0.832 (95% CI: 0.77–0.886, P < 0.001). The AUC of FGF21 combined with lipids (TG + TC + HDL + LDL) for the diagnosis of NAFLD was 0.910 (95% CI: 0.874–0.946, P < 0.001). There is a close association between elevated FGF21 levels and the development of NAFLD. The progression of NAFLD is complex and varied, and its pathogenesis is unclear. Early detection, prevention, and intervention may help slow NAFLD development or even reverse the disease. In this study, we found that the FGF21 level could be used as an auxiliary biological indicator for predicting NAFLD, and the role of FGF21 in the progression of NAFLD deserves to be investigated in the future.

Serum Autotaxin Level Positively Associates with Metabolic Associated Fatty Liver Disease and Hyperuricemia in Postmenopausal Women.

Autotaxin is an adipokine known to affect energy metabolism and lipid homeostasis. We aimed to evaluate serum autotaxin levels in metabolic associated fatty liver disease (MAFLD) and other metabolic disorders in postmenopausal women. Postmenopausal women who received an annual health examination were included. The metabolic and demographic characteristics of the subjects were collected, including age, gender, weight, height, blood pressure, and biochemical parameters. Serum autotaxin level was determined by ELISA. This cross-sectional includes 20 postmenopausal women and 20 age-paired healthy controls. MAFLD patients showed significant metabolic disturbance presented with increased BMI, blood pressure (P＜0.001) and decreased HDL-C (P＜0.05), as well as liver injury companied by elevated ALT (P＜0.05). Serum autotaxin levels were statistically higher in MAFLD (253.1±52.1 vs. 202.2±53.2 ng/mL; P &lt; 0.01) and positively correlated with ALT (P＜0.001), GGT and BMI (P＜0.01), SBP and TG (P＜0.05). Higher autotaxin group demonstrated worsen metabolic states with greater proportion of MAFLD, higher BMI (P＜0.01) and ALT (P＜0.05). Logistic regression analysis revealed that serum autotaxin levels would positively independently predicted MAFLD (OR 1.049, 95% CI 1.001-1.098, P＜0.05) with AUC of 0.763. Serum level of autotaxin is significantly elevated in hyperuricemia group (257.3±60.9 vs. 214.5±49.4 ng/mL; P &lt; 0.05), and positively correlated with uric acid level (P＜0.01). Serum autotaxin would also act as diagnosing parameter of hyperuricemia with AUC of 0.706. Among postmenopausal women, serum autotaxin level is significantly elevated in MAFLD and related to multiple metabolic characteristics, especially hyperuricemia, which would thus serve as a potential non-invasive biomarker as well as a therapeutic target.

Prevalence, Phenotypes, and Comorbidities of Polycystic Ovary Syndrome Among Indian Women

The prevalence of polycystic ovary syndrome (PCOS) varies across the globe. Indian studies on PCOS are limited by poor design, small sizes, regional representations, and varying methods. To estimate the nationwide prevalence of PCOS in India, examine the phenotypic spectrum, and assess the magnitude of comorbidities associated with PCOS. This cross-sectional study recruited 9824 women aged 18 to 40 years from November 1, 2018, to July 31, 2022, across 5 zones of the country. A prevalidated questionnaire dichotomized women into screen-positive and screen-negative groups. Relevant clinical, hormonal, and sonographic assessments categorized women as either women with criteria-based PCOS (ie, National Institutes of Health [NIH] 1990 criteria, Rotterdam 2003 criteria, or Androgen Excess and Polycystic Ovary Syndrome Society [AE-PCOS] criteria), women with partial phenotypes (hyperandrogenism, oligomenorrhea, or polycystic morphology labeled as pre-PCOS), or healthy women, in addition to quantitating various comorbidities. The prevalence and phenotypes of PCOS among women of reproductive age and the burden of comorbidities associated with PCOS. A total of 8993 women (mean [SD] age, 29.5 [6.2] years) were enrolled in this study; 196 women were already diagnosed with PCOS, 2251 were categorized as screen positive, and 6546 were categorized as screen negative. The mean (SD) age of screen-positive women (28.1 [6.4] years) was lower than that of screen-negative women (29.7 [6.1] years) (P < .001), and the mean (SD) age at menarche was higher in the former group (13.2 [1.3] vs 13.1 [1.2] years; P < .001). The national prevalence of PCOS was 7.2% (95% CI, 4.8%-10.8%) by NIH 1990 criteria, 19.6% (95% CI, 12.7%-29.2%) by Rotterdam 2003 criteria, and 13.6% (95% CI, 8.4%-21.6%) by AE-PCOS criteria. Overall, PCOS phenotypes C (501 [40.8%]) and D (301 [24.6%]) were the most common, and 492 women (pre-PCOS subgroup) had oligomenorrhea (n = 75), hyperandrogenism (n = 257), or polycystic ovarian morphology (n = 160) only. Among women with PCOS (n = 1224), obesity was present in 529 (43.2%), dyslipidemia in 1126 (91.9%), nonalcoholic fatty liver disease in 403 (32.9%), metabolic syndrome in 305 (24.9%), impaired glucose tolerance in 111 (9.1%), diabetes in 41 (3.3%), and hypertension in 101 (8.3%). The pre-PCOS subgroup (n = 492) displayed similar metabolic aberrations (dyslipidemia: 390 [79.3%]; metabolic syndrome: 78 [15.9%]; nonalcoholic fatty liver disease: 163 [33.1%]; impaired glucose tolerance: 62 [12.6%]; diabetes: 7 [1.4%]; and hypertension: 26 [5.3%]). In this cross-sectional study of reproductive-age women recruited across India, the prevalence of PCOS was high, with phenotype C being predominant. Most of these women had metabolic abnormalities. These findings are crucial for developing preventive and therapeutic strategies, potentially integrating PCOS management into national health programs.

Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression

Nonalcoholic steatohepatitis (NASH) is a prevalent chronic disease, yet its exact mechanisms and effective treatments remain elusive. Nuclear receptor subfamily 5 group A member 2 (NR5A2), a transcription factor closely associated with cholesterol metabolism in the liver, has been hindered from comprehensive investigation due to the lethality of NR5A2 loss in cell lines and animal models. To elucidate the role of NR5A2 in NASH, we generated hepatocyte-specific knockout mice for Nr5a2 (Nr5a2HKO) and examined their liver morphology across different age groups under a regular diet. Furthermore, we established cell lines expressing haploid levels of NR5A2 and subsequently reintroduced various isoforms of NR5A2. In the liver of Nr5a2HKO mice, inflammation and fibrosis spontaneously emerged from an early age, independent of lipid accumulation. Pyroptosis occurred in NR5A2-deficient cell lines, and different isoforms of NR5A2 reversed this form of cell death. Our findings unveiled that inhibition of NR5A2 triggers pyroptosis, a proinflammatory mode of cell death primarily mediated by the activation of the NF-κB pathway induced by reactive oxygen species (ROS). As a transcriptionally regulated molecule of NR5A2, aldehyde dehydrogenase 1 family member B1 (ALDH1B1) participates in pyroptosis through modulation of ROS level. In conclusion, the diverse isoforms of NR5A2 exert hepatoprotective effects against NASH by maintaining a finely tuned balance of ROS, which is contingent upon the activity of ALDH1B1.

The Efficacy and Safety of Liraglutide in Patients Remaining Obese 6 Months after Metabolic Surgery.

The safety and efficacy of liraglutide as a weight loss intervention in individuals who remain obese within 1year post-metabolic surgery remain unclear. This study aimed to evaluate the effects and safety of liraglutide (1.8mg) in patients with persistent obesity at 6months postoperatively. This retrospective cohort study included 61 patients who remained obese (body mass index [BMI] ≥ 28.0kg/m2) at 6months postoperatively. Among these patients, 27 were treated with 1.8mg of liraglutide for 12weeks, whereas 34 served as controls. The primary endpoint was the change in total weight loss (%TWL) after 24weeks. Changes in weight, BMI, complications, and adverse events were also assessed. The liraglutide group showed a greater reduction in %TWL than the control group (11.6% ± 1.1% vs. 4.9% ± 1.0%), with an estimated treatment difference of 6.6% (95% confidence interval [CI], 3.7-9.6%, P < 0.01). The adjusted mean differences in the reduction of weight and BMI between the liraglutide and control groups were -6.2kg (95% CI -8.9 to -3.4, P < 0.01) and -3.0kg/m2 (95% CI -4.2 to -1.7, P < 0.01), respectively. The liraglutide group exhibited increased rates of remission in non-alcoholic fatty liver disease and hypertension. No serious adverse reactions were observed. For patients who remained obese at 6months postoperatively, 12-week liraglutide treatment resulted in increased weight loss, improved metabolic control, and high rate of remission for obesity-related metabolic diseases after 24weeks. Earlier and more timely adjuvant weight loss medication intervention based on BMI within 1year postoperatively may enhance weight loss after metabolic surgery. Graphical abstract available for this article.

Long-term Outcomes and Risk Modifiers of MASLD Between Lean and Non-Lean Populations.

One-third of adults across the globe exhibit metabolic dysfunction-associated steatotic liver disease (MASLD) - formerly known as nonalcoholic fatty liver disease (NAFLD). To date, MASLD is the fastest-growing etiology of chronic liver disease and hepatocellular carcinoma (HCC). Besides the population with obesity, MASLD can also be found in lean populations, accounting for 13% of the global population, especially Asians. Notably, individuals with lean MASLD face equal or higher overall mortality rates compared to their non-lean counterparts. Risk modifiers encompass advanced age, hepatic fibrosis, and type 2 diabetes mellitus (T2DM). Moreover, the population with lean MASLD is associated with an increased risk of HCC, while their non-lean counterparts are more prone to cardiovascular outcomes and T2DM. Existing evidence indicates a similar risk of liver-related events and extrahepatic cancer between the two groups. However, MASLD-related genetic variants, such as PNPLA3 and TM6SF2, did not significantly affect mortality between the two populations. Still, underreporting alcohol consumption and regional representation limits the study's comprehensiveness. Longitudinal studies and mechanistic explorations are needed to understand differences in lean versus non-lean MASLD populations. This review highlights the need for awareness and tailored interventions in managing MASLD, considering lean individuals' unique risks.

Ferulic Acid Alleviates Lipid and Bile Acid Metabolism Disorders by Targeting FASN and CYP7A1 in Iron Overload-Treated Mice

Iron overload is a common complication in various chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD). Lipid and bile acid metabolism disorders are regarded as crucial hallmarks of NAFLD. However, effects of iron accumulation on lipid and bile acid metabolism are not well understood. Ferulic acid (FA) can chelate iron and regulate lipid and bile acid metabolism, but its potential to alleviate lipid and bile acid metabolism disorders caused by iron overload remains unclear. Here, in vitro experiments, iron overload induced oxidative stress, apoptosis, genomic instability, and lipid deposition in AML12 cells. FA reduced lipid and bile acid synthesis while increasing fatty acid β-oxidation and bile acid export, as indicated by increased mRNA expression of PPARα, Acox1, Adipoq, Bsep, and Shp, and decreased mRNA expression of Fasn, Acc, and Cyp7a1. In vivo experiments, FA mitigated liver injury in mice caused by iron overload, as indicated by reduced AST and ALT activities, and decreased iron levels in both serum and liver. RNA-seq results showed that differentially expressed genes were enriched in biological processes related to lipid metabolism, lipid biosynthesis, lipid storage, and transport. Furthermore, FA decreased cholesterol and bile acid contents, downregulated lipogenesis protein FASN, and bile acid synthesis protein CYP7A1. In conclusion, FA can protect the liver from lipid and bile acid metabolism disorders caused by iron overload by targeting FASN and CYP7A1. Consequently, FA, as a dietary supplement, can potentially prevent and treat chronic liver diseases related to iron overload by regulating lipid and bile acid metabolism.

Hepatic Expression of Endocannabinoid Receptors (CB1 and CB2) in Patients with Non-Alcoholic Steatohepatitis and Its Relationship with Metabolic Syndrome

Hepatic Expression of Endocannabinoid Receptors (CB1 and CB2) in Patients with Non-Alcoholic Steatohepatitis and Its Relationship with Metabolic Syndrome

The association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and non-alcoholic fatty liver disease in US adults: a cross-sectional study

The ratio of non-high-density lipoprotein cholesterol (non-HDL-C) to HDL-C (NHHR) is a novel lipid parameter used to assess the risk of cardiovascular disease. Previous studies have demonstrated an association between the NHHR and risk of non-alcoholic fatty liver disease (NAFLD). Owing to the lack of research exploring this relationship in specific populations, this study aimed to determine the potential link between the NHHR and risk of NAFLD among American adults in the United States. Data were retrieved from the National Health and Nutrition Examination Survey (NHANES) spanning 2017–2020. After excluding individuals with other liver diseases, alcohol abuse, and missing lipid data, a total of 6809 eligible adults were included for analysis. The NHHR was calculated as the ratio of (non-HDL-C) to HDL-C, while NAFLD was identified by liver steatosis detected by transient elastography. Multivariable weighted logistic regression models and restricted cubic spline (RCS) models were employed to investigate the relationship between the NHHR and risk of NAFLD. Subgroup and sensitivity analyses were also conducted to test the robustness of the results. As the NHHR increased, the prevalence of NAFLD rose progressively (5.88% vs. 8.75% vs. 12.24% vs. 15.77%, p < 0.001). In the overall population, after adjusting for confounding factors, each unit increase in the NHHR was associated with a 25% increase in NAFLD risk (OR = 1.25, 95% CI: 1.03–1.53, p = 0.0372). When the NHHR was analyzed as a categorical variable (quartiles), participants in the highest quartile had a significantly higher risk of NAFLD than those in the lowest quartile (OR = 2.6, 95% CI: 1.75–3.85, p = 0.009). RCS analysis further indicated a nonlinear dose–response relationship between the NHHR and risk of NAFLD (p non-linearity < 0.0001). This association remained significant in both subgroup and sensitivity analyses. This study confirmed that the NHHR, particularly at higher levels, was an independent risk factor for NAFLD. As a comprehensive lipid indicator, the NHHR had the potential to predict NAFLD risk. These findings provided new insights for the prevention and clinical management of NAFLD.

Increased inter-atrial and intra-atrial conduction times in pediatric patients with non-alcoholic fatty liver disease.

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.

Effect of rapamycin on hepatic metabolomics of non-alcoholic fatty liver rats based on non-targeted platform

Rapamycin (Rapa) is an inhibitor of mTOR complex, and its therapeutic effect on liver function was examined in non-alcoholic fatty liver disease (NAFLD) rats here. And the possible mechanism of Rapa in NAFLD was preliminarily elucidated based on the non-targeted metabolomics analysis. Adult male SD rats were fed with a high-fat and high-cholesterol diet (HFD) to establish NAFLD model. For Rapa group, 0.8 mg/(kg.d) Rapa was given to the HFD rats. Ultra-performance liquid chromatography and Q-Tof-mass spectrometry (UPLC and Q-TOF/MS) analysis were applied for the identification of metabolites in the serum of rats, which were annotated using Kyoto Encyclopedia of Genes and Genomes (KEGG). NAFLD rats presented with disturbed liver function, lipid metabolism and oxidative stress, but Rapa exerted a mitigating influence on the disorders. The metabolite profile data identified 579 metabolites that varied remarkably between the Rapa and HFD groups, with the main classes of amino acids and peptides, benzene, lipids and fatty acids. The differential metabolites were mainly involved in biosynthesis of cofactors, bile secretion, and glycerophospholipid metabolism were mainly enriched. In conclusion, Rapa has a potential protective effect against HFD-induced NAFLD, its hepatoprotective effect may achieved through mediating bile secretion and glycerophospholipid metabolism.

Heterogeneity of metabolic phenotypes in adolescent boys with obesity due to excess calories

The aim of the study was to determine the heterogeneity of metabolic parameters in teenage boys diagnosed with “obesity due to excess calories” using cluster analysis. Materials and methods. One hundred and twenty-three randomly selected patients aged 14 to 17 years diagnosed with “obesity due to excess calories” were examined. The statistical analysis included descriptive and analytical methods, in particular aimed to identify clusters of biochemical indicators, including serum fasting glucose level, insulin level, total cholesterol level, low density lipoproteins (LDLP), very low-density lipoproteins (VLDL), high density lipoproteins (HDLP) and triglycerides. Results. Two clusters of observations have been identified. The first cluster consisted of 72 patients (58.5%) having fasting glucose levels slightly below average, insulin levels above average, total cholesterol, triglycerides, LDLP and VLDL above average, and HDLP levels below average (“metabolically unhealthy” obesity). The second cluster included 51 teenagers (41.5%) who presented with opposite trends in metabolic characteristics (“metabolically healthy” obesity). The adolescents from the first cluster were slightly older, had higher body mass, body mass index (BMI) and z-BMI scores, and higher HOMA-IR scores. Arterial hypertension and non-alcoholic fatty liver disease were diagnosed statistically significantly more frequently in adolescents from this cluster. Conclusion. Teenage boys with obesity are a heterogeneous group in terms of the values of major metabolic indicators.

The association of fructose and fiber consumption and physical activity with non-alcoholic fatty liver disease in children and adolescents: a cross-sectional study.

Non-alcoholic fatty liver disease (NAFLD) is emerging as the most prevalent liver disease in overweight and obese children. While no cure exists, dietary and lifestyle modifications have been shown to improve the condition. This study investigates the relationship between fructose and fiber consumption, physical activity, and NAFLD in children. A cross-sectional study was conducted on 378 overweight and obese children aged 6-13 years. NAFLD diagnosis was confirmed via ultrasound, and dietary intake was assessed using a 147-item food frequency questionnaire (FFQ). Physical activity was evaluated using the Modifiable Activity Questionnaire (MAQ). Multivariable logistic regression models were applied to determine the associations. After excluding 53 participants due to incomplete data, 325 were included in the final analysis. The mean age was 9.2 ± 1.7 years, and 35% had NAFLD. No significant association was found between fructose intake and NAFLD (OR: 0.67, 95% CI: 0.35-1.29, P = 0.221). However, higher intake of legume fiber (OR: 0.48, 95% CI: 0.26-0.90, P = 0.03) and nut fiber (OR: 0.52, 95% CI: 0.28-0.95, P = 0.04) was significantly associated with a reduced risk of NAFLD. Physical activity showed a trend towards reduced NAFLD risk but was not statistically significant after adjustments (OR: 0.53, 95% CI: 0.22-1.04, P = 0.07). While fructose intake was not significantly linked to NAFLD in this population, fiber from legumes and nuts appeared protective. Further prospective studies are needed to confirm these findings and clarify the role of physical activity in NAFLD prevention.

Association between Body Fat Distribution and Nonalcoholic Fatty Liver Disease/Fibrosis Based on Race/Ethnicity.

Body fat distribution may impact nonalcoholic fatty liver disease (NAFLD) and significant fibrosis differently according to race/ethnicity. We determined the relationship between body fat distribution and NAFLD/significant fibrosis according to race/ethnicity. A cross-sectional study of 2,395 participants used the National Health and Nutrition Examination Survey 2017 to 2018. NAFLD and significant fibrosis (≥F2) were defined by controlled attenuation parameter scores and liver stiffness measurements on transient elastography, respectively. Visceral and subcutaneous fat volumes were defined by dual-energy X-ray absorptiometry. The odds ratio (OR) for NAFLD per 1-standard deviation in visceral fat volume and subcutaneous fat volume was 2.31 (95% confidence interval [CI], 1.50 to 3.39) and 1.93 (95% CI, 1.43 to 2.61) in total population, respectively. Visceral fat in non-Hispanic Blacks had the highest odds for NAFLD (OR, 2.86; 95% CI, 1.45 to 5.62), and non-Hispanic Whites (OR, 2.29; 95% CI, 1.19 to 4.40) and non-Hispanic Asians (OR, 1.61; 95% CI, 1.13 to 2.29) were in order. Significant associations between subcutaneous fat volume (OR, 2.10; 95% CI, 1.34 to 3.29; P=0.003) or visceral fat volume (OR, 1.35; 95% CI, 1.05 to 1.73; P=0.023) and significant fibrosis were noted among individuals with NAFLD. Hispanics had the highest odds for NAFLD-associated significant fibrosis (OR, 2.74; 95% CI, 1.32 to 5.70), and non-Hispanic Whites (OR, 2.35; 95% CI, 1.11 to 4.98) and non-Hispanic Asians (OR, 2.01; 95% CI, 1.01 to 4.01) were in order. Visceral adiposity was associated with NAFLD and significant fibrosis despite the association of subcutaneous adiposity in NAFLD and significant fibrosis. Racial/ethnic differences in the association between body fat distribution on NAFLD and significant fibrosis were noted.

Delphinidin or α-amyrin attenuated liver steatosis and metabolic disarrangement in rats fed a high-fat diet.

Non-alcoholic fatty liver disease (NAFLD) is a liver pathology concomitant with metabolic disarrangement. This study assessed the therapeutic impacts of delphinidin, an anthocyanin, or α-amyrin, a pentacyclic triterpenoid, on NAFLD in rats and the underlying mechanisms involved. NAFLD was established by feeding a high-fat diet (HFD) for 10 weeks, either alone or in combination with delphinidin (40 mg/kg, oral) or α-amyrin (20 mg/kg, oral). Delphinidin or α-amyrin ameliorated the metabolic and histopathological perturbations induced by HFD. These compounds markedly attenuated NAFLD-induced hepatic steatosis, as evidenced by a substantial decrease in body weight, insulin resistance, and liver and adipose tissue indices. Alongside normalization of the atherogenic index, both improved HFD-mediated abnormalities in serum lipids, liver enzymes, leptin, and ghrelin levels. Moreover, their intervention activated the NFE2 like bZIP transcription factor 2 and heme oxygenase 1 pathways and abrogated HFD-triggered activation of mitogen-activated protein kinase 1 signaling. These remedies inhibited hepatic apoptosis and modulated the gene expression of lipogenic enzymes. Furthermore, histological analysis corroborated the suppression of lipid accumulation and amelioration of hepatic architecture in the treated rats. Our findings highlight the hepatoprotective value of delphinidin or α-amyrin against NAFLD and related metabolic diseases through their insulin-sensitizing, anti-inflammatory, antioxidant, and antiapoptotic effects.

The deficiency of ALKBH5 contributes to hepatic lipid deposition by impairing VPS11-dependent autophagic flux.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Hepatic lipid deposition is a key factor in the development of NAFLD. N6-methyladenosine (m6A) modification, the most prevalent mRNA modification in eukaryotic cells, plays an important role in regulating hepatic lipid metabolism. However, its potential role in hepatic lipid deposition remains poorly understood. Histological and immunohistochemistry studies were used to investigate lipid deposition in free fatty acids (FFAs)-incubated LO2 cells, high-fat diet-fed mice models and clinical samples. Stable overexpression and knockdown of AlkB homolog 5 (ALKBH5) was manipulated to investigate the effects of ALKBH5 on m6A methylation and lipid metabolism in hepatocytes. RNA-sequencing transcriptome analysis and methylated RNA immunoprecipitation-quantitative-PCR analysis were used to reveal the potential downstream molecular targets of ALKBH5. ALKBH5 was down-regulated in fatty liver compared to normal liver in both humans and mice. Overexpression of ALKBH5 significantly improved FFA-induced lipid accumulation and promoted autophagosome-lysosome fusion in hepatocytes. Meanwhile, knockdown of ALKBH5 significantly increased the expression of microtubule-associated protein 1A/1B-light chain 3B and Sequestosome 1, leading to impaired autophagic flux and further lipid deposition in hepatocytes under FFA incubation. Overexpression of vacuolar protein sorting 11 (VPS11) reversed FFA-induced lipid accumulation in ALKBH5-silenced hepatocytes. Mechanistically, ALKBH5 alleviated hepatic lipid deposition and impaired autophagic flux by removing the m6A modification on VPS11 mRNA to promote its translation. Collectively, our findings revealed an epigenetic mechanism by which ALKBH5 alleviates hepatic lipid deposition by restoring VPS11-dependent autophagic flux, providing a potential target to counteract NAFLD.

Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors

Inhibiting apoptosis signal regulated kinase 1 (ASK1) is an attractive strategy for treating diseases such as non-alcoholic steatohepatitis and multiple sclerosis. Here, we report the discovery of a dibromo substituted quinoxaline fragment containing 26e as an effective small-molecule inhibitor of ASK1, with an IC50 value of 30.17 nM. In addition, the cell survival rate of 26e at different concentrations was greater than 80%, especially at 0.4 μM. Its cell survival rate was significantly higher than GS-4997, indicating its good safety in normal human liver LO2 cells. The Oil Red O staining experiment showed that 26e decreased the lipid droplets in a dose-dependent manner. Further biochemical analyses revealed that 26e could reduce the content of T-CHO, LDL, and TG in FFA-induced LO2 cells, and had the potential to treat non-alcoholic fatty disease. These findings provide a good choice for the future development of ASK1 inhibitors.