The natural flavonoid quercetin, which exhibits a range of biological activities, has been implicated in liver disease resistance in recent research. In vivo study attesting to quercetin's protective effect against metabolic-associated fatty liver disease (MAFLD) is inadequate, however. Here, our investigation explored the potential benefits of quercetin in preventing MAFLD in C57BL/6 mice fed a high-fat diet (HFD). The results revealed that quercetin ameliorated the aberrant enhancement of body and liver weight. The hepatic histological anomalie induced by MAFLD were also mitigated by quercetin. HFD-induced imbalance in serum LDL, HDL, AST, ALT, TG, and LDH was mitigated by quercetin. Mechanically, we found that quercetin improved lipid metabolism by reducing lipogenesis proteins including ACC, FASN, and SREBP-1c and enhancing β-oxidation proteins including PPARα and CPT1A. In vitro study demonstrated that quercetin regulated hepatic lipid metabolism by targeting SREBP-1c and PPARα. Additionally, quercetin enhanced the antioxidant capacity in HFD-treated mice by downregulating Nrf2 and HO-1 expressions and upregulating SOD and GPX1 expressions. The hyper-activation of inflammation was also restored by quercetin via eliminating the phosphorylation of IκBα and NF-κB p65. Collectively, our observations highlight that quercetin exerts hepatoprotective properties in MAFLD mice by regulating hepatic lipid metabolism, oxidative stress and inflammatory response.

Sufficient attention has not been given to machine learning (ML) models using longitudinal data for investigating important predictors of new onset of hypertension. We investigated the predictive ability of several ML models for the development of hypertension.

A total of 15 965 Japanese participants (men/women: 9,466/6,499, mean age: 45 years) who received annual health examinations were randomly divided into a training group (70%, n = 11,175) and a test group (30%, n = 4,790). The predictive abilities of 58 candidates including fatty liver index (FLI), which is calculated by using body mass index, waist circumference and levels of γ-glutamyl transferase and triglycerides, were investigated by statistics analogous to the area under the curve (AUC) in receiver operating characteristic curve analyses using ML models including logistic regression, random forest, naïve Bayes, extreme gradient boosting and artificial neural network.

During a 10-year period (mean period: 6.1 years), 2,132 subjects (19.1%) in the training group and 917 subjects (19.1%) in the test group had new onset of hypertension. Among the 58 parameters, systolic blood pressure, age and FLI were identified as important candidates by random forest feature selection with 10-fold cross-validation. The AUCs of ML models were 0.765-0.825, and discriminatory capacity was significantly improved in the artificial neural network model compared to that in the logistic regression model.

The development of hypertension can be simply and accurately predicted by each ML model using systolic blood pressure, age and FLI as selected features. By building multiple ML models, more practical prediction might be possible.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease. Farnesoid X receptor (FXR) agonists are emerging as promising therapies for fibrosis, steatosis, and metabolic dysfunctions. However, its efficacy and safety remain unclear.

A systematic search of PubMed, Embase, and Cochrane databases identified randomized controlled trials (RCTs) comparing FXR agonists with placebo in patients with MASLD. The main outcomes included improvement in fibrosis without worsening steatohepatitis, changes in liver chemistry and lipid profiles, and liver fat content (LFC). The safety outcomes assessed included side effects and treatment discontinuation rates. Heterogeneity was evaluated using I² statistics, with a random-effects model applied to the pooled analyses.

Ten RCTs involving 3,779 patients were included, of which 2,527 (67%) were randomized to receive FXR agonists. FXR agonists significantly improved fibrosis by ≥ 1 stage (RR, 1.52; 95% CI: [1.23, 1.88]; P < 0.0001) and reduced LFC (mean difference: -4.9%; 95% CI: [-8.26, -1.55]; P < 0.001). A higher proportion of patients achieved a ≥30% reduction in LFC (42.8% vs. 18.4%; RR, 2.42; 95% CI: [1.69, 3.46]; P < 0.00001). Significant reductions in alanine aminotransferase and gamma glutamyltransferase levels were observed, whereas alkaline phosphatase levels were increased. FXR agonists were associated with a slight reduction in High-Density Lipoprotein (HDL) cholesterol levels and a higher incidence of pruritus (37.8% vs. 18.7%; RR, 2.67; 95% CI: [1.63, 4.38]; P < 0.00001), leading to higher treatment discontinuation rates.

FXR agonists have the potential to improve fibrosis and steatosis in MASLD patients. However, safety concerns still remain. Further research is required to determine the long-term efficacy and tolerability of these drugs.

Metabolic dysfunction-associated steatohepatitis (MASH) is a complex metabolic syndrome, and the development of new drugs is urgently needed. Fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid absorption, metabolism and inflammation. Considering the synergistic effect of FABP and PPAR in the regulation of MASH pathophysiology, the development of FABP/PPAR multiple modulators might be a promising anti-MASH strategy. Herein, the first-in-class FABP/PPAR multiple modulators were designed by hybrid resveratrol and PPARs agonist Elafibranor. Among them, the compound 27 was identified as the optimal FABP/PPAR multiple modulator (FABP1 IC50 = 0.65 μM, FABP4 IC50 = 1.08 μM, PPARα EC50 = 9.19 μM, PPARγ EC50 = 2.20 μM, PPARδ EC50 = 1.58 μM). Further MST assay confirmed the direct interaction of compound 27 and FABP1, providing a robust validation of its target specificity. In MASH mice, compound 27 exhibited a better therapeutic effect than clinical candidate obeticholic acid in ameliorating multiple pathological features of MASH. This study reported the successful discovery of the first-in-class FABP/PPAR multiple modulators, which provided preliminary evidence that such multi-target agents have broad medical prospects.

China has a high prevalence rate of Metabolic-associated fatty liver disease (MAFLD), and there is currently limited understanding of the levels of exercise self-efficacy (ESE) among individuals with MAFLD. The objective was to explore the potential ESE patterns in older adults with MAFLD. A cross-sectional study was conducted on 800 older adults with fatty liver disease from five communities from April 20, 2023 to August 15, 2023. Latent profile analysis (LPA) and k-means clustering were used to determine the optimal number of ESE groups. Using univariate analysis and multivariate logistic regression to investigate the factors influencing profiles of ESE. A sample of 775 subjects met the diagnostic criteria for MAFLD. LPA yielded three profiles: the low-ESE, mild-ESE, and high-ESE groups, which comprised 25%, 28%, and 47% of the sample, respectively. K-means clustering further supported the categorization of ESE into three distinct classes. The multivariate logistic regression analysis revealed that diabetes, arthritis and/or arthrosis, as well as companionship during PA were significant influencing factors for the different profiles (p ​< ​0.05). Our findings suggest that the ESE of older patients with MAFLD is primarily at a moderate level or above. There was population heterogeneity in ESE among older patients with MAFLD. Diabetes mellitus, arthritis, and/or arthrosis, as well as companionship during PA were significant factors in influencing the likelihood of having high ESE.

Liver fat is associated with cardiometabolic disease, cerebrovascular disease, and dementia. Cerebrovascular disease, most often cerebral small vessel disease, identified by magnetic resonance imaging as white matter hyperintensities (WMHs) often contributes to dementia. However, liver fat's role in the relationship between cardiometabolic risk, WMHs, and cognitive performance is unclear.

In the UK Biobank cohort (N = 32,461, 52.6% female; mean age 64.2 ± 7.7 years; n = 23,354 in the cognitive performance subsample), we used linear regression to investigate associations between cardiometabolic factors measured at baseline and liver fat, WMHs, and cognitive performance measured at follow-up, which was 9.3 ± 2.0 years later on average. We used structural equation modeling to investigate whether liver fat mediated associations between cardiometabolic factors and WMHs and whether WMHs mediated associations between liver fat and cognitive performance.

Nearly all cardiometabolic factors were significantly associated with liver fat (|r| range = 0.03-0.41, p = 3.4 × 10-8 to 0) and WMHs (|r| = 0.04-0.15, p = 5.8 × 10-13 to 7.0 × 10-159) in regression models. Liver fat was associated with WMHs (r = 0.11, p = 4.3 × 10-82) and cognitive performance (r = -0.03, p = 1.6 × 10-7). Liver fat mediated the associations between cardiometabolic factors and WMHs (|βmediation| = 0.003-0.027, p mediation = 1.9 × 10-8 to 0), and WMHs mediated the associations between liver fat and cognitive performance (βmediation = -0.01, p mediation = 0).

Our findings indicate that liver fat mediates associations between cardiometabolic factors and WMHs and that WMHs mediate the association between liver fat and cognitive performance. This suggests that liver fat may be important for understanding the effects of cardiometabolic factors on cerebrovascular disease and cognitive function. Experimental studies are warranted to determine relevant targets for preventing vascular-driven cognitive impairment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the major causes of chronic liver disease among adolescents. However, epidemiological studies on MASLD in adolescents are still insufficient. In this study, we aim to investigate the global burden and the trend of MASLD in adolescents from 1990 to 2021.

The age-standardized incidence, prevalence, mortality, and disability-adjusted life years (DALYs) of MASLD were calculated based on the Global Burden of Disease (GBD) 2021 study and stratified by sex, socio-demographic index (SDI), GBD regions, and countries. The temporal trends were examined using the average annual percentage change (AAPC) and joinpoint regression.

From 1990 to 2021, the global trends of age-standardized incidence rate (ASIR) and age-standardized prevalence rate (ASPR) of MASLD show notable increase, and the male is significantly higher than the female in adolescents. According to the incidence and prevalence, nations with low SDI confront a higher burden of MASLD. Besides, the inequality of incidence and prevalence between different SDI regions have shrunk in 2021, but the inequality of DALYs and mortality are still exacerbated. Decomposition analysis revealed that population growth and epidemiological changes were the main reasons for the increase in the incidence of MASLD.

From 1990 to 2021, there is a significant upward trend in the incidence of MASLD among adolescents worldwide. Of particular note are male adolescents, East Asian regions, and groups living in high SDI countries.

Hepatic lipid accumulation is a hallmark of metabolically associated fatty liver disease (MAFLD), which contributes to the progression of cirrhosis and even hepatoma. However, the underlying mechanisms remain poorly understood. Protein phosphatase 4C (PP4C) is an important enzyme that exists widely in the body and participates in cell metabolism. Hypoxia can affect the development of metabolic diseases. In this study, we investigated the role of PP4C in hepatic lipid metabolism under hypoxia in vivo and in vitro. Hypoxia-inducible factor 2α (HIF2α), PP4C, phosphorylated AU-rich element RNA-binding factor 1(pAUF1), acetyl-CoA carboxylase 1 (ACC1), and carnitine palmitoyl transferase-1 (CPT1) were analyzed via western blotting and immunofluorescence. The mechanism by which PP4C affects hepatic lipid accumulation under hypoxia was evaluated in stable transfected cell lines. Compared with those in the 2200 m HFD group, body weight, triglyceride (TG), total cholesterol (TC), amino alanine transferase (ALT), aspartate transaminase (AST), and lipid accumulation were lower in the 4500 m HFD group (P < 0.05). Compared with those in the 4500 m ND group, ACC1 and PP4C levels were lower than in the 4500 m HFD group, but HIF2α, pAUF1, and CPT1 levels were greater (P < 0.05). Knockdown of HIF2α prevented the hypoxia-induced reduction of PP4C, confirming the regulatory role of the HIF2α-PP4C axis in hepatic lipid metabolism. PP4C could affect the phosphorylation and expression localization of AU-rich element RNA-binding factor 1 (AUF1). PP4C enhanced lipid accumulation by reducing pAUF1, while the knockdown of PP4C had the opposite effect; pAUF1 had no change. Compared with those in the control group, ACC1 levels were decreased and CPT1 levels were increased in the AUF1 overexpression group, whereas ACC1 and CPT1 levels were not altered in the AUF1 knockdown group (P < 0.05). In conclusion, hypoxia might improve lipid accumulation by downregulating PP4C via HIF2a. PP4C is involved in hepatic lipid metabolism by regulating AUF1 phosphorylation under different oxygen concentrations. PP4C might be a promising target for treating hepatic lipid accumulation.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder globally. The prevalence of NAFLD in the general population is estimated to be 25-30 %, making it the most common chronic liver condition in China as well as worldwide. Given the escalating disease burden and the scarcity of effective therapeutic interventions, there is a pressing unmet clinical need. Consequently, the development of novel pharmaceuticals has emerged as a pivotal research focus in recent years. Moreover, the advent of nano-delivery technology offers innovative solutions for NAFLD drug therapy. This paper presents a comprehensive examination of the pathogenesis and therapeutic targets of NAFLD. It critically reviews the latest advancements in nanomedicine research pertinent to NAFLD treatment. The review synthesizes a broad range of research findings to bridge the gap between current knowledge and emerging therapeutic strategies, and aims to inform and guide future research directions in NAFLD management.

Metabolic dysfunction-associated steatotic liver disease (MASLD) acts as an alternative for demarcating metabolic dysfunction-associated fatty liver disease (MAFLD). This study aimed to investigate the factors that significantly influence the relationship between MAFLD and MASLD in relation to the incidence of major cardiovascular outcomes.

A total of 340,998 participants in the UK Biobank study were included. Multivariable Cox proportional hazards models were used to estimate the effect of MAFLD and MASLD on the outcomes of cardiovascular diseases (CVDs) (coronary artery disease, stroke, heart failure, and CVD-related death) with hazard ratios (HRs) and 95 % confidence intervals (CIs). A total of 126,077 (36.97 %) participants had MAFLD and 97,418 (28.57 %) had MASLD. Over a median follow-up of 13.5 years (interquartile range 12.6-14.2), there were 41,548 new events of CVDs recorded. MAFLD (HR = 1.52; 95 % CI: 1.49-1.55) and MASLD (HR = 1.42; 95 % CI: 1.39-1.45) were associated with high risks of CVDs. Among the subtypes of MAFLD and steatotic liver disease (SLD), MAFLD diabetes subtype (HR = 2.26; 95 % CI: 2.17-2.35) and alcohol-associated liver disease (ALD) (HR = 1.65; 95 % CI: 1.55-1.76) exhibited the highest risk of CVDs. MAFLD overweight without MD subtype were not associated with CVDs. The effect of MAFLD on the CVD outcomes was consistent regardless of the presence of MASLD.

The metabolic health status and alcohol consumption function as more critical factors than obesity in assessing CVD outcomes in participants with MAFLD or MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a potential independent risk factor for cardiovascular disease (CVD)-associated and all-cause mortalities as they share common risk factors. We investigated the association between cardiometabolic risk factors for MASLD and CVD-associated and all-cause mortality risks in middle-aged and older Korean adults.

We used data from the Korean Genome and Epidemiology Study, a population-based prospective cohort study. Five cardiometabolic risk factors were assessed. MASLD was defined as liver steatosis with a fatty liver index (FLI) ≥60 and at least one cardiometabolic risk factor. The non-MASLD group included individuals with a FLI <60 or FLI ≥60 without cardiometabolic risk factors. The primary outcomes were CVD-associated and all-cause mortalities. Cox proportional hazard models were used to evaluate the association between cardiometabolic risk factors for MASLD and mortalities, adjusting for covariates. Multivariable Cox regression analysis revealed that the MASLD group had increased CVD-associated and all-cause mortality risks compared to the non-MASLD group. The presence of three or more and one or more cardiometabolic risk factors significantly increased the CVD-associated and all-cause mortality rate, respectively. The combination of hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and high glucose concentrations significantly increased both CVD-associated (hazard ratio [HR] 3.64; 95 % confidence interval [CI] 1.44-9.22; p = 0.006) and all-cause (HR 4.57; 95 % CI: 1.74-12.05; p = 0.002) mortality risks.

Cardiometabolic risk factors for MASLD are strongly associated with higher CVD-associated and all-cause mortality risks, highlighting the need to manage hypertriglyceridemia, low HDL-C, and high glucose concentrations.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as an important public health concern that poses a significant threat to human health and imposes a substantial economic burden. Research has demonstrated that ubiquitin ligase-mediated substrate protein ubiquitination is a pivotal factor influencing liver lipid homeostasis and metabolic abnormalities in MAFLD. Nevertheless, the specific enzyme molecules implicated in this regulatory process remain to be elucidated. We have published a transcriptome-overexpressing ubiquitin ligase, membrane-associated ring-CH-type finger 2 (MARCH2), in HepG2 cells, and subsequent reanalysis of these transcriptome data revealed a close association between MARCH2 and lipid metabolism.

By employing a range of methodologies, including recombinant adeno-associated virus (rAAV) transduction, lentiviral transduction, immunoblotting, quantitative PCR, tissue section staining, ubiquitination assays, serum biochemical analysis, immunoprecipitation, and mass spectrometry, this study investigated the functions and mechanisms of MARCH2 in the progression of MAFLD at the molecular, cellular, and organismal levels.

Overexpression of MARCH2, but not its catalytically inactive ligase variant, inhibited lipid accumulation in HepG2 cells. Additionally, MARCH2 undergoes K48-linked self-polyubiquitination and subsequent proteasomal degradation in response to oleic acid/palmitic acid stimulation. Furthermore, knockout of MARCH2 exacerbates the progression of MAFLD-related phenotypes, including increased body weight, impaired glucose tolerance, reduced insulin sensitivity, hypercholesterolemia, hepatic lipid accumulation, and steatosis, in high-fat diet-fed mice, irrespective of sex. Mechanistically, MARCH2 facilitates the polyubiquitination and degradation of fatty acid synthase (FASN) in the de novo lipogenesis pathway. And liver-specific overexpression of MARCH2 by rAAV effectively reduces FASN levels and further ameliorates MAFLD in ob/ob mice.

MARCH2 undergoes self-ubiquitination and plays an important role in maintaining the liver lipid homeostasis of MAFLD, and drug intervention in the MARCH2-FASN axis is a promising approach for treating systemic metabolic abnormalities in MAFLD.

Abnormal lipid accumulation is an important cause of metabolic dysfunction-associated fatty liver disease (MAFLD) progression and can induce several stress responses within cells. This study is the first to explore the role and molecular mechanism of stress granules (SGs) in MAFLD.

A gene knock-down model of G3BP1, a core SG molecule in mice and HepG2 cells, was constructed to explore the role of SGs in MAFLD induced in vivo by a high-fat diet or in vitro by palmitic acid (PA). Methods included metabolic phenotyping; western blotting; qPCR; and immunofluorescence, haematoxylin/eosin and masson staining. The downstream molecules of G3BP1 and its specific molecular mechanism were screened using RNA sequencing (RNA-seq).

G3BP1 and TIA1 expression were upregulated in high-fat diet-fed mouse liver tissues and PA-induced HepG2 cells, and the two molecules showed significantly increased colocalisation. G3BP1 knock-down slightly increased TIA1 expression in the livers of obese mice but not in lean mice. G3BP1 deficiency aggravated liver lipid deposition and insulin resistance in obese mice, and this phenotype was confirmed in vitro in PA-induced hepatocytes. RNA-seq demonstrated that G3BP1 slowed down MAFLD progression by inhibiting APOC3, possibly through a mechanistic suppression of APOC3 entry into the nucleus.

This study reveals for the first time a protective role for SGs in MAFLD. Specifically, knocking down the core G3BP1 molecule in SGs aggravated the progression of fatty acid-induced MAFLD through a mechanism that may involve the nuclear entry of APOC3. These findings provide a new therapeutic direction for MAFLD.

Based on an in-depth understanding of diabetes heterogeneity, five novel subtypes of adult-onset diabetes have been identified. This study investigates the differential impact of metabolic dysfunction-associated fatty liver disease (MAFLD) on these subtypes using a Mendelian randomization (MR) approach, while also exploring modifiable mediating factors.

Genetic variants associated with MAFLD were selected at the genome-wide significance threshold (P < 5 × 10-8), with 16 variants used to assess causal associations with the risk of severe autoimmune diabetes (SAID), mild obesity-related diabetes (MOD), severe insulin-resistant diabetes (SIRD), severe insulin-deficient diabetes (SIDD), and mild age-related diabetes (MARD). Two-step MR was used to estimate total, direct, and mediated effects, analyzing 55 potential mediators across five domains. The primary method used was inverse variance weighting (IVW) along with a series of sensitivity analyses to ensure robustness of the results. Genetically predicted MAFLD was significantly associated with increased risk of MARD (OR = 1.171, 95 % CI 1.091-1.256), SIDD (OR = 1.158, 95 % CI 1.056-1.270), and SIRD (OR = 1.267, 95 % CI 1.119-1.434), with suggestive evidence for SAID (OR = 1.161, 95 % CI 1.016-1.327), but no association with MOD. Among all subtypes, waist-to-hip ratio adjusted for BMI (WHRadjBMI) was a common mediator, with liver fat, alanine aminotransferase (ALT), gamma-glutamyl transferase, fasting insulin (FI), and BMI mediating at least three subtypes. Liver fat accounted for the largest proportion of mediation (43.63 %-73.09 %), followed by ALT (8.99 %-17.93 %) and FI (6.81 %-13.04 %).

This study underscores the causal relationship between MAFLD and specific diabetes subtypes, highlighting the importance of integrated management of liver lipid metabolism, abdominal obesity, and blood glucose regulation. These findings support personalized intervention strategies.

Growth/differentiation factor-15 (GDF-15) plays a crucial role in modulating inflammation and fibrosis and is emerging as a potential biomarker in metabolic diseases. This study investigated the association between circulating GDF-15 levels and the development of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM), with or without metabolic dysfunction-associated fatty liver disease (MAFLD).

In this prospective observational study, participants were stratified into three groups: those with T2DM and MAFLD (Group A) and those with T2DM and no MAFLD (Group B), alongside a healthy control group (Group C). Comprehensive clinical evaluations and laboratory assessments, including measurements of GDF-15, metabolic profiles, liver enzymes, and renal function, were performed.

GDF-15 levels demonstrated a stepwise elevation from controls to T2DM patients, with the highest levels observed in patients with MAFLD (1929 ± 412 pg/mL in Group A, 1655 ± 368 pg/mL in Group B, and 1246 ± 245 pg/mL in Group C; p < 0.001). DKD was diagnosed in 51.4 % of patients in Group A compared to 37.1 % in Group B (p < 0.001). Multivariate analysis identified GDF-15 as the sole independent predictor of DKD (p = 0.01). ROC curve analysis revealed that a GDF-15 cutoff value of ≥1890.51 pg/mL provided an AUC of 0.951, with a sensitivity of 94.2 % and specificity of 87.1 %.

Elevated GDF-15 levels are independently associated with an increased risk of DKD in T2DM patients, particularly in those with MAFLD. These findings highlight the potential of GDF-15 as an early biomarker for DKD.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising globally. Recent studies have suggested connections between exposure to endocrine disrupting chemicals (EDCs) and the development of MASLD. Phthalates, which are commonly utilized as plasticizers, in building materials and consumer items, exhibit endocrine disrupting effects and have been shown to interfere with lipid metabolism in mechanistic studies. The objective of this systematic review was to examine the association between MASLD and exposure to phthalates in the adult human populations. We searched PubMed, Scopus and Web of Science for studies published from the inception of each database until December 12, 2024. The literature search yielded 10 cross-sectional studies, which were analyzed in detail. The key findings of this study indicate a potential correlation between the prevalence of MASLD and exposure to certain phthalates. Among the phthalates examined, the metabolites of bis(2-ethylhexyl) phthalate (DEHP) - namely MECPP, MEHHP, and MEOHP, demonstrated the strongest and most frequent associations with MASLD. All the current studies followed cross-sectional study designs, which limits the possibility to establish a causal relationship between MASLD and phthalate exposure. Therefore, longitudinal studies are needed to corroborate these findings and shed light on the involvement of phthalate exposure in MASLD.

Nonalcoholic fatty liver disease (NAFLD), now known by the name of metabolic dysfunction-associated fatty liver disease (MAFLD), with increased global incidence, has been recognized as a significant metabolic disorder. NAFLD includes a spectrum liver disease from hepatocellular fat accumulation (isolated steatosis) to an advanced form of liver injury known as nonalcoholic steatohepatitis (NASH), which refers to distinct histologic features, including hepatocellular steatosis and injury, necroinflammation, and eventually fibrosis. Nonobese or lean individuals associated with metabolic dysregulation usually demonstrated diverse risk factors compared to obese MAFLD. The presence of normal range body mass index (BMI) and excess visceral adiposity with increased cardiometabolic and renal comorbidities, along with sarcopenia, has been evidenced to be associated with lean MASH. Genetic predispositions accompanying lifestyle and environmental factors contribute to disease initiation and progression. The genetic influence in pathophysiology indicated the significant contributions of the following genes: PNPLA3, TM6SF2, APOB, LIPA, MBOAT7, and HSD17B13, and the impact of their disease-specific variants in the development of obesity-independent MASH. The epigenetic modifications exhibited differential DNA methylation patterns in the genes involved in lipid metabolism, particularly hypomethylation of PEMT. Diet-induced and genetic animal models of lean MASH, including Slc: Wistar/ST rats, PPAR-α, PTEN, and MAT1A knockout mice models, are indicated to be pivotal in the exploration of disease progression and observing the effect of therapeutic interventions. This comprehensive review comprises the molecular and genetic pathophysiology, molecular diagnostics, and therapeutic aspects of lean MASH to enunciate a diagnostic approach that combines detailed clinical phenotyping regarding genomic analysis.

Legacy per- and polyfluoroalkyl substances (PFAS) can promote dyslipidemia; however, evidence is lacking for alternative and precursor PFAS. We investigated associations between serum concentrations of 31 PFAS and concurrently measured lipids and liver function biomarkers.

PFAS, lipids, and liver function biomarkers were analyzed in serum samples provided by 282 adult females participating in a 2018-2021 follow-up study of a Canadian pregnancy cohort. We examined percent differences in outcomes continuously for 17 PFAS with >50% detection and as detected vs. not detected for 14 PFAS with 10-50% detection. We also examined associations with the sum of 7 PFAS recommended by the National Academies of Sciences, Engineering, and Medicine guidance report on PFAS testing and 17 PFAS. We used weighted quantile sum (WQS) and quantile g-computation models to estimate joint associations.

Each two-fold increase in concentrations of PFHxS, PFOS, PFNA, PFDA, PFHpS, and Σ7PFAS were associated with up to 7% higher total and LDL cholesterol and the TC:HDL ratio. Individuals with detectable concentrations of N-EtFOSA, N-MeFOSA, PFBS, and 9Cl-PF3ONS had up to 17% higher total and LDL cholesterol and TC:HDL. Each one-quartile increase in the mixture of 7 PFAS was associated with up to 10% higher total and LDL cholesterol. Adding additional PFAS to the mixture (17 PFAS) made estimates less precise in WQS models and attenuated associations to the null in quantile g-computation models.

Alternative and precursor PFAS, including replacements for legacy PFAS, are associated with higher cholesterol levels; prospective studies are required to confirm these findings.

Dietary protein plays a crucial role in the growth and development of children and adolescents. However, recent evidence has shown inconsistent findings regarding the impact of dietary protein sources on health outcomes. This study aimed to investigate the association between total, animal, and plant protein intake and the odds of metabolic dysfunction-associated fatty liver disease (MAFLD) in overweight and obese children and adolescents.

This cross-sectional study included 505 participants (52.9% males) aged 6-18 years, with a body mass index (BMI)-for-age z-score ≥ 1 based on WHO standards. MAFLD diagnosis followed established consensus definitions. Dietary intake of total, animal, and plant protein was assessed using a validated 147-item food frequency questionnaire. Adjusted logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for MAFLD across protein intake and subtype quartiles.

The participants had a mean age of 10.0 ± 2.3 years and a mean BMI-for-age z-score of 2.70 ± 1.01. Higher animal protein intake was significantly associated with an increased likelihood of MAFLD (highest vs. lowest quartile OR: 2.31; 95% CI: 1.01-5.30). Conversely, higher plant protein intake was significantly associated with reduced odds of MAFLD (highest vs. lowest quartile OR:0.48;95% CI:0.23-0.96). No significant relationship was found between total protein intake and MAFLD odds.

Our findings highlight the significance of dietary protein source in the odds of MAFLD among overweight and obese children and adolescents. Further studies are warranted to confirm these findings and explore the underlying mechanisms.

The concept of metabolic dysfunction-associated steatotic disease (MASLD) is increasingly being recognized. The mechanisms contributing to hepatocellular injury include oxidative stress owing to mitochondrial dysfunction, endoplasmic reticulum (ER) stress owing to abnormal protein accumulation in the rough ER, and disruption of cellular homeostasis and metabolic regulation to autophagic dysfunction. However, the morphological abnormalities of these intracellular organelles remain unclear.

Liver tissues from model mice of MASLD, patients with MASLD, and respective controls were subjected to histopathological examination using light microscopy, and intracellular organelles were analyzed via transmission electron microscopy (TEM).

In model mice of MASLD, the progression of MASLD pathology was associated with abnormalities in mitochondria, glycogen granules, and rough ER. Based on these findings, the electron microscopic observations of these intracellular organelles were classified, weighted, and evaluated in liver tissues of patients with MASLD. The electron microscopic findings were significantly relatively frequent in patients with MASLD and correlated with existing histopathological scoring.

Using TEM, we identified characteristic abnormalities in intracellular organelles specific to MASLD. These findings contribute to the understanding of the mechanisms underlying hepatocellular injury in MASLD.

Deregulation of amino acid (AA) metabolism has been reported in several pathological conditions, including metabolic diseases (e.g., obesity and diabetes), cardiovascular diseases, and cancer. However, the role of alterations in AA levels in chronic liver disorders such as metabolic dysfunction-associated steatotic liver disease (MASLD) remains largely unexplored. In this study we aimed to evaluate the hepatic AA composition in patients with different stages of MASLD, and their relationship with MASLD-related risk factors. A case-control study was conducted in 40 patients with obesity undergoing bariatric surgery at Virgen de la Arrixaca University Hospital (Murcia, Spain), where MASLD diagnosis was confirmed by histological analysis of liver biopsies, and hepatic AA levels were measured using ultra-performance liquid chromatography high-resolution time-of-flight mass spectrometry. Our results revealed that the hepatic AA profile was significantly altered in patients with MASLD. More specifically, comparison between MASLD patients revealed a significant increase in hepatic levels of arginine, glycine and cystine in MASH samples compared to steatotic livers. In addition, hepatic concentrations of arginine, lysine and cystine positively correlated with histopathological diagnosis and other MASLD-related parameters, including transaminases and CK-18 levels. These findings suggest that alterations in certain hepatic AA levels such as arginine, lysine, glycine and cystine in MASLD patients could have translational relevance in understanding the onset of this disease.

Patients with type 2 diabetes mellitus (T2DM) exhibit an elevated risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). The uric acid to high-density lipoprotein cholesterol ratio (UHR) has emerged as a novel metabolic biomarker implicated in MASLD pathogenesis. This study aimed to evaluate the association between UHR and MASLD in a T2DM population.

In this cross-sectional study, we analyzed clinical data from 1081 T2DM patients (464 without MASLD, 617 with MASLD). Physiological and biochemical parameters were collected and analyzed. UHR was calculated as [uric acid (mg/dL)/HDL-C (mg/dL)] × 100%. Univariate and multivariate logistic regression analyses were performed to examine the association between UHR and MASLD.

T2DM patients with MASLD had significantly higher UHR levels than those without MASLD (12.12[9.06-16.83] vs 10.36[7.65-14.08], p<0.001). UHR showed a strong positive correlation with TG/HDL (r =0.673, p < 0.001), moderate correlations with TG (r = 0.516, p < 0.001) and TC/HDL (r =0.548, p < 0.001), weak but significant associations with BMI (r = 0.330), WHR (r = 0.289), HOMA-IR (r = 0.121), ALT (r = 0.123), and GGT (r = 0.267) (all p < 0.05). Multivariate logistic regression showed that elevated UHR levels were significantly associated with increased MASLD risk (adjusted OR = 1.057, 95% CI: 1.016-1.100, p = 0.006), after adjusting for age, diabetes duration, BMI, blood pressure, and biochemical confounders.

Elevated UHR is independently associated with MASLD in T2DM patients, suggesting its clinical relevance in MASLD screening among this high-risk population.

Insulin resistance plays a pivotal role in the progression of type 2 diabetes mellitus (T2DM). An in-depth investigation into the role of insulin resistance scores in evaluating T2DM combined with metabolic-associated fatty liver disease (MAFLD) and liver fibrosis holds significant importance for clinical decisions and personalized treatment.

The study screened patients with diabetes from Taizhou Central Hospital from June 2020 to May 2024. In conjunction with the National Health and Nutrition Examination Survey (NHANES) database, various statistical methods such as logistic regression analysis, restricted cubic spline, and receiver operating characteristic curves were employed to complete data analysis.

This study encompassed 3776 patients with T2DM, including 1074 diagnosed with MAFLD. Insulin resistance scores in the MAFLD group were significantly elevated. Compared with nonfibrotic patients, those with T2DM and liver fibrosis exhibited notably higher Chinese visceral adiposity index (CVAI) scores and notably lower triglyceride-glucose index and visceral adiposity index scores; the incidence of hypertension, coronary heart disease, stroke, and peripheral arterial disease were significantly elevated. Among other insulin resistance scores, the CVAI score demonstrated the highest value for correlating with the MAFLD and liver fibrosis in patients with T2DM. The NHANES database, encompassing data from 6763 individuals, validated the aforementioned findings, further affirming that the CVAI score exhibited optimal consistency with the risk of T2DM with MAFLD and liver fibrosis.

The insulin resistance scores were significantly elevated in T2DM combined with MAFLD. The CVAI score demonstrated the best predictive effect on MAFLD and liver fibrosis.

Physical activity (PA), sedentary behavior (SB), metabolic syndrome (MetS), and non-alcoholic fatty liver disease (NAFLD) have been linked in previous studies. Nevertheless, it is unclear whether MetS has a mediating influence on the relationships among physical activity, sedentary behavior, and non-alcoholic fatty liver disease. This study aims to assess the connections between physical activity, sedentary behavior, and non-alcoholic fatty liver disease and to explore the extent to which metabolic syndrome acts as a mediator in this association.

A total of 3351 adults from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018 were included in our study. Physical activity and sedentary behavior were categorized as work activity (WA), recreational activity (RA), walking/bicycling (for commuting) and sedentary behavior to investigate the association with metabolic syndrome and non-alcoholic fatty liver disease. Besides, mediation analysis was utilized to determine the extent to which metabolic syndrome mediates the relationships among inadequate physical activity, prolonged sedentary behavior, and non-alcoholic fatty liver disease.

Regression analysis revealed that a reduced risk of developing NAFLD was associated with sufficient recreational activity (OR = 0.61, 95% CI: 0.44-0.83, P = 0.004), while an increased risk of MetS was observed in sedentary behavior group (OR = 1.28, 95% CI: 1.00-1.64, P < 0.05). In addition, strong associations were detected between MetS and NAFLD. Mediation analysis indicated that metabolic syndrome accounts for 17.9% of the influence that recreational activity has on the risk of NAFLD. Subgroup analysis indicated sex differences in these associations. Specifically, recreational activity may not significantly influence the risk of developing NAFLD in females, and the mediating role of MetS was no longer significant in both sex-specific subgroups.

In the general adult population, metabolic syndrome may account for nearly 18% of the association between insufficient recreational activity and non-alcoholic fatty liver disease.

To assess the performance of fibrosis-4 index (FIB-4), non-alcoholic fatty liver disease fibrosis score (NFS) and aspartate aminotransferase to platelet ratio index (APRI) for advanced fibrosis in metabolic dysfunction-associated fatty liver disease (MAFLD) subgroups categorized by concomitant liver conditions.

We conducted a multicentered study comprising inpatients with type 2 diabetes mellitus (T2DM) and MAFLD. Participants were categorized into two groups: MAFLD with pure metabolic etiologies (MAFLD-P) and MAFLD with mixed etiologies (MAFLD-M). Diagnostic performance of FIB-4, NFS and APRI was assessed by area under receiver operating characteristic curve (AUC), sensitivity and specificity.

This study comprised a total of 1475 participants, with a mean (SD) age of 58.4 (13) years and 835 (56.6%) males. FIB-4 and APRI had higher AUCs for advanced fibrosis in the MAFLD-M group than in the MAFLD-P group (MAFLD-M vs MAFLD-P: FIB-4 0.680 vs 0.591, p = 0.0442; APRI 0.723 vs 0.631, p = 0.0363). No significant difference was observed in the AUC of NFS between the two subgroups (MAFLD-M 0.572 vs MAFLD-P 0.617; p = 0.3237). Besides, the sensitivity of FIB-4 (69.6% vs 54.0%; p = 0.019) and APRI (43.5% vs 26.1%; p = 0.005) was higher in the MAFLD-M group. However, no significant difference in sensitivity of NFS and specificity of FIB-4, NFS and APRI was observed between subgroups.

In this diagnostic study of the T2DM population, FIB-4 and APRI showed better performance for identifying advanced fibrosis in MAFLD with mixed etiologies.

The global rise in obesity and diabetes has been paralleled by a rising incidence of metabolic dysfunction-associated steatotic liver disease (MASLD). Although previous studies have explored the association between body roundness index (BRI) and MASLD, the specific relationship in non-diabetic Japanese adults requires further investigation. This study analyzed data from 15,299 participants enrolled in the NAGALA cohort (2004-2015) to explore the association between BRI and MASLD through multivariable logistic regression, stratified analysis, and restricted cubic spline modeling. The prevalence of MASLD was 14.46%, with 13.73% occurring in non-obese individuals (BMI < 30). After adjusting for all confounding factors, BRI demonstrated a significant association with MASLD, yielding an adjusted odds ratio of 1.72 (95% CI 1.48-1.99). The restricted cubic spline model revealed a nonlinear relationship, with an inflection point at 3.06. Stratified analyses revealed stronger associations in individuals with lower BMI (≤ 24 kg/m2).

The incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) is high among U.S. adults, but studies on its occurrence in different ethnic and age groups are limited. The aim of the present study was to assess MAFLD occurrence among the U.S. adults by considering demographic characteristics, physical indices, and lifestyle conditions.

This study utilized the National Health and Nutrition Examination Survey (NHANES) data 2009-2018 from 23,546 participants aged ≥ 20 years. Variables such as age, sex, race, body mass index (BMI), waist circumference (WC), blood pressure, sedentary behavior, sleep, and depression were analyzed.

Among 9933 participants, 3562 had MAFLD (34.1%), with notably higher percentages of Mexican-Americans (54.1%) and lower percentages of blacks (20.5%). The incidence of MAFLD was significantly greater (P < 0.001) in males (39%) than in females (29.2%), which was particularly evident within the 36-40 years age group. The MAFLD incidence exhibited an age-dependent pattern, initially increasing and subsequently declining (except for whites). Compared to white MAFLD patients, black MAFLD patients exhibited greater BMI, WC, systolic blood pressure (SBP), and diastolic blood pressure (DBP) values, whereas values for these measures were lower among Mexican-American patients. Logistic regression analysis adjusting for age and sex revealed that depression was more common among MAFLD patients (P < 0.001), except for severe depression (P > 0.05). Notably, the MAFLD incidence was not significantly associated with sedentary behavior or sleep duration.

The MAFLD incidence varies across different racial, age, and sex groups, and targeted interventions are essential for reducing the burden of MAFLD. However, further research is necessary to explore the correlations among MAFLD incidence, sleep patterns, and an inactive lifestyle.

Considering recent revisions in the nomenclature for fatty liver disease, alongside limited data on sex-specific differences in its cardiovascular/mortality outcomes, this study aims to investigate the prevalence and impact of metabolic-associated fatty liver disease (MAFLD) on cardiovascular disease (CVD) and mortality in men and women over a 12-year follow-up period.

In this large population-based cohort study, 7101 individuals aged ≥ 30 were enrolled. The prevalence of MAFLD was investigated in both genders. After excluding individuals with a history of previous CVD, 6331 participants were followed up for CVD and mortality over 12 years. Steatosis was defined as fatty liver index (FLI) ≥ 60. Multivariate-adjusted hazard ratios (HRs) were calculated for CVD and mortality.

The prevalence of MAFLD was 43.2%, higher in men (46.5%) than women (40.6%). Men with MAFLD (47.7 ± 12.1) were younger than women (52.2 ± 11.1). In the 12-year follow-up of 6331 individuals, multivariable-adjusted CVD HRs for MAFLD were 1.36 (1.10-1.67) in men and 1.48 (1.16-1.88) in women. Adjusted mortality HRs were 1.17 (0.86-1.59) and 1.38 (1.00-1.91) in men and women, respectively. Among patients with MAFLD, a subgroup with diabetes faced the highest hazard for CVD and mortality.

This study found that MAFLD is more common in men at a younger age. Despite the higher prevalence in men, women with MAFLD face a greater risk of cardiovascular events and mortality. Findings highlight the importance of gender-specific considerations in primary prevention programmes for MAFLD-related cardiovascular disease and mortality.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a significant hepatic manifestation of metabolic syndrome, with its prevalence increasing globally alongside the epidemics of obesity and diabetes. MAFLD represents a continuum of liver damage, spanning from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH). This condition can advance to more severe outcomes, including fibrosis and cirrhosis. Fibroblast growth factor receptors (FGFRs) are a family of four receptor tyrosine kinases (FGFR1-4) that interact with both paracrine and endocrine fibroblast growth factors (FGFs). This interaction activates the phosphorylation of tyrosine kinase residues, thereby triggering downstream signaling pathways, including RAS-MAPK, JAK-STAT, PI3K-AKT, and PLCγ. In the context of MAFLD, paracrine FGF-FGFR signaling is predominantly biased toward the development of liver fibrosis and carcinogenesis. In contrast, endocrine FGF-FGFR signaling is primarily biased toward regulating the metabolism of bile acids, carbohydrates, lipids, and phosphate, as well as maintaining the overall balance of energy metabolism in the body. The interplay between these biased signaling pathways significantly influences the progression of MAFLD. This review explores the critical functions of FGFR signaling in MAFLD from three perspectives: first, it examines the primary roles of FGFRs relative to their structure; second, it summarizes FGFR signaling in hepatic lipid metabolism, elucidating mechanisms underlying the occurrence and progression of MAFLD; finally, it highlights recent advancements in drug development aimed at targeting FGFR signaling for the treatment of MAFLD and its associated diseases.

The continuum of metabolic syndrome encompasses a spectrum of dysfunctions impacting obesity-linked insulin resistance, glucose homeostasis, lipid metabolism and pro-inflammatory immune responses. The global prevalence of metabolic diseases, including diabetes, chronic liver disease, cardiometabolic disease and kidney disease, has surged in recent decades, contributing significantly to population mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is a leading cause of liver disease worldwide. MASLD poses a significant global health challenge with its rising prevalence, placing a substantial burden on healthcare systems, impacts patient well-being and incurs significant economic costs. Addressing MASLD requires a comprehensive understanding of its interconnected factors, including its prevalence, healthcare burden and economic implications. Lack of awareness, imprecise non-invasive diagnostic methods and ineffective preventive interventions are core components of the MASLD-related problem.

The aim of this article was to summarise the global burden of MASLD from the payer's perspective.

We carried out a review of the global comprehensive burden of MASLD. These topics led to discussions and insights by an expert panel during the 7th Metabolic Continuum Roundtable meeting, which took place in November 2023. This meeting focused on the burden, patient-reported outcomes and health economics, from payor and societal perspectives, and aimed to identify opportunities for improving patient care, optimise resource allocation and mitigate the overall impact on individuals and society related to MASLD. During the roundtable, an emphasis emerged on the need for greater awareness and strategic deployment of diagnostic, therapeutic and preventative measures to address MASLD effectively.

The global burden of MASLD is high and growing. Prioritising the prevention of metabolic dysregulation and timely therapeutic interventions can yield a holistic strategy to combat MASLD, its progression and potentially lower disease costs.

NCT06309992.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic condition with an incompletely understood pathogenesis. In this study, five candidate genes-RAG1, CKAP2, CENPK, TYMS, and BUB1-were identified as being associated with NAFLD progression through integrative bioinformatics analyses. A predictive model incorporating these genes demonstrated strong robustness and diagnostic accuracy. Single-nucleus RNA sequencing analysis further revealed that RAG1 plays a potential role in hepatocytes of NAFLD patients. Functional experiments using RNA interference to suppress RAG1 expression in HepG2 cells treated with oleic and palmitic acids showed reduced total glyceride and cholesterol levels, mitigated lipid accumulation, and alterations in pathways related to lipid metabolism, inflammation, and fibrosis. Furthermore, adeno-associated virus-specific knockdown of RAG1 in hepatocytes attenuated hepatic steatosis in high-fat diet-fed mice. These findings suggest that investigating the molecular mechanisms of hub genes like RAG1 may advance our understanding of NAFLD pathogenesis and inform therapeutic development.

Gallstone formation is associated with metabolic dysfunction. Recently, new definitions of steatotic liver disease (SLD) have been proposed, including metabolic dysfunction-associated SLD (MASLD) and moderate alcohol intake (MetALD). We investigated the effects of MASLD/MetALD on gallstone formation.

This multicenter observational cohort study enrolled 8766 consecutive health-check examinees who underwent abdominal ultrasonography between 2008 and 2021 (total observation period 39,105.9 person-years). All patients were classified into non-SLD, MASLD, or MetALD groups. The effect of MASLD on gallstone development was evaluated using multivariate Cox regression analysis.

Age, male sex, and MASLD were identified as independent risk factors for gallstone development. MASLD was associated with a significantly higher risk of developing gallstones than non-SLD (hazard ratio [HR] 1.7112; 95% confidence interval [CI] 1.4294-2.0486; p < 0.0001) and MetALD (HR 1.3516, 95% CI 1.0130-1.8033, p = 0.0406). However, the risk of MetALD did not significantly differ between the SLD and non-SLD groups. Hypertension was the only significant independent cardiometabolic risk factor for gallstone development in the MASLD group (HR 1.4350, 95% CI 1.0545-1.9528; p = 0.0216). Random forest analysis and directed acyclic graphs identified hypertension as the most important direct factor affecting gallstone development in patients with MASLD.

MASLD was an independent risk factor for gallstone development, whereas MetALD presented a similar risk as non-SLD. Moderate alcohol consumption may reduce the risk of gallstone formation in patients with MASLD. Hypertension may be the most significant cardiometabolic risk factor for gallstone development in patients with MASLD.

Metabolic-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition globally, characterized by suboptimal treatment outcomes. Traditional therapies often fail to address the multifaceted pathogenesis of MAFLD, which involves lipid metabolism, inflammation, and gut-liver axis dysregulation. JiGuCao Capsule formula (JCF), a patented Chinese medicine, has demonstrated clinical efficacy in liver disease treatment, indicating its potential as a new therapeutic option for MAFLD.

This study aimed to investigate the therapeutic effects and underlying mechanisms of JCF in treating MAFLD, particularly focusing on its impact on liver pathology, intestinal health, and gut microbiota composition.

A MAFLD mouse model was developed by administering a high-fat diet and 5% fructose water for 16 weeks. At week 8, mice exhibited significant steatosis, inflammation, and insulin resistance. Fifty mice were allocated into two groups: the normal diet (ND) group with 19 mice and the high-fat feed diet (HFD) group with 31 mice. Seven mice from each group were sacrificed at week 8 for serological and histopathological assessments. The remaining mice were allocated into ND (n = 6), HFD (n = 6), HFD + JCFL (human equivalent dose,780 mg/kg, n = 6), HFD + JCFH (threefold the human equivalent dose, 2340 mg/kg, n = 6), HFD + Polyene Phosphatidylcholine (PPC) (human equivalent dose,177.84 mg/kg, n = 6) and ND+ JCF (human equivalent dose,780 mg/kg, n = 6) groups. Daily gavage started at week 9. At week 16, after fasting, body weight and liver condition were recorded, and mice were euthanized with pentobarbital sodium. Mouse tissues and feces were collected for histopathological, molecular biological, and multi-omics analyses.

JCF effectively slowed MAFLD progression in mice by decreasing hepatic lipid accumulation and inflammation. Treatment with JCF significantly reduced hepatic triglycerides and inflammatory markers, including TNF-α and IL-6. JCF enhanced lipid metabolism, repaired the intestinal barrier, and lowered inflammatory cytokines in the intestines, as indicated by reduced serum LPS and restored tight junction proteins expression, such as claudin-1 and occludin. Fecal microbiota analysis indicated that JCF treatment elevated Lactobacillus levels and reduced Colidextribacter levels, correlating with enhanced metabolic profiles. The primary bioactive compounds identified in JCF responsible for these therapeutic effects were betulinic acid, cholic acid, deoxycholic acid, oleanolic acid, and pectolinarigenin. Transcriptomic analysis showed that JCF regulated key pathways involved in lipid metabolism, including the pparγ-cd36 axis and modulation of ox-LDL levels. The results indicate that JCF effectively mitigates MAFLD by influencing the gut-liver axis and lipid metabolism.

JCF alleviates MAFLD by modulating the gut-liver axis and lipid metabolism. Its effects involve improving gut barrier function, regulating microbiota, and targeting the pparγ-cd36 axis. Active compounds like betulinic acid support its therapeutic potential. JCF shows promise as a novel treatment for MAFLD, with further clinical studies needed.

Metabolism associated fatty liver disease (MAFLD) has emerged as a growing global health challenge with limited effective treatments. Research on nuclear receptors offers promising new therapeutic avenues for MAFLD. The liver X receptor (LXR) has gained attention for its roles in tumors and metabolic and inflammatory diseases; However, its effects on MAFLD treatment remain a subject of debate. This review explores the therapeutic role of LXRα in MAFLD, focusing on its functions in the intestine, hepatic and adipose tissue, and summarizes recent advancements in LXRα ligands over the past five years. In the intestine, LXRα activation enhances the efflux of non-biliary cholesterol and reduces inflammation in the gut-liver axis by regulating intestinal high-density lipoprotein synthesis and its interaction with lipopolysaccharide. In the liver, LXRα activation facilitates cholesterol transport, influences hepatic lipid synthesis, and exerts anti-inflammatory effects. In adipose tissue, LXRα helps delay MAFLD progression by managing lipid autophagy and insulin resistance. Ligands that modulate LXRα transcriptional activity show considerable promise for MAFLD treatment.

Μetabolic dysfunction-associated steatotic liver disease (MASLD) comprises a heterogeneous condition in the presence of steatotic liver. There can be a hierarchy of metabolic risk factors contributing to the severity of metabolic dysfunction and, thereby, the associated risk of both liver and extrahepatic outcomes, but the precise ranking and combination of metabolic syndrome (MetS) traits that convey the highest risk of major adverse liver outcomes and extrahepatic disease complications remains uncertain. Insulin resistance, low-grade inflammation, atherogenic dyslipidaemia and hypertension are key to the mechanisms of liver and extrahepatic complications. The liver is pivotal in MetS progression as it regulates lipoprotein metabolism and secretes substances that affect insulin sensitivity and inflammation. MASLD affects the kidneys, heart and the vascular system, contributing to hypertension and oxidative stress. To address the global health burden of MASLD, intensified by obesity and type 2 diabetes mellitus epidemics, a holistic, multidisciplinary approach is essential. This approach should focus on both liver disease management and cardiometabolic risk factors. This Review examines the link between metabolic dysfunction and liver dysfunction and extrahepatic disease outcomes, the diverse mechanisms in MASLD due to metabolic dysfunction, and a comprehensive, personalized management model for patients with MASLD.

Evidence regarding the role of acute kidney injury (AKI) in long-term development of metabolic dysfunction-associated fatty liver disease (MAFLD) is limited. We aimed to investigate the associations between AKI and liver-related events in patients with MAFLD.

This study involved 50,499 Chinese adults with MAFLD from the China Renal Data System (CRDS) database. We identified AKI using patient-level serum creatinine data according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. The primary outcome was a composite of liver-related mortality and major adverse liver outcomes. The secondary outcome was an escalation of fibrosis-4 (FIB-4) risk scores. Cox proportional hazard models were performed to assess the association between AKI and the study outcomes.

The median age of the patients was 59.17 years, with 54.7% being male. There were 3,711 (7.3%) patients who experienced AKI during hospitalization. A total of 1,660 (3.3%) patients experienced composite liver outcome. Patients with AKI during hospitalization had higher risk of composite liver outcomes (adjusted hazard ratio (aHR) 1.83 [95% confidence interval 1.38;2.41] P < 0.001), especially among those with severe AKI (stage 2/3) (aHR 2.36 [1.57;3.54] P < 0.001). Regarding the secondary outcome, AKI was also associated with an increased risk of escalation of FIB-4 risk scores (aHR 1.28 [1.14;1.44] P < 0.001). These associations remained consistent across various subgroups and sensitivity analyses.

AKI was significantly associated with an increased risk of liver-related events among patients with MAFLD. These findings suggest that enhanced vigilance toward AKI may be justifiable in MAFLD patients.