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.

Metabolic Associated Fatty Liver Disease (MAFLD) impacts approximately 25% of the global population. Between April 2023 and July 2023, 60 patients with MAFLD, along with 60 age, ethnicity, and sex-matched healthy controls (HCs), were enrolled from the Inner Mongolia Autonomous Region, China. Analysis of gut microbiota composition and plasma metabolic profiles was conducted using metagenome sequencing and LC-MS. LEfSe analysis identified five pivotal species: Eubacterium rectale, Dialister invisus, Pseudoruminococcus massiliensis, GGB3278 SGB4328, and Ruminococcaceae bacteria. In subgroup analysis, Eubacterium rectale tended to increase by more than 2 times and more than double in the non-obese MAFLD group, and MAFLD with moderate hepatic steatosis (HS), respectively. Plasma samples identified 172 metabolites mainly composed of fatty acid metabolites such as propionic acid and butyric acid analogues. Ruminococcaceae bacteria have a strong positive correlation with β-alanine, uric acid, and L-valine. Pseudoruminococcus massiliensis has a strong positive correlation with β-alanine. Combinations of phenomics and metabolomics yielded the highest accuracy (AUC = 0.97) in the MAFLD diagnosis. Combinations of phenomics and metagenomics yielded the highest accuracy (AUC = 0.94) in the prediction of the MAFLD HS progress. Increases in Eubacterium rectale and decreases in Dialister invisus seem to be indicative of MAFLD patients. Eubacterium rectale may predict HS degree of MAFLD and play an important role in the development of non-obese MAFLD. Eubacterium rectale can generate more propionic acid and butyric acid analogues to absorb energy and increase lipid synthesis and ultimately cause MAFLD.

A healthy diet has been recommended for non-alcoholic fatty liver disease (NAFLD). We aim to investigate the associations of diet quality indices with the risk of developingmetabolic-associated fatty liver disease (MAFLD).

We conducted this nested case-control study by recruiting 968 cases with MAFLD and 964 controls from the participants of the baseline phase of the Sabzevar Persian Cohort Study (SPCS). MAFLD was defined as having a fatty liver index ≥ 60 plus at least one of the following: overweight or obese, Type II diabetes mellitus, or evidence of metabolic dysregulation. Healthy Eating Index-2015 (HEI-2015) and Alternative Healthy Eating Index-2010 (AHEI-2010) were calculated from a validated food frequency questionnaire. We estimated the associations of HEI-2015 and AHEI-2010 with MAFLD risk using multivariable logistic regression.

Among those in the highest relative to the lowest quintile of HEI-2015 and AHEI-2010, the multivariable-adjusted odds ratios (OR) were 0.45 (95% CI [confidence interval] 0.29-0.69; P trend = 0.002) and 0.55 (95% CI 0.35-0.85; P trend = 0.04), respectively.

The results of our study suggest that there is a significant associationbetween adherence to a healthy diet, indicated by a higher score of HEI or AHEI, and a reduced likelihood of developingMAFLD.

The online version contains supplementary material available at 10.1007/s40200-024-01544-x.

Noninvasive assessment of liver fat content is crucial due to the high global prevalence of nonalcoholic fatty liver disease. Algorithms based on ultrasound (US) attenuation coefficient (AC) for estimating liver fat content are commercially available, but a lack of consensus exists regarding the best estimation protocol. The aim of our study was to evaluate the influence of the size of the region of interest (ROI) on the US AC.A prospective study was conducted. An abdominal US was done for 86 outpatients. A sampling box was positioned within the liver parenchyma, approximately 2 cm beneath the liver capsule with a ROI, measuring about 2 × 4 cm and then 4 × 5 cm, precisely placed at the center of this sampling box. Five readings of the AC were captured, and the average of these measurements was employed to assess the severity of hepatic steatosisA statistically significant difference between AC with 2 different ROI sizes was shown (P < 0.001) with AC values with 2 × 4 cm ROI were higher than those obtained with 4 × 5 cm ROI (AC mean 0.668 VS 0.653). However, the agreement between AC values obtained with 2 different ROI sizes was excellent (correlation coefficient 0.941)An ROI size dependence is observed in the measurement of AC in the liver. A standardized acquisition protocol with a fixed size of the ROI needs to be developed to minimize differences in AC measurements and to assess changes in serial measurements reliably.

This study investigates the potential of Bifidobacterium bifidum 1007478 (BB478) and its metabolite indole-3-lactic acid (ILA) in alleviating non-alcoholic steatohepatitis (NASH) induced by a high-fat diet (HFD) and fructose exposure.

A zebrafish model of NASH was established by exposure to HFD and fructose. BB478 was administered, and the effects on liver lipid accumulation, oxidative stress, and inflammation were assessed. ILA production by BB478 was confirmed, and its impact on hepatic lipogenesis and inflammatory pathways was evaluated. The involvement of the aromatic hydrocarbon receptor (AhR) was also examined using an AhR inhibitor.

BB478 supplementation inhibited lipid accumulation in the liver, reduced triglycerides (TG) and total cholesterol (TC), and mitigated oxidative stress, as evidenced by lower levels of reactive oxygen species (ROS) and malondialdehyde (MDA). ILA, produced by BB478, could alleviate the hepatic damage and fat deposition in liver. Mechanistically, it suppressed hepatic lipogenesis by downregulating lipogenesis-related genes, including sterol response element binding protein 1 (SREBP1) and fatty acid synthase (FASN). ILA also inhibited the expression of pro-inflammatory cytokines to suppress inflammation. The therapeutic effects of ILA were reversed by the AhR inhibitor, indicating that ILA's actions are AhR-dependent.

These findings reveal the potential of ILA, produced by Bifidobacterium bifidum, as a therapeutic agent for NASH. The mechanistic insights into AhR-mediated effects provide a foundation for further exploration of ILA as a novel approach for managing liver diseases.

Per- and polyfluoroalkyl substances (PFAS) have been reported to exert hepatotoxic effects; however, their impact on nonalcoholic fatty liver disease (NAFLD) remains unclear. This study aimed to investigate the association between PFAS exposure and NAFLD in Korean adults, thereby contributing to the generalization of PFAS's hepatotoxic effects. Using data from the 2018-2020 Korean National Environmental Health Survey (KoNEHS), we analyzed 2635 Korean adults. PFAS exposure levels were estimated based on the serum concentrations of five PFAS. NAFLD was assessed using two steatosis-related indices (hepatic steatosis index [HSI] and fatty liver index [FLI]) and two fibrosis-related indices (fibrosis-4 index [FIB-4] and aspartate aminotransferase to platelet ratio index [APRI]). The models included these indices as continuous and dichotomous variables, the latter based on diagnostic criteria from previous studies. Associations with PFAS exposure were examined using multiple linear regression and robust Poisson regression models. Positive associations were observed between PFAS exposure and three of the four continuous indices, excluding the FLI, as well as the prevalence of NAFLD diagnosed using these indices. Specifically, the HSI showed a significant association only with perfluorononanoic acid, whereas fibrosis-related indices (FIB-4 and APRI) were significantly associated with all five individual PFAS. The associations were stronger in female and non-obese groups when stratified by sex and obesity status. The results of the Bayesian kernel machine regression analysis evaluating the health effects of PFAS mixtures indicated an association between PFAS mixtures and NAFLD, particularly fibrosis-related indices. Additionally, significant associations with NAFLD indices were mostly observed in females and non-obese groups, supporting the findings from the individual PFAS exposure analyses. Our findings suggest that PFAS are associated with NAFLD, particularly for fibrosis. Considering the high serum PFAS concentrations in the Korean population, continuous monitoring and prospective cohort studies are warranted.

Caffeic acid (CA) and its derivative, chlorogenic acid (CGA), have shown promise in preventing and alleviating fatty liver disease. CA, compared to CGA, has much lower production costs and higher bioavailability, making it a potentially superior feed additive. However, the efficacy, mechanistic differences, and comparative impacts of CA and CGA on fatty liver disease in laying hens remain unclear. This study aimed to evaluate and compare the effects of CA and CGA on production performance, egg quality, and fatty liver disease in laying hens.

A total of 1,440 61-week-old Hyline Brown laying hens were randomly divided into 8 groups and fed diets supplemented with basal diet, 25, 50, 100 and 200 mg/kg of CA, and 100, 200 and 400 mg/kg of CGA (CON, CA25, CA50, CA100, CA200, CGA100, CGA200 and CGA400, respectively) for 12 weeks. Both CA and CGA improved production performance and egg quality, while reducing markers of hepatic damage and lipid accumulation. CA and CGA significantly decreased TG, TC, and LDL-C levels and increased T-SOD activity. Transcriptomic and proteomic analyses revealed that CA and CGA reduced hepatic lipid accumulation through downregulation of lipid biosynthesis-related genes (ACLY, ACACA, FASN, and SCD1) and enhanced lipid transport and oxidation genes (FABPs, CD36, CPT1A, ACOX1, and SCP2). Of note, low-dose CA25 exhibited equivalent efficacy to the higher dose CGA100 group in alleviating fatty liver conditions. Mechanistically, CA and CGA alleviated lipid accumulation via activation of the ADPN-AMPK-PPARα signaling pathway.

This study demonstrates that dietary CA and CGA effectively improve laying performance, egg quality, and hepatic lipid metabolism in laying hens, with CA potentially being more economical and efficient. Transcriptomic and proteomic evidence highlight shared mechanisms between CA25 and CGA100. These findings provide a foundation for CA and CGA as therapeutic agents for fatty liver disease and related metabolic diseases in hens, and also offer insights into the targeted modification of CGA (including the isomer of CGA) into CA, thereby providing novel strategies for the efficient utilization of CGA.

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health challenge, with evidence indicating that hepatic inflammation and fibrosis are heterogeneous processes. Purpose To measure liver mechanical property heterogeneity using MR elastography (MRE) and evaluate its potential as a biomarker for tissue inflammation and fibrosis in patients with MASLD. Materials and Methods Mechanical tissue heterogeneity in MASLD was assessed at three-dimensional vector MRE pixel-wise histogram analysis of shear stiffness and loss modulus in preclinical and clinical studies. The preclinical study involved 25 rats that were examined monthly, whereas the clinical study analyzed data from 179 participants across two prospective studies (September 2015 to November 2022), including some who underwent bariatric surgery at pretreatment and posttreatment MRE examinations. Mean and coefficient of variation (CV) of shear stiffness and loss modulus were calculated for each examination. Nonparametric tests and Spearman correlation coefficient were used to compare MRE-derived tissue mechanics with biopsy-confirmed fibrosis and inflammation and assess correlations with portal pressure and histopathologic hepatic fibrosis. Results The preclinical study showed that, in cirrhotic livers, CV of loss modulus positively correlated with portal pressure and fibrosis area ratio variation (ρ = 0.52 [P = .008] and 0.55 [P = .005], respectively). The clinical study showed that, in 10 healthy volunteers (median age, 36.5 years; IQR, 34.0-38.8 years; five females) and 169 participants with MASLD (median age, 50.1 years; IQR, 41.0-58.2 years; 118 females), CV of sheer stiffness (from 0.12 to 0.30 in healthy participants to participants with stage 4 fibrosis) and loss modulus (from 0.31 to 0.51 in healthy participants to participants with grade 3 inflammation) increased with increasing severity of fibrosis and inflammation, respectively. In 36 participants who underwent bariatric surgery, the CV of sheer stiffness decreased at the 1-year follow-up, from 0.16 (IQR, 0.14-0.18) to 0.14 (IQR, 0.12-0.16) (P = .009). Conclusion Tissue mechanical heterogeneity assessed at MRE positively correlated with progression of MASLD, demonstrating potential as a biomarker for liver disease severity and therapeutic intervention. ClinicalTrials.gov Identifier: NCT02565446 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Moura Cunha in this issue.

The classification of steatotic liver disease (SLD) has evolved, incorporating all conditions characterized by hepatic lipid accumulation. SLD represents a continuum of disorders that are shaped by the dynamic factors of alcohol intake and cardiometabolic risk factors. This updated classification has profound implications for both the management and research of SLD, especially with the new distinct category of patients with both metabolic and alcohol-related liver disease. In this Perspective, we highlight the pivotal role of alcohol within the SLD framework. We introduce the 'SLD burden paradox': a concept illustrating the disparity in which metabolic dysfunction-associated steatotic liver disease is more prevalent, yet individuals with SLD and excessive alcohol intake (such as in metabolic and alcohol-related liver disease and in alcohol-related liver disease) account for greater global liver-related morbidity and mortality. We explore strategies to mitigate the effect of SLD on morbidity and mortality, emphasizing the importance of early detection and reducing stigma associated with alcohol intake. Our discussion extends to methods for assessing and monitoring alcohol intake together with the critical role of managing cardiometabolic risk factors in patients across the SLD spectrum. Conclusively, we advocate for a coordinated care framework that adopts a person-centric approach when managing SLD, aiming to improve outcomes and patient care.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to type 2 diabetes mellitus (T2DM) through a common root in insulin resistance. The more severe stage, metabolic dysfunction-associated steatohepatitis (MASH), increases the risk for cardiovascular complications, liver cirrhosis and hepatocellular carcinoma. Several trials investigating established antidiabetic-drugs in patients with T2DM and MASLD have yielded promising results. Therefore, we aimed to systematically review the effect of T2DM-drug treatment on MALSD parameters.

Medical databases were searched until January 2025 for controlled trials in patients with T2DM and MASLD/MASH. Studies that evaluated the effect of T2DM-medication on the severity of MASLD/MASH in T2DM patients were included. The quality of the studies was assessed by three independent reviewers using a set of Cochrane risk-of-bias tools.

Of 1748 references, 117 studies fulfilled the inclusion-criteria and were assessed for eligibility in full-text. Fifty-two articles were included. Data included a total of 64.708 patients and study populations ranged from 9 to 50.742. Heterogeneity in study-design and analysis hampered the comparability of the results. Most evidence was present for GLP-1 receptor agonists, SGLT2-inhibitors and PPAR-γ-agonists for regression of liver fibrosis and MASH.

Studies on the value of T2DM-drug treatment in the improvement of MASLD vary significantly in study design, size and quality. GLP-1 receptor agonists, PPAR-γ-agonists, SGLT2-inhibitors may all be preferred pharmacological interventions for patients with MASLD/MASH and T2DM. Newer agents like dual GLP-1/GIP or triple GLP-1/GIP/Glucagon agonists will likely play an important role in the treatment of MASLD/MASH in the near future.

The impact of metabolic syndrome (MetS) traits on chronic kidney disease (CKD) risk in metabolic dysfunction-associated steatotic liver disease (MASLD) is unknown. We investigated the impact of type and number of MetS traits and liver fibrosis on prevalent CKD and incident end-stage renal disease (ESRD) risk in SLD.

234 488 UK Biobank participants' were analysed. Hepatic steatosis index (> 36 for SLD, < 30 for no SLD) and MRI-proton density fat fraction (≥ 5.56%) were used to identify SLD. MetS traits were identified using MASLD criteria. Advanced fibrosis (FIB-4 score > 2.67) was determined using FIB-4 scores. eGFR < 60 mL/min/1.73 m2 or albuminuria > 3 mg/mmol identified prevalent CKD. A validated algorithm identified incident ESRD. Binary logistic and Cox regressions were used to test associations with prevalent CKD ([adjusted odds ratios (ORs)]) and incident ESRD (adjusted hazard ratios [HRs]) respectively.

102 410 participants (41.2%) had SLD. 64.4% had MetS. 1.3% had FIB-4 score > 2.67. With SLD and only one MetS trait, hypertension (OR 1.35, 95% CI 1.35-1.72) or type 2 diabetes (T2D) (OR 1.89, 95% CI 1.06-3.38) increased risk of prevalent CKD. MetS (≥ 3 traits) increased prevalent CKD risk (OR 1.94, 95% CI 1.75-2.15), which was further increased by advanced liver fibrosis (OR 4.29, 95% CI 3.36-5.47). CKD prevalence increased with increasing MetS traits. Over 13.6 years (median follow-up), MetS was associated with increased risk of developing ESRD (HR 1.70, 95% CI 1.19-2.43).

In MASLD, hypertension, and T2D, number of MetS traits and liver fibrosis increased risk of prevalent CKD and presence of MetS increased the risk of incident ESRD.

The Cardiovascular-kidney-metabolic (CKM) syndrome is a health disorder caused by interactions between cardiovascular disease, kidney disease, and metabolism-related risk factors. The stress hyperglycemia ratio (SHR) has been shown to correlate with the prognosis of participants with diabetes mellitus, heart failure, and myocardial infarction. However, the predictive value of SHR in the CKM syndrome population is unclear and requires further exploration.

This study analyzed 19,345 participants from the National Health and Nutrition Examination Survey (1999-2018). CKM syndrome was staged according to the American Heart Association (AHA) guidelines. SHR was calculated using fasting blood glucose (FBG) and glycated hemoglobin type A1c (HbA1c). Participants were grouped into four quartiles based on SHR. The primary and secondary outcomes were all-cause mortality and cardiovascular mortality, respectively. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to evaluate the association between SHR and outcomes. Then, the potential nonlinear relationship was explored using restricted cubic spline (RCS) analysis. We also performed subgroup analyses to assess the effects of different variables.

A total of 2,736 all-cause deaths and 699 cardiovascular deaths were recorded during a median follow-up period of 115 months. Kaplan-Meier analysis revealed that participants in quartile 2 had the lowest risk for both all-cause and cardiovascular mortality (Log Rank P < 0.05). Multivariate Cox regression demonstrated the lowest all-cause mortality in the 2nd quartile (HR = 0.84, 95% CI = 0.73-0.97, P = 0.015) and the highest all-cause mortality in the 4th quartile (HR = 1.19, 95% CI = 1.03-1.37, P = 0.018), compared with the 1st quartile group of SHR. The RCS curve demonstrated a U-shape association of SHR with both all-cause and cardiovascular mortality, with the lowest points of 0.89 and 0.91, respectively.

SHR is strongly correlated with prognosis in the CKM syndrome population, with high or low SHR increasing the risk of death. This index shows great potential for predicting the risk of death in this population.

Several anthropometric indices, such as body mass index and waist circumference, have been used as clinical screening tools for the prediction of nonalcoholic fatty liver disease (NAFLD). To further refine these clinical tools for NAFLD, the body roundness index (BRI) has recently been evaluated. In this systematic review and meta-analysis, the objective was to evaluate the relationship and predictive capability of the BRI in identifying NAFLD.

A comprehensive search was conducted in PubMed, Embase, Web of Science, and Scopus up to December 31, 2024. Eligibility criteria included observational studies on adults (≥ 18 years old) with measured BRI and its association with NAFLD. The Joanna Briggs Institute tool was used for risk of bias assessment. Meta-analyses used random-effects models to pool data on mean difference, odds ratio, sensitivity, specificity, and the area under the curve (AUC), with heterogeneity and publication bias assessed.

Ten studies involving 59,466 participants were included. The pooled mean difference in BRI between the NAFLD and non-NAFLD groups was 1.73 (95% confidence interval [CI]: 1.31-2.15). The pooled sensitivity and specificity of BRI for diagnosing NAFLD were 0.806 and 0.692, respectively. The pooled AUC for BRI was 0.803 (95% CI: 0.775-0.830), indicating good diagnostic accuracy. Unlike subgroup analysis by country, subgroup analysis by sex showed no significant differences. Higher BRI values were associated with increased odds of NAFLD (pooled OR = 2.87, 95% CI: 1.39; 5.96). Studies provided mixed results on the predictive ability of BRI compared to other indices like body mass index, mostly favoring BRI over conventional indices.

BRI demonstrates a good diagnostic performance for NAFLD, suggesting it may be a valuable clinical tool for NAFLD assessment. Further research is necessary to validate these findings and strengthen the evidence base.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by metabolic dysfunction and inflammation burden, involving a significant enhancement of cellular glycolytic activity. Here, we elucidate how a positive feedback loop in liver macrophages drives MASLD pathogenesis and demonstrate that disrupting this cycle mitigates metabolic stress and macrophage M1 activation during MASLD. We detect elevated expression of hexokinase 2 (HK2) and H3K18la in liver macrophages from patients with MASLD and MASLD mice. This lactate-dependent histone lactylation promotes glycolysis and liver macrophage M1 polarization by enriching the promoters of glycolytic genes and activating transcription. Ultimately, the HK2/glycolysis/H3K18la positive feedback loop exacerbates the vicious cycle of enhancing metabolic dysregulation and histone lactylation and the inflammatory phenotype of liver macrophages. Myeloid-specific deletion of Hk2 or pharmacological inhibition of the transcription factor HIF-1α significantly disrupts this deleterious cycle. Therefore, our study illustrates that targeting this amplified pathogenic loop may offer a promising therapeutic strategy for MASLD.

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.

Previous studies demonstrate that GDF15 and its related signaling activators may be affected by exercise training, leading to the suppression of inflammatory factors and the promotion of immune-metabolic balance. Therefore, the purpose of the study was to evaluate the effect of high-intensity interval training (HIIT) on amelioration of inter-organ crosstalk between liver and hypothalamus of the high-fat diet (HFD)-induced metabolic dysfunction-associated fatty liver disease (MAFLD) rats in a two-phase study. In this regard, rats were initially divided into two groups, the normal diet-inactive (NS) and the HFD groups. HFD course lasted 12 weeks to induce MAFLD in the latter group. After ensuring the induction of MAFLD, 25 rats were divided into three groups: the HFD-inactive group (HS), the HFD-HIIT group (HH), as well as the HFD-aerobic group (HA). The training interventions were consistently applied over a period of eight weeks, five days a week, with each session lasting 40-60 min, and the duration of the whole research was 21 weeks. The results of this study displayed that HIIT intervention promotes hypothalamic Gdf15 gene expression and there were similar alterations in genes expression of Foxo1 and Akt2. Moreover, our results confirmed that HIIT ameliorated hypothalamic NFKB gene expression and there was a similar trend in genes expression of Tnfa and Il1b following both HIIT as well as aerobic training protocols. Taking these findings together, it is concluded that interventions, particularly exercise training, uniquely contribute to the reduction of hypothalamic-associated inflammatory responses that result in prolonged and chronic increases in GDF15.

Treating metabolic dysfunction-associated fatty liver disease (MAFLD) and reducing the occurrence of MAFLD-associated liver cancer remain challenging. Two-dimensional (2D) tantalum carbide (Ta4C3) MXene nanozymes (MXenzymes) exhibit antioxidant and anti-inflammatory activities and have thus attracted considerable attention in the fields of oncology and engineering. However, the potential mechanism of action and bioactive properties of Ta4C3 in MAFLD remain uncertain. In our study, Ta4C3 not only inhibited lipid accumulation and disrupted lipid metabolism in hepatocytes but also reduced cell death caused by fatty acids by decreasing intracellular reactive oxygen species (ROS) levels, which significantly promoted the polarization of M1 macrophages to M2 macrophages by alleviating oxidative stress and further suppressing inflammatory factor expression. In mice fed a methionine-choline-deficient (MCD) diet, Ta4C3 reduced lipid accumulation, the infiltration of inflammatory cells, and liver cell apoptosis by modulating the cellular microenvironment through its anti-inflammatory and antioxidant properties. Therefore, Ta4C3 can be used as a multifunctional bioactive material to alleviate hepatic steatosis and inflammation in individuals with MAFLD/metabolic dysfunction-associated steatohepatitis (MASH) because of its robust antioxidant and anti-inflammatory effects.

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.

Epidemiological evidence suggests that non-alcoholic fatty liver disease (NAFLD) may increase the risk of atrial fibrillation (AF). However, the findings are inconsistent, and the causality remains to be established.

We conducted two-step, two-sample Mendelian randomization (MR) analysis to assess the association between genetically predicted NAFLD (i.e. chronically elevated serum alanine aminotransferase levels [cALT], imaging-based and biopsy-confirmed NAFLD) and AF. Subsequently, we further performed Mendelian randomization to investigate the causal relationship between non-alcoholic steatohepatitis (NASH), a subtype of NAFLD, and AF. The inverse variance weighted (IVW) method was used as the primary approach to reveal the potential causation between the exposure and outcome.

There was no significant causal association between NAFLD diagnosed based on cALT, confirmed by imaging, or verified by biopsy, and an increased risk of atrial fibrillation. Furthermore, the results of the IVW method revealed a positive causal effect of NASH on AF (OR=1.113, 95% CI=1.025-1.209, P = 0.011). In the reverse analysis, however, no evidence supported a significant genetic association between AF and NASH (OR=0.974, 95% CI=0.934-1.016, P = 0.214).

A causal relationship existed between NASH and the risk of AF. However, no significant genetic association has been observed between NAFLD and AF risk. This suggests that managing the progression of NAFLD may hold potential value in preventing the onset of AF.

Nonalcoholic fatty liver disease (NAFLD) with advanced liver fibrosis is associated with cardiovascular disease (CVD).

This work aimed to examine if markers of vascular injury mediate the link between liver fibrosis noninvasive tests (LFNITs) and CVD events, and to compare the incremental predictive value of LFNITs over established CVD risk scores.

Consecutively recruited individuals (n = 1692) with or without clinically overt coronary artery disease (CAD) from the Athens Cardiometabolic Cohort, were analyzed. Fibrosis-4 index (FIB-4), NAFLD Fibrosis score (NFS), and BARD score were evaluated for direct and indirect associations with indices of subclinical arterial injury including carotid maximal wall thickness (maxWT) and pulse wave velocity (PWV) and with a composite of major adverse cardiovascular events (MACE) that consisted of cardiac death, acute myocardial infarction, or coronary revascularization (39-month median follow-up).

FIB-4 was the only LFNIT that was consistently associated with multiple markers of vascular injury, irrespective of CAD presence and after controlling for traditional risk factors, surrogates of insulin resistance, or obesity (adjusted P < .05 for all). FIB-4 was also independently associated with CAD presence (adjusted odds ratio [OR] 6.55; 3.48-12.3; P < .001). Increased FIB-4 greater than 2.67 was incrementally associated with an increased risk for MACE (OR [95% CI] 2.00 [1.12-3.55], ΔAUC [95% CI] 0.014 [0.002-0.026]). These associations were mediated by maxWT rather than PWV. Only FIB-4 (>3.25) was independently and incrementally associated with all-cause mortality (adjusted P < 0.05).

In a cardiometabolically diverse population, the incremental associations of LFNITs with CVD outcomes were mediated by atherosclerotic burden rather than arterial stiffening. FIB-4 consistently demonstrated associations with all study end points. These findings provide mechanistic insights and support the clinical applicability of FIB-4 in CVD prevention.

The primary etiology of liver disease is non-alcoholic fatty liver disease (NAFLD), which can progress to non-alcoholic steatohepatitis, cirrhosis, and ultimately hepatocellular carcinoma. The efficacy of plant-derived polyphenolic compounds has been extensively demonstrated with respect to various aspects and recently proved to be effective at preventing and treating NAFLD. To describe the sources and functions of polyphenolic constituents and clarify the therapeutic effects of polyphenolic constituents on NAFLD, resveratrol (RSV), which has significant therapeutic effects, was selected for a comprehensive analysis. Bibliometric and network pharmacology analyses revealed a strong correlation between insulin resistance (IR), oxidative stress, steatosis, and NAFLD, as well as the significance of intestinal flora and therapeutic interventions for NAFLD. This study reviewed the mechanisms by which RSV acted against NAFLD and explored techniques to enhance its bioavailability. These findings offer new insights into the treatment of NAFLD and the development of innovative RSV formulations.

Studies have shown that postmenopausal women have more metabolic abnormalities than premenopausal women. No consensus exists on how serum uric acid (sUA) affects metabolism-associated fatty liver disease (MAFLD) in postmenopausal women.This prospective observational study examined this link using National Health and Nutrition Examination Survey (NHANES) 2017 to 2020 data. We divided women's sUA levels into four quartiles and used logistic regression, subgroup analyses, and restricted triple spline methods to compare the prevalence of MAFLD in postmenopausal and non-menopausal women. We also used histograms to analyze the effect of BMI-based indices. This population-based study involved 4477 women, including 1139 postmenopausal women aged 55-73 years. Multivariate logistic regression showed that, in the fully adjusted model, we found that participants in the highest quartile of sUA had a statistically significant 254% increased risk of MAFLD compared with participants in the lowest quartile (OR: 3.54; 95% CI 3.54 1.47-8.55; P < 0.001). Subgroup analyses showed no significant interaction between sUA levels and specific subgroups P( > 0.05 for all interactions). Additionally, RCS and threshold analysis showed a linear correlation (P = 0.186) and an ideal inflection point of 4.6 (P = 0.818) to the left. Right of the inflection point, the effect size was 1.524 (95% CI 1.291-1.814; P < 0.01). Histograms demonstrated that postmenopausal BMI increased sUA's influence on MAFLD and higher sUA levels and BMI may enhance the prevalence of MAFLA in US postmenopausal women. The results of this study suggest that monitoring sUA levels in the postmenopausal period is critical in determining the occurrence of and interventions for MAFLD.

Background: Triglyceride glucose (TyG) and its related index (TyG-body mass index, TyG-BMI) are recognized as markers for nonalcoholic fatty liver disease (NAFLD), but their associations with metabolic dysfunction-associated steatotic liver disease (MASLD) and significant liver fibrosis (SLF) risk are less studied. Therefore, this study explores the effectiveness of these indices in assessing MASLD and SLF risk in the U.S. population. Methods: Utilizing data from the National Health and Nutrition Examination Survey (NHANES), a cross-sectional study involving 5520 participants from the general population was performed. This research measured demographic, anthropometric, biochemical, comorbid, and lifestyle characteristics, all of which are considered risk factors for MASLD/SLF. Results: Upon controlling for confounding variables, only the TyG-BMI was found to have a consistent positive association with the risk of MASLD and SLF. Specifically, for each standard deviation increase, the odds ratio (OR) and 95% confidence interval (CI) were 4.44 (3.64-9.26, p for trend < 0.001) for MASLD and 2.48 (2.15-2.87, p for trend < 0.001) for SLF. Significant interactions were identified among age, sex, and the risk of MASLD associated with the TyG-BMI. The TyG-BMI also had a significant threshold effect on the risk of MASLD at a cutoff point of 180.71. Furthermore, the area under the receiver operating characteristic curve (AUC) revealed that the TyG-BMI better predicted the risk of MASLD and SLF (AUC 0.820, 95% CI 0.810-0.831; AUC 0.729, 95% CI 0.703-0.756, respectively). In addition, the integrated discrimination improvement (IDI), decision curve analysis (DCA), and net reclassification index (NRI) also demonstrated the satisfactory predictive ability of the TyG-BMI. Conclusions: Within this large dataset, the TyG-BMI was independently associated with both the MASLD score and the SLF in the MASLD cohort. Its predictive efficacy consistently surpassed that of TyG and other noninvasive models, indicating that TyG-BMI has potential for the early identification of MASLD and SLF risk.

To assess the prevalence of metabolic associated steatotic liver disease (MASLD) in patients with primary aldosteronism (PA) compared to benign adrenal adenomas, and to evaluate the impact of hormonal excess in inducing MASLD.

Single-centre retrospective study.

Hepatic steatosis was assessed by liver/spleen (L/S) ratio from unenhanced abdomen computed tomography images (reference value < 1.1) in a cohort of 41 patients with PA without cortisol cosecretion, 20 unilateral (uPA) and 21 bilateral (BPA), 50 with nonfunctioning adrenal incidentalomas (NF-AI), 48 with mild autonomous cortisol secretion (MACS) and 10 with adrenal Cushing Syndrome (CS).

Hepatic steatosis was increased in patients with PA at diagnosis: L/S ratio was lower in PA than NF-AI (1.1 vs. 1.25, p < 0.001) and MACS (1.1 vs. 1.21, p 0.007), but was similar to adrenal CS (1.1 vs. 1.15, p = 0.147). A improvement in L/S ratio after medical or surgical treatment was observed in PA patients, resulting in reduced liver steatosis. MASLD prevalence was higher in PA compared to MACS (49% vs. 25%, p < 0.05) and NF-AI (49% vs. 14%, p < 0.001), but similar to CS (49% vs. 45%, p = 0.61). uPA patients had higher MASLD prevalence compared to BPA group 71% (53%-89%) versus 25% (7%-43%).

Prevalence of MASLD was increased in PA (higher in uPA than BPA) compared to MACS and NFAI, and similar to adrenal CS.

This study investigated the role of RAP1B in hepatic lipid metabolism and its implications in obesity and associated metabolic disorders, focusing on the molecular mechanisms through which RAP1B influences lipid accumulation, inflammation and oxidative stress in liver tissues and hepatocyte cell lines.

Liver-specific RAP1B-knockout (LKO) and overexpression (OE) mice were generated and fed a high-fat diet for 18 weeks to evaluate systemic and hepatic metabolic changes. Comprehensive metabolic phenotyping included measurements of body weight, body fat content, activity levels, energy expenditure (EE), respiratory exchange ratio (RER), glucose tolerance test and insulin tolerance test. RAP1B-knockdown AML12 hepatocytes were used for in vitro studies. Comprehensive transcriptome and metabolome analyses identified differentially expressed genes and key metabolic shifts. Biochemical and histological analyses were performed to assess lipid accumulation, oxidative stress and inflammatory markers.

We found that LKO mice exhibited significant reductions in body weight, fat pad size and liver mass, along with decreased hepatic lipid accumulation due to enhanced lipid breakdown. These mice demonstrated improved glucose tolerance and insulin sensitivity without changes in food intake. Liver histology showed reduced F4/80-positive macrophage infiltration, indicating decreased inflammatory cell recruitment. Additionally, markers of oxidative stress were significantly lower, and molecular analysis revealed downregulation of the MAPK(p38) and NF-κB signaling pathways, further supporting an anti-inflammatory hepatic environment. In contrast, OE mice showed increased liver weight, aggravated hepatic lipid accumulation driven by enhanced lipogenesis, worsened insulin resistance and elevated inflammation.

This study highlights RAP1B's pivotal role in hepatic metabolism and positions it as a potential therapeutic target for obesity and related metabolic disorders.

Scavenger receptor class A member 3 (SR-A3) is implicated in metabolic diseases; however, the relationship between SR-A3 and metabolic dysfunction-associated fatty liver disease (MAFLD) has not been documented. Here, we show that hepatic SR-A3 expression is significantly reduced in human and animal models in the context of MAFLD. Genetic inhibition of SR-A3 in hamsters elicits hyperlipidemia, hyperglycemia, insulin resistance, and hepatic steatosis under chow-diet condition, yet escalates in diet-induced MAFLD. Mechanistically, SR-A3 ablation enhances E3 ligase XIAP-mediated proteasomal ubiquitination of PTEN, leading to AKT hyperactivation. By contrast, hepatic overexpression of human SR-A3 is sufficient to attenuate metabolic disorders in WT hamsters fed a high-fat-high-cholesterol diet and ob/ob mice via suppressing the XIAP/PTEN/AKT axis. In parallel, pharmacological intervention by PTEN agonist oroxin B or lipid lowering agent ezetimibe differentially corrects MAFLD in hamsters.

The metabolic dysfunction-associated steatotic liver disease (MASLD) paradigm represents a significant departure from the previous nonalcoholic fatty liver disease (NAFLD) framework, offering a non-stigmatizing approach that enhances awareness and accelerates patient understanding. Our primary aim was to investigate the potential relationship between blood lead and manganese exposure and the onset of MASLD.

Using data from the National Health and Nutrition Examination Survey (NHANES) database spanning from 2017 to 2020, a cross-sectional study included 4,475 participants was performed to assess the relationship. The statistical analysis used throughout the study included multivariable linear regression and multiple logistic regression models, adjusted for potential confounders to ensure robust and reliable results. We applied a thorough multivariable analysis, examining various factors including age, sex, and ethnicity to enhance the robustness of our findings.

Employing linear regression models in our study, we observed a clear positive correlation between elevated levels of blood lead and manganese and Controlled attenuation parameter (CAP). Additionally, employing multiple logistic regression models for detailed analysis, we noted a significant increase in the likelihood of MASLD with higher levels of blood lead and manganese.

The findings of this study strongly suggest a notable correlation between increased levels of blood lead and manganese with both CAP and the presence of MASLD. This study represents a population-based approach, enhancing the generalizability of the findings to the broader U.S.

Fat-1, an enzyme encoded by the fat-1 gene, is responsible for the conversion of endogenous omega-6 polyunsaturated fatty acids into omega-3 polyunsaturated fatty acids in Caenorhabditis elegans. To better investigate whether the expression of Fat-1 will exert a beneficial function in dyslipidemia and metabolic dysfunction-associated fatty liver disease (MAFLD), we established an adeno-associated virus 9 expressing Fat-1. We found that adeno-associated-virus-mediated expression of Fat-1 markedly reduced the levels of plasma triglycerides and total cholesterol but increased high-density lipoprotein levels in male wild-type hamsters on both chow diet and high-fat diet as well as in chow-diet-fed male LDLR-/- hamsters. Fat-1 ameliorated diet-induced MAFLD in wild-type hamsters by enhancing fatty acid oxidation through the hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent pathway. Mechanistically, Fat-1 increased the levels of multiple lipid derivatives as ligands for PPARα and simultaneously facilitated the nuclear localization of PPARα. Our results provide new insights into the multiple therapeutic potentials of Fat-1 to treat dyslipidemia, MAFLD, and atherosclerosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

Pituitary stalk interruption syndrome (PSIS) is an infrequently occurring congenital condition, and there exists a dearth of systematic investigative work focusing on the clinical features and long-term outcomes in adult patients. Individuals who have reached adulthood with PSIS are at an increased risk of developing metabolic disorders, including metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction associated fatty liver disease (MAFLD), which are also one of the main factors for the poor prognosis of these patients. An analysis was conducted on the clinical data of adult PSIS patients who visited the endocrinology department of the First Medical Center of the People's Liberation Army General Hospital from January 2005 to August 2023. Patients were grouped based on their MAFLD and MS status, and the differences in clinical characteristics and risk factors between the groups were analyzed. Machine learning models were used to construct a prediction model for the occurrence of MAFLD in adult PSIS patients and to analyze high-risk predictors. Out of 136 PSIS adult patients, 93.3% were male. The prevalence of MAFLD was 55.5%, and MS was 22.3%. Patients with a history of growth hormone (GH) treatment were less likely to develop MAFLD (P = 0.032). MAFLD patients exhibited higher rates of hypertension, hyperuricemia, obesity, MS, and dyslipidemia. Multiple risk factors may contribute to MS, while no significant link was found between MS and hormone replacement. However, GH non-treatment may serve as the notable predictor of MAFLD in PSIS patients revealed by the Ridge regression model of machine learning model with the highest predictive performance of a mean area under the curve (AUC) of 0.82. The prevalence of MS and MAFLD is high among adult patients with PSIS. Multiple risk factors may contribute to these two diseases, and after constructing a predictive model, we found that MAFLD may be closely linked to the previous lack of GH treatment.

Globally, metabolic dysfunction-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), is a common chronic liver disease. The progression of MAFLD leads to a vicious cycle in which oxidative stress results from the disease that is augmenting de-novo lipid levels and increases steatosis. Most non-enzymatic antioxidants are present in food. Therefore, the present review summarizes the findings of studies on food-derived antioxidants and presents an oxidative stress-related regulatory network in MAFLD, offering new ideas for MAFLD prevention and treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects roughly 1 in 3 adults and is a leading cause of liver transplants and liver related mortality. A deeper understanding of disease pathogenesis is essential to assist in developing blood-based biomarkers.

Here, we use data-independent acquisition mass spectrometry to assess disease-state associated protein profiles in human liver, blood plasma, and white adipose tissue (WAT).

In liver, we find that MASLD is associated with an increased abundance of proteins involved in immune response and extracellular matrix (ECM) and a decrease in proteins involved in metabolism. Cell type deconvolution of the proteome indicates liver endothelial and hepatic stellate cells are the main source of ECM rearrangements, and hepatocytes are the major contributor to the changes in liver metabolism. In the blood, profiles of several MASLD-associated proteins correlate with expression in WAT rather than liver and so could serve as suitable liver disease predictors in a multi-protein panel marker. Moreover, our proteomics-based logistic regression models perform better than existing methods for predicting MASLD and liver fibrosis from human blood samples.

Our comprehensive proteomic analysis deepens the understanding of liver function and MASLD pathology by elucidating key cellular mechanisms and multi-organ interactions, and demonstrates the robustness of a proteomics-based biomarker panel to enhance diagnosis of MASLD and significant fibrosis.

Background: The prevalence of fatty liver disease in people living with human immunodeficiency virus (PLHIV) is significantly higher than in general population. This study aims to compare the burden of fatty liver disease in Egyptian PLHIV using both metabolic dysfunction-associated fatty liver disease (MAFLD) and steatotic liver disease (SLD) criteria. Methods: A retrospective cross-sectional study was conducted on PLHIV attending the HIV reference center at Embaba Fever Hospital in Egypt between November 2019 and July 2021. Data collection included demographics, comorbidities, physical examination, laboratory tests, liver ultrasound, controlled attenuation parameter, and liver stiffness measurement using Fibroscan®. Results: The prevalence of SLD and MAFLD was 26.92% and 21.15%, respectively. The concordance between MAFLD and SLD definitions was low (kappa = 0.465). The presence of SLD was significantly associated with increased odds of significant fibrosis (P = 0.045). However, MAFLD was not significantly associated with fibrosis (P = 0.369). Conclusion: SLD demonstrates a stronger association with significant fibrosis than MAFLD in PLHIV. This highlights the potential of SLD as a more inclusive and representative classification for steatosis in PLHIV.

Nonalcoholic fatty liver disease (NAFLD) has been identified as an emerging risk factor for hepatocellular carcinoma (HCC). Identifying non-cirrhotic NAFLD patients at risk for HCC is crucial. We aimed to investigate the utility of noninvasive tests (NITs) as predictors for HCC and to determine optimal and cost-effective NIT cutoffs for HCC surveillance in non-cirrhotic NAFLD patients.

Medline, EMBASE, and Scopus databases were searched for studies evaluating the relationship between NITs and HCC in this population. Random-effects models were used to estimate hazard ratios or risk ratios and 95% confidence interval (95% CI). Cutoffs of NITs for identifying high-risk patients for HCC were determined.

This systematic review comprised 20 studies. A meta-analysis of 379 194 patients was conducted using six studies with individual patient data and five studies with aggregate data. Among NITs studied, fibrosis-4 index (FIB-4), aspartate aminotransferase to platelet ratio index (APRI), and NAFLD fibrosis score (NFS) were significantly associated with HCC, with pooled risk ratio (95% CI) of 9.21 (5.79-14.64), pooled hazard ratio of 12.53 (6.57-23.90), and 13.32 (6.48-27.37), respectively. FIB-4, APRI, and NFS of more than 2.06, 0.65, and 0.51 resulted in the highest area under the receiver operating characteristics of 0.83, 0.80, and 0.85, respectively. Surveillance in patients with FIB-4 ≥ 5.91 and NFS ≥ 2.85 would be cost-effective with an annual HCC incidence of ≥15 per 1000 patient-years.

FIB-4, APRI, and NFS are associated with HCC development in non-cirrhotic NAFLD patients. Different NIT cutoffs may be used to enroll high-risk NAFLD patients for HCC surveillance, according to resource availability in different settings.