To examine the relationship between lipid profile and non-alcoholic fatty liver (NAFL), compare the predictive strengths of different lipid indicators to NAFL, and explore the possible mechanisms.

Male workers from a baseline survey of a cohort of workers in southern China were included. Basic information was collected through face-to-face interviews. Plasma concentrations of fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were determined using a blood biochemical analyzer. Liver sonography was used to identify NAFL cases. Regression models were used to calculate ORs, and examine the association between C-reactive protein (CRP) levels and lipid profiles. Restricted cubic spline regression with four knots was used to examine the dose-response relationship, and mediation analysis was employed to examine the mediation effect.

h Among the 4016 male workers, 829 (20.64%) were diagnosed with NAFL. Compared with normal lipid profile, individuals with abnormal lipid profile had higher prevalence of NAFL (OR=2.27, 95%CI: 1.85-2.79 for TG; OR=1.45, 95%CI: 1.03-2.04 for TC; OR=1.56, 95%CI: 1.21-2.02 for HDL; OR=1.65, 95%CI: 1.25-2.18 for LDL; OR=2.28, 95%CI: 1.87-2.77 for dyslipidaemia) after adjusting for potential confounders. Dose-response relationships were observed among TG, HDL, and NAFL. In addition, no significant mediation effect of C-reactive protein (CRP) was found in the association between lipid profiles and NAFL.

Abnormal TG, TC, HDL, and LDL levels were all positively associated with NAFL, while CRP has no mediating effect, and TG tended to be a better predictor of NAFL.

Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a growing health concern worldwide. Among the pursuit of therapeutic interventions, interest in natural bioactive compounds has intensified because of their potential hepatoprotective effects. This systematic review aims to evaluate the impact of plant-derived hydrolysates and peptides on MAFLD through the current literatures, encompassing their mechanisms of action. Key outcomes evaluated included changes in liver enzymes, liver lipid content, inflammation markers, and histopathological improvements. Preliminary findings suggest a potential beneficial effect of plant-derived hydrolysates and peptides on the improvement of MAFLD-related parameters, with mechanisms implicating antioxidant, anti-inflammatory, and lipid-lowering properties. This review highlights emerging evidence supporting the potential therapeutic role of plant-derived hydrolysates and peptides in the management of MAFLD. However, more well-designed clinical trials with larger sample sizes and longer durations are warranted to elucidate their efficacy, optimal dose, and long-term safety.

Steatosis is characterized by an increase in free fatty acids, such as palmitic acid (PA), in hepatocytes and the accumulation of triglycerides in the liver. However, the role of intracellular autophagy in PA accumulation-induced hepatotoxicity is not clearly understood. Therefore, in this study, we investigated the effects of PA on autophagy in hepatocytes and its underlying mechanism of action. Treatment of HepG2 cells with PA induced a significant increase in intracellular p62 and LC3-II levels, suggesting inhibition of autophagy. Furthermore, PA inhibited autophagic flux in HepG2 cells, as monitored using GFP-RFP-LC3. Mechanistically, PA increased the phosphorylation of the Ser12 and Thr29 residues of LC3, which are autophagy inhibition markers, through protein kinase A (PKA) and protein kinase C (PKC) signaling. Finally, PKA and PKC inhibitors restored PA-induced autophagic flux inhibition, reduced intracellular lipid accumulation, and rescued the altered expression of lipogenic genes, such as SREBP-1c, in HepG2 cells. Thus, our study demonstrates the mechanism of autophagy inhibition by PA in hepatocytes and provides a potential therapeutic approach for preventing and treating hepatic steatosis.

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Age-related ocular diseases, including diabetic retinopathy (DR), age-related macular degeneration (AMD), cataract and glaucoma may lead to visual impairment and even to blindness. Metabolic diseases, such as obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) have emerged as potential risk factors of age-related ocular diseases, especially DR. Visceral adiposity has been associated with increased risk of DR and AMD in most clinical studies, although body mass index has to-date provided conflicting association with DR and AMD. In addition, obesity is recognized as a risk factor of cataract and glaucoma. Similarly to obesity, MASLD appears to be associated with DR in patients with type 1 diabetes mellitus, but probably not in those with type 2 diabetes mellitus. A potential positive association between MASLD and AMD, glaucoma and cataract is supported by limited evidence to-date, thus needing further investigation. Altered secretion patterns of adipokines (adiponectin, leptin, lipocalin-2, resistin) and hepatokines [adropin, fetuin-A, fibroblast growth factor (FGF)-21, retinol binding protein (RBP)-4] seem to disrupt ocular homeostasis and contribute to the development of age-related ocular diseases in the context of obesity and MASLD. In this regard, novel adipokine-based and hepatokine-based therapies may be added to the treatment options for ocular diseases in the future. This narrative review aimed to summarize evidence on the interconnection of obesity and MASLD with age-related ocular diseases, with a specific focus on the roles of adipokines and hepatokines as mediators of these potential associations.

Nonalcoholic fatty liver disease (NAFLD) is mainly related to genetics, obesity, insulin resistance, and type 2 diabetes. Probiotic Lactiplantibacillus plantarum Lb41 (Lb41) has not been reported to have hepatoprotective effects. Therefore, the aim of this study is to investigate the preventive effects of Lb41 against NAFLD in high-fat diet (HFD)-fed mice for preventing NAFLD.

To induce fatty liver, the mice were given HFD for 5 weeks, followed by silymarin (200 mg/kg) or Lb41 (108 or 109 colony forming units/day) with the HFD for 7 weeks. After 12 weeks, body weight, histological change, serum and hepatic lipid profiles, etc. was performed compared to control and silymarin.

Lb41 had significantly reduced body weight (4.87 g) and serum lipids (triglycerides (77.64%), total cholesterol (67.53%), and low-density lipoprotein (40.50%) compared with the HFD group (P < 0.05). Lb41 significantly relieved HFD-associated hepatic injury by reducing aspartate transaminase (0.49-0.57 fold), alanine transaminase (0.49-0.51 fold), and alkaline phosphatase (0.76-0.90 fold) (P < 0.05). Additionally, they had decreased expression levels of peroxisome proliferator-activated receptor (PPAR) γ and sterol regulatory element-binding protein 1c and increased the expression levels of acyl-CoA oxidase, PPARα, carnitine palmitoyltransferase 1, acetyl CoA carboxylase 1, and fatty acid synthase in liver cells. Insulin and leptin levels decreased in the Lb41 treatment group compared with those in the HFD group. Meanwhile, adiponectin levels increased, similar to those in the normal diet group.

Based on these findings, Lb41 probiotics have possible hepatoprotective effects and could be used as functional food materials.

Liver steatosis (LS) is a condition that is characterised by hepatic fat accumulation unrelated to significant alcohol consumption. This study explored the serum proteomic profile associated with LS in people living with HIV (PLWH).

The study cohort comprised 266 PLWH, 21.1% and 78.9% of whom had LS and no LS, respectively. Serum samples were analysed using liquid chromatography coupled with mass spectrometry (LC-MS).

Among the 220 proteins detected, afamin (AFM) and apolipoprotein F (APOF) were identified as proteins associated with LS. Differential expression of AFM and APOF was observed in under- and normoweight patients, emphasising their potential as biomarkers in patients without overweight or obesity.

These findings suggest that the identified proteins could serve as promising biomarkers of LS in PLWH, paving the way for further investigations into the roles of these proteins in LS development in this unique population.

This Obesity Medicine Association (OMA) Expert Joint Perspective examines steatotic liver disease (SLD), which is composed of metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH) in children with obesity. The prevalence of obesity is increasing, rates have tripled since 1963 from 5 % to now 19 % of US children affected in 2018. MASLD, is the most common liver disease seen in children, can be a precursor to the development of Type 2 Diabetes (T2DM) and is the primary reason for liver transplant listing in young adults. We must be vigilant in prevention and treatment of MASLD in childhood to prevent further progression.

This joint clinical perspective is based upon scientific evidence, peer and clinical expertise. The medical literature was reviewed via PubMed search and appropriate articles were included in this review. This work was formulated from the collaboration of eight hepatologists/gastroenterologists with MASLD expertise and two physicians from the OMA.

The authors who are experts in the field, determined sentinel questions often asked by clinicians regarding MASLD in children with obesity. They created a consensus and clinical guideline for clinicians on the screening, diagnosis, and treatment of MASLD associated with obesity in children.

Obesity and the comorbidity of MASLD is increasing in children, and this is a medical problem that needs to be addressed urgently. It is well known that children with metabolic associated chronic disease often continue to have these chronic diseases as adults, which leads to reduced life expectancy, quality of life, and increasing healthcare needs and financial burden. The authors of this paper recommend healthy weight reduction not only through lifestyle modification but through obesity pharmacotherapy and bariatric surgery. Therefore, this guidance reviews available therapies to achieve healthy weight reduction and reverse MASLD to prevent progressive liver fibrosis, and metabolic disease.

This study aimed to explore the causal relationship between age at menarche (AAM) and non-alcoholic fatty liver disease (NAFLD), leveraging data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) alongside Mendelian randomization (MR) analyses. Notably, this research represents the first attempt to link AAM to NAFLD using genetic methodologies, thereby providing novel insights into the interplay between these two conditions.

Cross-sectional data from 2730 participants were analyzed using logistic regression to evaluate the association between AAM and NAFLD risk. A two-sample MR study was performed to investigate causal relationships, utilizing genetic data from large-scale genome-wide association studies (GWASs). The inverse variance weighted (IVW) method served as the primary MR analysis approach.

A significant negative association between AAM and NAFLD was found in Model 3 (OR = 0.85, 95 % CI: 0.74-0.97). Participants in the highest AAM quintile exhibited a 68 % reduction of NAFLD prevalence compared to those in the lowest AAM quintile (OR = 0.32, 95 % CI: 0.11-0.97). MR analysis confirmed a potential negative causal association (discovery: OR = 0.81, 95 % CI: 0.73-0.90; validation: OR = 0.80, 95 % CI: 0.66-0.96).

Our findings indicate a potential causal association between AAM and NAFLD, suggesting that early AAM may serve as a potential risk marker for NAFLD. This highlights the importance of incorporating AAM into clinical risk assessment tools and developing targeted prevention strategies for at-risk populations. Further research is needed to clarify the underlying mechanisms and to explore the potential benefits of early intervention.

Increasing evidence supports a higher risk of abnormal liver function parameters due to unfavorable lifestyles. We therefore explored the synergistic effects of various lifestyle factors on liver function.

8710 participants from Guangzhou Biobank Cohort Study were included. Five lifestyle factors including non-smoking, non-alcohol use, physically active, non-central and non-general obesity were assessed and a Healthy Lifestyle Index (HLI) (0-5, a higher score indicates healthier lifestyle) was generated. Multivariable linear regression was used to examine the association of HLI with liver function parameters, yielding regression coefficients (βs) and 95% confidence intervals (CIs).

A total of 8710 participants with an average age of 64.67 years (standard deviation = 6.07) were included. Of them, 71.65% were women. After adjusting for sex, age, education, family income, and comorbidities, compared with those with HLI of zero, those with HLI scores of 1, 2, 3, 4, and 5 showed a lower ALT level by -5.85 IU/L (95% CI: -10.73, -0.97), -9.97 IU/L (95% CI: -14.53, -5.42), -11.34 IU/L(95% CI: -15.86, -6.82), -12.81 IU/L (95% CI: -17.33, -8.30), and - 14.15 IU/L (95% CI: -18.68, -9.62), respectively (P for trend < 0.001), and a lower AST level by 1.82 IU/L (95% CI: -4.85,1.21), -3.74 IU/L (95% CI: -6.57, -0.91), -4.47 IU/L (95% CI: -7.28, -1.66), -4.69 IU/L (95% CI: -7.49, -1.88), and - 4.75 IU/L (95% CI: -7.57, -1.94), respectively (P for trend < 0.001). Similar trends were observed for a higher ALB level with higher healthy lifestyle scores (P for trend = 0.003).

A healthy lifestyle was associated with optimal liver function parameters, highlighting the importance of advocating for health-conscious behaviors to potentially mitigate the incidence of liver dysfunction.

Research investigating the impact of the non-essential metal (NEM) mixture on non-alcoholic fatty liver disease (NAFLD) among the elderly is presently insufficient. This study investigated the relationships between individual NEMs, their mixtures, and NAFLD in elderly individuals residing in Chinese communities.

The analysis included 2741 participants drawn from the baseline survey of a longitudinal study. Urinary concentrations of aluminum (Al), gallium (Ga), arsenic (As), cesium (Cs), barium (Ba), thallium (Tl), uranium (U), and cadmium (Cd) were quantified using inductively coupled plasma mass spectrometry (ICP-MS). NAFLD diagnosis was determined using abdominal ultrasound imaging. Logistic regression and restricted cubic spline (RCS) models were utilized to evaluate the relationships between individual NEMs and NAFLD. Additionally, Bayesian kernel machine regression (BKMR) and quantile-based computation regression (QGC) models were employed to assess the impact of the NEM mixture on NAFLD.

After adjusting for covariates, Tl was significantly associated with an increased likelihood of NAFLD (OR 1.26, 95% CI 1.10-1.44). Both RCS and BKMR models confirmed a linear relationship between urine Tl and the risk of NAFLD. Additionally, both BKMR and QGC models highlighted a significant connection between the NEMs mixture and NAFLD, identifying Tl as the primary driver. Significant interactions were observed between Tl and Ba, as well as between Tl and hypertension (Pinteraction = 0.055) and Tl and central obesity (Pinteraction = 0.008), collectively demonstrating synergistic impacts on NAFLD risk.

The NEM mixture is associated with a higher risk of NAFLD in Chinese old adults, with Tl as the primary contributor. Additional investigation is required to validate these findings and shed light on underlying biological pathways through which co-exposure to NEMs contribute to NAFLD.

Sexual dimorphism plays a critical role in disease pathophysiology, but the subtlety and complexity of these differences, along with a lack of precise comparative methods, hinder the advancement of precision medicine and drug development. This limitation is particularly evident in metabolic dysfunction-associated steatotic liver disease (MASLD), where sex-specific molecular mechanisms remain insufficiently understood. To address this gap, we employed an advanced integrative N-glycoproteomics and proteomics approach to systematically analyze sex-biased molecular signatures in primary mouse hepatocytes (PMHs) under healthy and MASLD conditions. Our analysis identified 280 sex-biased proteins and 39 sex-biased N-glycosites, and KEGG enrichment revealed that female-biased molecules were primarily involved in lipid metabolism, while male-biased molecules were associated with inflammation and cytoskeletal remodeling. A combined dataset of 302 sex-biased molecules was further analyzed using protein-protein interaction (PPI) analysis and Rc value calculations, resulting in the identification of 21 hub proteins and 2 hub N-glycosites as MASLD-associated sex-biased signatures. Notably, MASLD amplified proteomic sex differences while attenuating them in N-glycosylation. Western blot validation of key signatures, including female-biased MVK and male-biased LGALS3, highlighted distinct molecular adaptations between the sexes in MASLD progression. Our study introduced an advanced analytical framework for high-resolution comparative molecular profiling by integrating N-glycoproteomics with proteomics, providing valuable insights into sex-biased molecular signatures, enhancing preclinical model development, and advancing sex-specific therapeutic strategies in MASLD research and broader biological systems.

The natural course of metabolic dysfunction-associated steatotic liver disease (MASLD) in the population with metabolically healthy obesity (MHO) has not been adequately explored. In the present narrative review, we summarize the evidence regarding the association between MHO and MASLD prevalence, incidence and progression.

Cross-sectional, population-based, cohort studies have shown an increased prevalence of hepatic steatosis and fibrosis in subjects with MHO compared with metabolically healthy non-obese individuals (MHNO). In large-scale longitudinal cohort studies among metabolically healthy subjects, increasing body mass index (BMI) has been found to be independently associated with an increased incidence of MASLD and progressive hepatic fibrosis over a mean follow-up period of 2.2-7.7 years. With regard to advanced MASLD, the prevalence of steatohepatitis and clinically significant liver fibrosis is lower in MHO compared with subjects with metabolically unhealthy obesity (MUO). The presence of MASLD has been proposed as a strong risk factor for metabolic health deterioration in MHO. Furthermore, subjects with MHO and MASLD display an elevated 10-year cardiovascular risk and a three-fold increased risk of incident diabetes compared with MHO without MASLD. MASLD may also predict the failure to convert from MUO to MHO after a weight loss intervention.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver condition associated with metabolic syndrome, often aggravated by inflammation and mitochondrial dysfunction. This study aims to explore the therapeutic potential of magnoflorine, an alkaloid with known anti-inflammatory properties, in ameliorating NAFLD by modulating mitochondrial autophagy and inhibiting the NLRP3 inflammasome.

Male C57BL/6 J mice were fed a high-fat diet (HFD) for 16 weeks to induce NAFLD. Magnoflorine (5 and 10 mg/kg) was administered by gavage daily for 16 weeks. Liver and serum samples were analyzed for lipid profiles, inflammation markers, and autophagy-related proteins, and liver histology was examined to assess changes.

Magnoflorine treatment improved dyslipidemia in NAFLD mice, shown by decreased serum triglycerides, total cholesterol, and LDL-C, and increased HDL-C. Histological analysis showed reduced hepatic steatosis and inflammation, with less lipid droplet accumulation and hepatocyte ballooning. Western blot results indicated upregulation of Parkin and PINK1, and downregulation of NLRP3, ASC, and caspase-1, with lower serum IL-1β levels, reflecting reduced inflammation.

Magnoflorine offers a promising approach for mitigating NAFLD progression through modulating mitochondrial autophagy and inhibiting inflammation.

MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) is a growing global concern. Nutraceuticals offer an appealing approach by targeting key mechanisms, such as oxidative stress, inflammation, lipid metabolism, and insulin resistance. This narrative review examines the role of various nutraceuticals in MASLD treatment, including silymarin, vitamin E, omega-3, curcumin, berberine, and coenzyme Q10. Some of them show promising biochemical and metabolic changes, while others produce conflicting results due to relevant studies' design and endpoints. To bridge the gap between research and reality, we summarize the data, create an interpretation heatmap, and develop a practical supplement guide. Regardless of their potential, nutraceuticals should be viewed as add-ons to lifestyle interventions rather than standalone treatments. Future research should focus on well-designed, long-term studies to prove efficacy, dosing, and combination strategies for personalized MASLD management.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), has become a great public healthcare burden and is closely associated with type 2 diabetes (T2D) and insulin resistance. However, there is no specific treatment for MASLD. Recent clinical findings have indicated a possible beneficial effect of sodium-glucose cotransporter 2 (SGLT2) on MASLD. This study aimed to investigate the effects of dapagliflozin (Dapa) on MASLD in T2D mice.

Four-week-old ob/ob mice were fed with a high-fat diet (HFD) for 8 weeks and then randomly divided into two groups supplemented with Dapa or vehicle for another 12 weeks. C57BL/6J mice fed with a standard chow diet (CD) were used as the control group. Metabolic outcomes, liver pathology, lipidomics and insulin signaling were assessed.

We showed that Dapa reduced body weight and ameliorated hyperglycemia and fatty liver in obese diabetic ob/ob mice. Compared with vehicle, dapa improved the NAFLD activity score mainly by attenuating fat deposition. Importantly, Dapa decreased the expression levels of mRNAs and proteins related to fatty acid synthesis and increased the expression levels of β-oxidation-related factors. We also found that Dapa treatment improved insulin signaling by increasing PI3K and Akt phosphorylation.

Dapa protects mice from diet-induced weight gain and improves hepatic lipotoxicity and insulin resistance in diabetic MASLD mice. Our results revealed that Dapa has a therapeutic effect on MASLD and could be a potential drug candidate for the treatment of MASLD.

Diabetes, affecting 18.3% of young adults in Mexico (6), is influenced by both genetic factors and shared unhealthy habits within families.

To determine the metabolic abnormalities in relatives of people with T2D, stratified by body mass index.

This observational, descriptive study was conducted at the Center for Comprehensive Care for Patients with Diabetes (CAIPaDi). The study involved relatives of participants with type 2 diabetes mellitus (T2DM), recruited between June 2017 and December 2020. The relatives were people without diabetes, including spouses, siblings, offspring, or close family members aged 18 to 65 who spent over four days a week with the patient. Exclusion criteria included relatives diagnosed with diabetes, smokers, or any individual from a patient-relative pair that was excluded. All participants underwent laboratory tests and body measurements. Relatives were classified into three groups based on body weight: normal weight, overweight, and obesity. The relatives attended four monthly visits and then annual evaluations. Ethical approval was obtained.

The study enrolled 220 relatives of people with T2DM, 69% women, median age 49±12 years; 19.5% with normal weight, 40.4% overweight, and 40% with obesity. Prediabetes (39.4%), dyslipidemia (67.2%), and abnormal liver function tests (32.2%) were prevalent. Higher levels of triglycerides and LDL cholesterol were associated with increased risk for comorbid conditions. Anxiety and depression showed no significant differences across weight categories.

These results highlight the importance of overweight and obesity as factors associated with the presence of comorbidities and the metabolic syndrome. It is essential to implement strategies to promote healthy habits among family members of people with diabetes, especially in those who are overweight or obese to reduce the risk of developing future metabolic and cardiovascular diseases.

Dysregulated programmed cell death pathways mechanistically contribute to hepatic inflammation and fibrogenesis in non-alcoholic steatohepatitis (NASH). Identification of cell death genes may offer insights into diagnostic and therapeutic strategies for NASH.

Data from multiple NASH cohorts were integrated, and 12 machine learning algorithms were applied to identify key dysregulated cell death-related genes and develop a binary classification model for NASH. Spearman's rank correlation coefficients quantified associations between these genes and clinical markers, immune infiltration profiles, and signature genes encoding pro-inflammatory mediators, metabolic regulators, and fibrotic drivers. Gene set enrichment analysis (GSEA) was performed to delineate the mechanistic underpinnings of these key genes. Consensus clustering analysis was then used to stratify patients with NASH into distinct phenotypic subgroups based on expression levels of these genes.

A NASH prediction model, developed using the random forest (RF) algorithm, demonstrated high diagnostic accuracy across multiple cohorts. Four key genes, enriched in lipid metabolism and inflammation pathways, were identified. Their transcriptional levels were significantly correlated with the non-alcoholic fatty liver disease activity score (NAS), hepatic inflammatory infiltration, molecular signatures of metabolic dysregulation (lipid homeostasis regulators), and fibrosis progression. These genes also enabled accurate classification of patients with NASH into clusters reflecting varying disease severity.

A binary classification model, developed using the RF algorithm, accurately identified patients with NASH. The four cell death genes, identified through 12 machine learning algorithms, represent potential biomarkers and therapeutic targets for NASH. These genes contribute to inflammation-related immune cell activation, lipid metabolism dysregulation, and liver fibrosis, highlighting the complex interplay between cell death and NASH progression.

Polysaccharides, as macromolecular carbohydrates present in various medicine and food homology, have gained growing recognition for their potential in combating obesity through multiple mechanisms. Their natural origin and favorable safety profile have made polysaccharides from medicine and food homology (PMFH) an area of significant research interest, particularly in the context of developing effective, safe, and sustainable interventions for obesity management. This review summarized the classification and biological properties of PMFH and then elucidated the pathological characteristics of obesity. We primarily focused on the effects of PMFHs on obesity, with particular attention to the potential mechanisms mediated through the gut-liver axis. These mechanisms encompassed the improvement of fat metabolism imbalances, manager of appetite and energy balance, adjustment of intestinal microbial imbalances, and alleviation of oxidative stress and inflammation. The findings provided critical theoretical insights and data to support the development of anti-obesity dietary and pharmaceutical products. In brief, this review outlined future research directions regarding the potential mechanisms underlying the anti-obesity effects of PMFH, particularly those involving the gut-liver axis.

Dysfunctional mitochondrial metabolism and sustained de novo lipogenesis (DNL) are characteristics of metabolic dysfunction-associated steatotic liver disease (MASLD), a comorbidity of obesity and type 2 diabetes. Fructose, a common sweetener and a potent inducer of lipogenesis, contributes to the etiology of MASLD.

Our goal was to determine whether higher rates of DNL, through its biochemical relationships with mitochondria, can contribute to dysfunctional induction of oxidative networks in the liver.

Male C57BL/6JN mice were given a low-fat (10% fat kcal, 49.9% corn starch kcal), high-fat (HF; 60% fat kcal), or HF/high-fructose diet (HF/HFr; 25% fat kcal, 34.9% fructose kcal) for 24 wk. In a follow-up study, mice on normal feed pellets were provided either 30% fructose in drinking water (FW) to induce hepatic DNL or regular water (NW) for 14 d. Hepatic mitochondria and liver tissue were used to determine oxygen consumption, reactive oxygen species (ROS) generation, tricarboxylic acid (TCA) cycle activity, and gene/protein expression profiles.

Hepatic steatosis remained similar between HF and HF/HFr fed mice livers. However, lipogenic and lipid oxidation gene expression profiles and the induction of TCA cycle metabolism were all higher (P ≤ 0.05) in HF/HFr livers. Under fed conditions, the upregulation of DNL in FW livers occurred in concert with higher mitochondrial oxygen consumption (basal; 1.7 ± 0.21 compared with 3.3 ± 0.14 nmoles/min, P ≤ 0.05), higher ROS (0.87 ± 0.09 compared with 1.25 ± 0.12 μM, P ≤ 0.05) and higher flux through TCA cycle components P ≤0.05. Furthermore, TCA cycle activity and lipid oxidation remained higher during fasting in the FW livers P ≤ 0.05.

Our results show that fructose administration to mice led to the concurrent induction of mitochondrial oxidative networks and DNL in the liver. Sustained induction of both DNL and mitochondrial oxidative function could accelerate cellular stress and metabolic dysfunction during MASLD.

Steatotic liver disease (SLD) affects about 1 billion people globally, making its proper management essential to prevent progression to more severe stages.

The aim of this study was to evaluate medical management concerning hepatic steatosis incidentally identified by ultrasound in patients undergoing elective cholecystectomy.

This observational, cross-sectional, and retrospective study included patients aged 18 years or older who underwent elective cholecystectomy at Hospital do Trabalhador, in Curitiba/PR, between 2018 and 2022. Patients with external ultrasound reports or incomplete data in their medical records were excluded. Medical records, laboratory tests, and ultrasound reports were analyzed to evaluate the prevalence of steatosis in these patients.

The study sample consisted of 355 patients, and 103 (29.01%) of them presented steatosis on ultrasound. Older age (P=0.0022), male sex (P=0.03009), higher body mass index (P<0.001), obesity (P<0.001), hypertension (P<0.001), dyslipidemia (P=0.0072), and elevated levels of oxaloacetic and pyruvic aminotransferases (P=0.02112) were associated with the presence of this finding. No action was taken regarding the presence of steatosis in 60.19% of patients. Approximately 39.81% had the finding recorded in their medical records, 6.80% received lifestyle change counseling, and 4.85% were investigated for the stage of steatosis.

A significant prevalence of hepatic steatosis was incidentally identified in the ultrasound of patients undergoing cholecystectomy. However, the approach to this finding was insufficient, highlighting the need for substantial improvements on its management and investigation.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition with a steadily increasing prevalence. Evidence indicates that both smoking and obesity are significant risk factors for NAFLD, yet the extent to which smoking influences NAFLD through weight gain remains unclear. This study aimed to dissect the intricate relationship between smoking, body mass index (BMI), and NAFLD using Mendelian randomization (MR) analysis. We leveraged data from 30 genome-wide association studies involving over 1.2 million individuals, from which 123 single nucleotide polymorphisms were selected as instrumental variables for smoking. BMI data were sourced from the Genetic Investigation of Anthropometric Traits (GIANT) consortium, encompassing more than 700,000 individuals, with 521 single nucleotide polymorphisms serving as instrumental variables. NAFLD data were obtained from multiple databases, including the eMERGE Network, UK Biobank, Estonian Biobank, and FinnGen, comprising 8434 cases and 770,180 controls. All participants in this study were of European ancestry. We first applied univariate MR analysis to assess the causal relationship between smoking, NAFLD, and BMI. Subsequently, multivariate MR was used to assess the effect of smoking on NAFLD after adjusting for BMI. The coefficient product method was used to calculate the mediating effect of BMI. Results found that both smoking and high BMI were able to increase the risk of NAFLD, with odds ratios of 1.83 (95% confidence interval [CI]: 1.31-2.55) and 1.58 (95% CI: 1.42-1.77), respectively. BMI mediated 73.3% (95% CI: 62.3%-80.5%) of the effect of smoking on NAFLD. The findings support weight control and the encouragement of smoking cessation, especially in obese populations, as strategies to reduce the risk of NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is understudied among US adolescents despite rising obesity rates.

This study analysed the prevalence and trends of obesity and MASLD among US adolescents aged 12-17 using data from the National Health and Nutrition Examination Survey (NHANES). We developed a new screening model utilizing FibroScan-measured controlled attenuation parameter (CAP) scores, body measurements and blood chemistry data from 2017 to 2020 to assist in analysing MASLD trends from 1999 to 2020.

Between 2017 and 2020, the prevalence of obesity and MASLD was approximately 20%, with about 70% of obese adolescents affected by MASLD. The condition was more common in boys, particularly among Mexican American adolescents. Additionally, 97.2% of those with NAFLD also had MASLD. Adolescents with MASLD had significantly higher body weight, waist circumference, triglyceride levels and alanine transaminase (ALT) levels, along with lower high-density lipoprotein (HDL) cholesterol and an increased risk of liver fibrosis. Insufficient physical activity and poor diet quality were key risk factors for developing MASLD. From 1999 to 2020, the prevalence of MASLD rose significantly, paralleling the increasing rates of obesity.

The study underscores the pressing need to screen at-risk adolescents for metabolic issues associated with steatotic liver diseases, given the rising obesity rates among adolescents. The high overlap between MASLD and NAFLD diagnoses indicates that the transition from NAFLD to MASLD can be effectively integrated into paediatric practice.

Obesity, characterized by chronic low-grade inflammation, is a significant health concern. Phytochemicals found in plants are being explored for therapeutic use, particularly in combating obesity. Among these, theobromine, commonly found in cocoa and chocolate, shows promise. Although not as extensively studied as caffeine, theobromine exhibits positive effects on human health. It improves lipid profiles, aids in asthma treatment, lowers blood pressure, regulates gut microbiota, reduces tumor formation, moderates blood glucose levels, and acts as a neuroprotective agent. Studies demonstrate its anti-obesity effects through mechanisms such as browning of white adipose tissue, activation of brown adipose tissue, anti-inflammatory properties, and reduction of oxidative stress. This study aims to suggest theobromine as a potential therapeutic agent against obesity-related complications.

Obesity is not a single diagnosis, and the association of 'metabolically unhealthy' obesity with cardiovascular disease is well-described. However, the relationship between metabolically healthy obesity (MHO) and atrial fibrillation (AF) is still debated.

Our objective is to investigate the association between MHO and the risk of AF.

A comprehensive search of databases, including PubMed, EMBASE, Web of Science, and the Cochrane Library regarding longitudinal studies of MHO and risk of AF was performed. Random effects were used to pool the effect estimates.

Nine cohort studies comprising 4,250,557 participants were included. The pooled results revealed that individuals with MHO were associated with a greater incidence of AF than those with a metabolically healthy normal weight (HR: 1.34, 95 % CI: 1.26 to 1.42) with moderate certainty according to the Grading of Recommendations Assessment, Development, and Evaluation assessment. Individuals with MHO were associated with a lower risk of AF compared with participants with metabolically unhealthy obesity (RR: 0.48, 95 % CI: 0.36 to 0.64). Individuals with MHO were not significantly associated with the risk of AF as compared to metabolically unhealthy normal weight (HR: 1.04, 95 % CI: 0.89 to 1.22).

MHO is associated with a greater incidence of AF, highlighting the importance of weight reduction in individuals without metabolic disorders in reducing the risk of AF.

PROSPERO - registration number CRD42023432195.

A growing number of steatotic grafts have been used in liver transplantation (LT), including hepatocellular carcinoma (HCC) patients. However, the impact of steatotic grafts on the prognosis of HCC recipients remains unclear. This study aims to evaluate the impact of steatotic graft in long-term prognosis for HCC recipients and development an algorithm for minimizing the risk of these grafts.

The clinicopathologic data of HCC patients undergoing LT from 2003 to 2022 in the United Network for Organ Sharing database was analyzed. The disease-free survival (DFS) and overall survival (OS) of recipients were compared between non-steatotic (macrosteatosis <30 %) and steatotic (macrosteatosis ≥30 %) graft groups after propensity score matching (PSM). Interaction analysis was conducted to identify factors that amplified the negative impact of steatotic grafts on DFS.

A total of 8345 eligible HCC patients were included. Three factors exhibited significant interaction effect with steatotic grafts: cold ischemia time ≥6h (HR = 1.447; P = 0.023), donor body mass index ≥40 (HR = 1.771; P = 0.018) and recipient with non-alcoholic fatty liver disease (HR = 1.632; P = 0.032). Hazard Associated with Macrosteatotic Liver (HAML) score was created based on these three factors. In HAML ≥1 cohort, the DFS and OS of steatotic graft group were significantly reduced compared to non-steatotic graft group. But in HAML = 0 cohort, no significant differences in DFS and OS were observed between the two groups.

The risk of steatotic grafts in LT for HCC could be minimized through evaluating HAML score.

Non-alcoholic fatty liver disease is one of the most common chronic diseases all around the world, which significantly correlates with metabolic disorders and inflammatory cycles. Sarcopenia is a decrease in the mass of skeletal muscles interacting with factors such as inflammatory processes and chronic diseases. It can also lead to the aggravation of chronic diseases.

The study population was randomly selected and entered into the research based on exclusion and inclusion criteria. Non-alcoholic fatty liver disease was confirmed in all members of the study population by ultrasound. Patients' serum ferritin level was assessed, and their NFS and Fib 4 scores were calculated. Sarcopenia was diagnosed by measuring the thickness of the rectus femoris by ultrasonography. The correlation between these variables was evaluated and analyzed by statistical software.

According to statistical analysis, there is a significant association between the serum ferritin level and sarcopenia (P-value < 0.001). Besides, there is a significant association between NFS, Fib4, and sarcopenia (P-value = 0.024, 0.000).

This research's results reflect the correlation between serum ferritin and sarcopenia; however, it cannot conclude a cause-and-effect relationship between these variables.

Altered lipid metabolism is a crucial jeopardy cause for developing non-alcoholic fatty liver disease (NAFLD). Among various lipid metrics, the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (NHHR) has recently emerged as a promising indicator showing significant potential in predicting the prevalence of NAFLD. This study aimed to provide novel insights for the prevention of NAFLD by examining the relationship between NHHR and the prevalence of NAFLD. To identify the connection between NHHR and NAFLD, this study utilized descriptive analysis, multivariate logistic regression, and restricted cubic spline regression to investigate data collected by the National Health and Nutrition Examination Survey performed from 2017 to 2020. Furthermore, the connection between NHHR and the controlled attenuation parameter (CAP) was assessed using multiple linear regression, smoothed curve fitting, and threshold effect analysis. The NAFLD group showed higher NHHR levels than the non-NAFLD group (2.990 vs 2.240, P < 0.001). Multiple logistic and linear regression analyses indicated significant positive associations between NHHR and its quartiles with both the prevalence of NAFLD and CAP levels. Additionally, NHHR was positively associated with the prevalence of NAFLD in a linear dose-response relationship. Furthermore, smoothed curve fitting demonstrated a positive relationship between NHHR and CAP, with a threshold effect at an inflection point of 3.398. Higher NHHR levels were significantly associated with the prevalence of NAFLD and steatosis, and maintaining NHHR in the appropriate range may reduce these conditions.

To investigate whether endometriosis is associated with the risk of incident nonalcoholic fatty liver disease (NAFLD).

Data were retrieved from Nurses' Health Study II with participants followed up from 1995 to 2017. A total of 61,649 participants were included in this prospective cohort study. The exposure of this study was laparoscopically confirmed endometriosis. We performed Cox proportional hazard regression analyses to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) of the association between endometriosis and NAFLD.

A total of 4,774 incident NAFLD cases were recorded during a 1,313,067 person-years of follow-up. In the multivariable adjusted model, laparoscopically confirmed endometriosis was positively associated with the risk of NAFLD (HR: 1.17, 95% CI: 1.07 - 1.29). The results of the mediation analyses revealed that the association was partly attributable to hysterectomy/oophorectomy (31.6% mediated, 95% CI: 18.8-47.9%), hypercholesterolemia, hypertension and infertility. Further analysis revealed that the interaction effect of age was significant for the association between endometriosis and NAFLD (P = 0.01).

Laparoscopically confirmed endometriosis was positively associated with the risk of incident NAFLD. Awareness of the potential NAFLD risk should be raised for clinicians and patients during the regular follow-up of endometriosis.

Previous research has indicated that the fasting plasma glucose to high-density lipoprotein cholesterol ratio (FHR) is a novel biomarker for assessing cardiovascular disease prognosis. The objective of this study is to investigate the potential relationship of FHR with non-alcoholic fatty liver disease (NAFLD).

The present study employed a retrospective design and included 14,251 participants who underwent health examinations. Restricted cubic spline regression and multivariable logistic regression were used to assess the relationship of NAFLD with FHR. The performance of the FHR in identifying NAFLD was analyzed through receiver operating curve analysis.

After adjustment for confounders, a positive association of FHR with NAFLD was observed in the multivariable logistic regression model. Compared to the lowest FHR quartile, the odds ratios for the 2, 3, and 4 quartiles were 1.49 (1.14, 1.94), 2.03 (1.57, 2.63), and 2.34 (1.79, 3.06), respectively. Additionally, restricted cubic spline regression analysis revealed a nonlinear relationship of FHR with NAFLD prevalence with a potential threshold effect. The prevalence of NAFLD remained nearly unchanged when the FHR was less than 3, but increased progressively when the ratio exceeded 3. Further receiver operating curve analysis demonstrated that the FHR significantly outperformed fasting plasma glucose or high-density lipoprotein cholesterol alone in identifying NAFLD, with an optimal threshold identified at 3.89.

The FHR is a new index used to identify NAFLD, and the incorporation of the FHR into the risk stratification assessment system for NAFLD may be of significant help.

Obesity, characterized by the excessive accumulation of white adipose tissue, is a significant global health burden and a major risk factor for a range of diseases, including malignancies and metabolic disorders. Individuals with high visceral fat content are particularly susceptible to severe complications such as type 2 diabetes, cardiovascular diseases, and liver disorders. However, the pathogenesis of obesity-related metabolic diseases extends beyond simple adiposity. Chronic obesity triggers a prolonged inflammatory response, which leads to tissue fibrosis and sustained organ damage, contributing to multi-organ dysfunction. This review explores the autoimmune mechanisms and inflammatory pathways underlying obesity-induced type 2 diabetes, atherosclerosis, and non-alcoholic fatty liver disease, with an emphasis on their interrelated pathophysiology and the potential for therapeutic interventions.

A large number of patients with non-obese non-alcoholic fatty liver disease (NAFLD) in China remain undiagnosed and untreated due to insufficient awareness and ineffective pharmacotherapy. Therefore, a convenient, predictive marker and diagnostic tools are imperative. This study aimed to investigate the ability of the triglyceride glucose index (TyG) in predicting non-obese NAFLD.

An observational cross-sectional study.

Department of Health Management, large urban academic medical centre and DRYAD database data.

This study included 456 patients with non-obese NAFLD and matched 456 non-fatty liver controls according to age, sex and body mass index (BMI).

The receiver operating characteristic (ROC) curve was used to evaluate the predictive role of the TyG index in non-obese NAFLD. Based on the TyG index, a clinical prediction model for non-obese NAFLD was constructed, then the prediction model was verified by the DRYAD database (n=11 562).

TyG in non-obese NAFLD was higher than that in controls (9.00 (8.66-9.40) vs 8.46 (8.10-8.83), p<0.001). Logistic regression analysis showed that TyG was an independent risk factor for non-obese NAFLD (OR=9.03, 95% CI: 5.46 to 14.94, p<0.001). ROC analysis showed that the area under the curve (AUC) was 0.78, the sensitivity was 82.5%, the specificity was 60.5%. Based on the TyG index, sex, age and BMI, the AUC of the predictive model for non-obese NAFLD was 0.78 (95% CI: 0.75 to 0.81, p<0.001). Using the DRYAD database to verify the prediction model, the AUC of the verification group was 0.85 (95% CI: 0.84 to 0.86, p<0.001).

The high level of the TyG may be an independent risk factor for non-obese NAFLD. The prediction model for non-obese NAFLD based on the TyG index has good clinical prediction value.

Adipogenesis is the healthy expansion of white adipose tissue (WAT), serving as a compensatory response to maintain metabolic homeostasis in the presence of excess energy in the body. Therefore, the identification of novel regulatory molecules in adipogenesis, specifically membrane receptors such as G protein-coupled receptors (GPCRs), holds significant clinical promise. These receptors can serve as viable targets for pharmaceuticals, offering potential for restoring metabolic homeostasis in individuals with obesity. We utilized trajectory inference methods to analyze three distinct single-nucleus sequencing (sNuc-seq) datasets of adipose tissue and systematically identified GPCRs with the potential to regulate adipogenesis. Through verification in primary adipose progenitor cells (APCs) of mice, we discovered that ADGRD1 promoted the differentiation of APCs, while GPR39 inhibits this process. In the obese mouse model induced by a high-fat diet (HFD), both gain-of-function and loss-of-function studies validated that ADGRD1 promoted adipogenesis, thereby improving metabolic homeostasis, while GPR39 inhibited adipogenesis, leading to metabolic dysfunction. Additionally, through the analysis of 2,400 ChIP-seq data and 1,204 bulk RNA-seq data, we found that the transcription factors (TFs) MEF2D and TCF12 regulated the expression of ADGRD1 and GPR39, respectively. Our study revealed the regulatory role of GPCRs in adipogenesis, providing novel targets for clinical intervention of metabolic dysfunction in obese patients.

Glucagon plays a central role in hepatic adaptation during fasting, with the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) traditionally associated with increased gluconeogenesis. However, recent experimental models and clinical studies have challenged this view, suggesting a more complex interplay between PCK1 and glucagon, which extends beyond gluconeogenesis and has broader implications for metabolic regulation in health and disease.

This review provides a comprehensive overview of the current evidence on the multifaceted roles of PCK1 in glucagon-dependent hepatic adaptation during fasting, which is crucial for maintaining systemic homeostasis not only of glucose, but also of lipids and amino acids. We explore the relationship between PCK1 deficiency and glucagon resistance in metabolic disorders, including inherited PCK1 deficiency and metabolic dysfunction-associated steatotic liver disease (MASLD), and compare findings from experimental animal models with whole-body or tissue-specific ablation of PCK1 or the glucagon receptor. We propose new research platforms to advance the therapeutic potential of targeting PCK1 in metabolic diseases.

We propose that hepatic PCK1 deficiency might be an acquired metabolic disorder linking alterations in lipid metabolism with impaired glucagon signaling. Our findings highlight interesting links between glycerol, PCK1 deficiency, elevated plasma alanine levels and glucagon resistance. We conclude that the roles of PCK1 and glucagon in metabolic regulation are more complex than previously assumed. In this (un)expected scenario, hepatic PCK1 deficiency and glucagon resistance appear to exert limited control over glycemia, but have broader metabolic effects related to lipid and amino acid dysregulation. Given the shift in glucagon research from receptor inhibition to activation, we propose that a similar paradigm shift is needed in the study of hepatic PCK1. Understanding PCK1 expression and activity in the glucagon-dependent hepatic adaptation to fasting might provide new perspectives and therapeutic opportunities for metabolic diseases.

Hepatic lipid droplet (LD) accumulation is a hallmark of nonalcoholic fatty liver disease (NAFLD). Although the clinical efficacy of berberine (BBR) in treating NAFLD has been established, the mechanism remains uncertain. This study is to evaluate the effects of BBR on hepatic LDs and investigate the underlying mechanisms. Using high-fat diet-induced obese (DIO) mice as the model for NAFLD, BBR was administered daily by gavage for 4 weeks. Liver tissue was examined for changes in lipid deposition and histology. Transcriptomics was performed to screen differently expressed genes. The potential targets of BBR against NAFLD were then determined by Western Blot and immunostaining. In oleic acid (OA)-induced HepG2 cells, the link between BBR and potential targets was further elucidated through the activation or antagonism of PPARα. The binding of BBR to potential targets was predicted using molecular docking. BBR significantly reduced hepatic steatosis by decreasing LD size rather than number. Transcriptomics with validation demonstrated that BBR modulated the expression of LD-associated proteins CIDEA and PLIN4 in the liver. Further investigations revealed that BBR reversed the abnormal elevation of BSCL2 and PLIN2 in steatotic livers. Finally, we found that BBR reduced LD size in OA-induced HepG2 cells by regulating BSCL2 and PPARα-mediated CIDEA/PLIN4/PLIN2. Notably, BBR could bind well to PPARα and BSCL2. BBR can attenuate hepatic steatosis in DIO mice by reducing LD size through the regulation of LD-associated proteins.

Polysaccharides possessing hypoglycemic effects have shown promising results in treating diabetes. Polygonatum sibiricum polysaccharide (PSP) is one of the most active ingredients in the Chinese medicine P. sibiricum Redoute with many biological activities. However, its efficacy in alleviating type 2 diabetes mellitus (T2DM) remains unexplored. Our aim is to evaluate the protective effect of PSP against T2DM by measuring body weight and serum biochemical indicators, examining the histopathological images of pancreatic and liver tissues, detecting fecal short-chain fatty acid (SCFA) content, and analyzing the intestinal flora diversity and the microbiota structure in T2DM mice. The findings indicated that PSP treatment in T2DM mice could obviously decrease the fasting blood glucose and fasting insulin levels, ameliorate glucose tolerance, insulin resistance, lipid, and inflammatory factor levels, attenuate pancreatic and liver damage, and increase the fecal SCFA content. In addition, PSP could modulate the composition of gut microbiota in T2DM mice, resulting in the relative abundance of Firmicutes decreasing and that of Bacteroidetes increasing, along with the abundance of beneficial flora significantly increasing, especially SCFA-producing bacteria. The findings indicate that PSP administration protected against diabetes by controlling disordered glucolipid metabolism and modulating the gut microbiota, which provides a valuable strategy for the utilization of PSP to treat T2DM.

The transcription factor sex-determining region Y-related high-mobility group-box gene 9 (SOX9) plays a critical role in organ development. Although SOX9 has been implicated in regulating lipid metabolism in vitro, its specific role in metabolic dysfunction-associated steatohepatitis (MASH) remains poorly understood. This study aimed to investigate the role of SOX9 in MASH pathogenesis and explored the underlying mechanisms.

MASH models were established using mice fed either a methionine- and choline-deficient (MCD) diet or a high-fat, high-fructose diet. To evaluate the effects of SOX9, hepatocyte-specific SOX9 deletion or overexpression was performed. Lipidomic analyses were conducted to assess how SOX9 influences hepatic lipid metabolism. RNA sequencing was employed to identify pathways modulated by SOX9 during MASH progression. To elucidate the mechanism further, HepG2 cells were treated with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor to test whether SOX9 acts via AMPK activation.

SOX9 expression was significantly elevated in hepatocytes of MASH mice. Hepatocyte-specific SOX9 deletion exacerbated MCD-induced MASH, whereas overexpression of SOX9 mitigated high-fat, high-fructose-induced MASH. Lipidomic and RNA sequencing analyses revealed that SOX9 suppresses the expression of genes associated with lipid metabolism, inflammation, and fibrosis in MCD-fed mice. Furthermore, SOX9 deletion inhibited AMPK pathway activation, while SOX9 overexpression enhanced it. Notably, administration of an AMPK inhibitor negated the protective effects of SOX9 overexpression, leading to increased lipid accumulation in HepG2 cells.

Our findings demonstrate that SOX9 overexpression alleviates hepatic lipid accumulation in MASH by activating the AMPK pathway. These results highlight SOX9 as a promising therapeutic target for treating MASH.

Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), involves hepatic lipid accumulation, inflammation, and fibrosis. It can progress to cirrhosis or hepatocellular carcinoma without timely treatment. Current treatment options for MASH are limited. This study explores the therapeutic effects of fluorofenidone (AKF-PD), a novel small-molecule compound with antifibrotic and anti-inflammatory properties, on MASH in mouse model. Mice fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) were treated with AKF-PD, resulting in reduced serum ALT, AST, hepatic lipid accumulation, liver inflammation, and fibrosis. Network pharmacology and RNA-sequencing analyses suggested that AKF-PD influenced multiple metabolic, inflammatory, and fibrosis-related pathways. Further experiments verified that AKF-PD activated hepatic AMPK signaling, leading to the inhibition of the downstream SREBF1/SCD1 pathway and the activation of autophagy. Additionally, AKF-PD suppressed the expression of various inflammatory factors, reduced macrophage infiltration, and inhibited NLRP3 inflammasome activation. Moreover, AKF-PD attenuated liver fibrosis by inhibiting TGFβ1/SMAD signaling. In conclusion, this study reveals that AKF-PD effectively decreases hepatic lipid accumulation, liver inflammation and fibrosis in a CDAHFD-induced MASH model, positioning AKF-PD as a promising candidate for the treatment of MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, represents a prevalent condition ranging from simple steatosis to advanced stages associated with liver cancer. Asymptomatic presentation in the majority of cases underscores the need for non-invasive, cost-effective methods to stratify degree of hepatic steatosis. This cross-sectional study aimed to assess the association between obesity and lipid-related indices with the degree of hepatic steatosis in MASLD patients. 150 individuals recently diagnosed with metabolic dysfunction-associated steatotic liver disease were recruited. Anthropometric measurements, including weight, height, and waist circumference (WC), were taken, alongside biochemical parameters such as alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides (TG), high-density lipoprotein, low-density lipoprotein, and fasting plasma glucose, following a 12-h fasting period. Various indicators of obesity and lipid metabolism, including body mass index, waist-to-height ratio (WHtR), a body shape index, lipid accumulation product (LAP), triglyceride-glucose index (TyG), visceral adiposity index, and hepatic steatosis index (HSI), were calculated. The diagnosis of MASLD and degree of hepatic steatosis were established through abdominal ultrasound examination. Data analysis was performed utilizing SPSS version 22. All the investigated indices displayed an area under the curve (AUC) surpassing 0.5, implying a correlation with the degree of hepatic steatosis. Notably, TyG-WC, TyG-WHtR, LAP, and a cardiometabolic obesity index showed the highest AUC values (> 0.7), indicating a relatively strong association with degree of hepatic steatosis. Specifically, in females, TyG-WC (AUC = 0.797, 95% CI 0.712-0.882, threshold = 865.991), while in males, LAP (AUC = 0.746, 95% CI 0.593-0.899, threshold = 74.290), demonstrated the highest AUC values. TyG-WHtR, TyG-WC, and LAP exhibited significant correlations with the degree of hepatic steatosis. Given their non-invasive nature and easy measurement, they hold promise for potential clinical utility, pending validation in additional studies.