Although liver biopsy is considered the most reliable diagnostic tool for metabolic dysfunction-associated steatohepatitis (MASH), it is invasive and can be costly. Clinicians are increasingly relying on routine biomarkers and other noninvasive tests (NITs) for diagnosis. We examined real-world diagnostic pathways for patients newly diagnosed with MASH with a primary focus on NITs.

This retrospective, observational study analyzed healthcare claims data (Merative MarketScan Commercial and Medicare Databases) from patients in the United States newly diagnosed with MASH from October 1, 2016, to March 31, 2023. Patients ≥18 years old with ≥12 months of continuous enrollment with medical and pharmacy benefits prior to diagnosis were included. Diagnostic pathways leading up to MASH diagnosis, including NITs (blood-based and imaging-based tests) and liver biopsies were assessed. Prevalence of comorbid conditions, MASH-associated medication use, and the diagnosing physician specialty were also examined.

A total of 18,396 patients were included in the analysis. Routine laboratory tests (alanine aminotransferase [ALT], albumin, aspartate aminotransferase [AST], cholesterol, complete blood count, and hemoglobin A1c) were performed among ≥70% of patients prior to MASH diagnosis, including 89% of patients with a liver enzyme test (ALT and/or AST). More than 75% of patients had necessary laboratory tests to calculate AST to platelet ratio index (APRI) and fibrosis-4 index (FIB-4) scores. The most common imaging performed was ultrasound (62%); liver biopsy was only performed in 10% of patients. There was a high prevalence of cardio metabolic risk factors such as hyperlipidemia (66%), hypertension (62%), obesity (58%), type 2 diabetes (40%), and cardiovascular disease (21%). Nearly half of the patients (49%) were diagnosed by a primary care physician.

This study highlights real-world diagnostic pathways among patients newly diagnosed with MASH, supporting previous findings that liver biopsies are infrequently used in favor of noninvasive methods.

Nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease are global public health issues associated with high morbidity and mortality. Both diseases are also interlinked. Little is known about the meaning of NAFLD in hemodialysis (HD) patients. Therefore, the aim of our study was to investigate the difference in oxidative stress and inflammation in HD patients with or without advanced NAFLD. Seventy-seven HD patients were included (65.14 ± 12.34 years, 59.2% male) and divided according to abdominal ultrasound and two-dimensional shear wave elastography (2D-SWE) measurements into two groups: 1) no NAFLD or no advanced NAFLD (2D-SWE <9 kPa) and 2) advanced NAFLD (2D-SWE ≥9 kPa). Medical history data and blood results were collected. HD patients with advanced NAFLD had significantly higher levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG; p = 0.025), tumor necrosis factor-alpha (TNF-α; p = 0.023), and intercellular adhesion molecule 1 (ICAM-1; p = 0.015) in comparison to HD patients without advanced NAFLD. Interleukin 6 (IL-6) was higher in the advanced NAFLD group, but the difference was of borderline significance (p = 0.054). There was no significant difference in high-sensitivity C-reactive protein (hs-CRP), and vascular cell adhesion molecule 1 (VCAM-1) between groups. In binary logistic regression analysis, advanced NAFLD was significantly associated with 8-OHdG and ICAM-1. In conclusion, higher oxidative stress and inflammation levels are present in HD patients with advanced NAFLD.

With the rapid development of biomedical technology, there is an increasing demand for accurate analysis of biomolecules and their interactions. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a novel soft ionization biomass spectrometry technology that can accurately assess the molecular weight of samples quickly and sensitively, and it plays an important role in the analysis and detection of large molecule substances, drug research, and life sciences. In recent years, due to the outstanding performance of nanomaterials, they have been widely used as matrices in drug metabolism research and cancer detection. This paper aims to review the latest research progress of nanomaterials as new matrices for MALDI-TOF MS in enhancing biomedical analysis, discus its value and limitations, and look forward to its future research direction.

NAFLD is a global and complex liver disease caused by multiple factors. Intrahepatocellular steatosis is the primary prerequisite for the occurrence and development of NAFLD. It has been shown that miR-125b-5p is highly correlated with NAFLD, and ESRRA is a factor that regulates lipid metabolism. The purpose of our study is to investigate whether miR-125b-5p regulates FFA-induced steatosis in L02 cells by targeting ESRRA.

Estrogen-related receptor alpha (ESRRA) was identified as a direct target of miR-125b-5p through database prediction and a dual-luciferase reporter gene assay. L02 cells were induced with free fatty acids (OA:PA, 2:1) at concentrations of 0.3 mM, 0.6 mM, 0.9 mM, 1.2 mM and 1.5 mM for 24 h, 48 h and 72 h, respectively. The degree of hepatocyte steatosis and triglyceride content were separately manifested by oil red O staining and colorimetric method. Cell viability per group was detected by CCK-8 assay. Eventually, 0.9 mM and 24 h were screened out as the optimal concentration and time for establishing the in-vitro model of hepatic steatosis. Followingly, miR-125b-5p and ESRRA were knocked down by transient transfection. We monitored the expressions of lipid metabolism factors SREBP-1c, ACC1 and FAS and determine triglyceride content within the cells per group. The data showed that knockdown of ESRRA led to down-regulation of the expressions of SREBP-1, ACC1, FAS and triglyceride content. Meanwhile, knockdown of ESRRA and miR-125b-5p resulted that the expressions of ESRRA, SREBP-1, ACC1, FAS and triglyceride content rebounded.

MiR-125b-5p down-regulates the expressions of lipid metabolism-related factors by negatively regulating ESRRA, thereby improving hepatic steatosis.

Chronic liver diseases, including metabolic dysfunction-associated steatosic liver disease (MASLD) and hepatocellular carcinoma (HCC), are on the rise, potentially due to daily exposure to complex mixtures of chemical compounds forming part of the exposome. Understanding the mechanisms involved in hepatotoxicity of these mixtures is essential to identify common molecular targets that may highlight potential interactions at the molecular level. We illustrated this issue with two families of environmental contaminants, per- and polyfluoroalkyl substances (PFAS) and heterocyclic aromatic amines (HAAs), both of which could be involved in the progression of chronic liver diseases, and whose toxicity may be potentiated by interactions at the level of xenobiotic metabolism. In the study of exposome effects on chronic liver disease, New Approach Methodologies (NAMs) including omics analyses and data from various in vitro, in vivo and in silico approaches, are crucial for improving predictivity of toxicological studies in humans while reducing animal experimentation. Additionally, the development of complex in vitro human liver cell models, such as organoids, is essential to avoid interspecies differences that minimize the risk for humans. All together, these approaches will contribute to construct Adverse Outcome Pathways (AOPs) and could be applied not only to PFAS mixtures but also to other chemical families, providing valuable insights into mixture hepatotoxicity prediction in the study of the exposome. A better understanding of toxicological mechanisms will clarify the role of environmental contaminant mixtures in the development of MASLD and HCC, supporting risk assessment for better treatment, monitoring and prevention strategies.

The LiverRisk score (LRS) has recently been proposed to predict liver fibrosis and future development of liver-related outcomes in the general population. Here, we performed an external validation of this score.

We used data from National Health and Nutrition Examination Survey 2017-2020, a United States population-based cohort to assess the diagnostic accuracy of the LRS to detect a liver stiffness measurement (LSM) ≥8 and ≥12 kPa. Performance was tested among the entire general population and clinically relevant subgroups.

The cohort comprised 7,025 participants (aged 49 [33-63], 49% male), and 9.7% had an LSM ≥8 and 3.2% had an LSM ≥12 kPa. The area under the receiver characteristic operator curve (AUC) in the overall population was 0.73 (95% confidence interval [CI] :0.71-0.75) and 0.78 (95% CI: 0.74-0.81) to detect an LSM ≥8 and ≥ 12 kPa, respectively, significantly outperforming the fibrosis 4 index (FIB-4) but not the nonalcoholic fatty liver disease fibrosis score, steatosis-associated fibrosis estimator (SAFE), or metabolic dysfunction-associated fibrosis 5 (MAF-5). Performance was consistent among most subgroups, but AUC levels to detect an LSM ≥8 kPa decreased to <0.70 among participants aged 18-40 or 60-80 years, blacks, and individuals with diabetes or liver steatosis. The LRS categorized 80.5% as very low risk, 17.7% as low risk, and 1.8% as at risk, prevalence of an LSM ≥8 in these groups was 6.3%, 20.8%, and 50.5%, respectively. The sensitivity to detect an LSM ≥8 kPa was 47.3% in the overall population (but dropped to 21.3% for individuals aged 18-40 years) despite applying the lowest cut-off, which should yield the highest sensitivity.

The LRS score is a promising new tool to predict liver fibrosis; however, its diagnostic accuracy attenuates especially among patients aged 18-40 or 60-80 years. The overall sensitivity was only 47.3% at the lowest LRS cut-off. Further studies assessing cost-benefit ratios according to the LRS compared to FIB-4 and other risk scores such as MAF-5 and SAFE are required to determine its usefulness in referral strategies.

Metabolic-associated fatty liver disease (MAFLD) has become an increasingly prevalent liver disorder worldwide, being closely associated with obesity, metabolic syndrome, and insulin resistance. Bile acids (BAs), beyond their traditional role in lipid digestion, play a pivotal part in regulating lipid and glucose metabolism as well as inflammatory responses. Recent investigations have recognized BAs as key factors in the onset and progression of MAFLD, mainly via their interactions with nuclear receptors such as the farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor (TGR5). Additionally, active compounds derived from traditional Chinese medicine (TCM) have shown promising potential in the treatment of MAFLD. This study systematically reviews and analyzes the molecular mechanisms and recent progress in the application of TCM active ingredients for MAFLD treatment, with a focus on their regulation of BAs. These active ingredients, including saponins, flavonoids, polysaccharides, and sterols, exert therapeutic effects through diverse mechanisms, such as modulating BA synthesis and mediating receptor-signaling pathways, and are expected to restore metabolic homeostasis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to cognitive decline and dementia risk. We aimed to investigate the association between MASLD and brain ageing and explore the role of low-grade inflammation.

Within the UK Biobank, 30 386 chronic neurological disorders-free participants who underwent brain magnetic resonance imaging (MRI) scans were included. Individuals were categorised into no MASLD/related SLD and MASLD/related SLD (including subtypes of MASLD, MASLD with increased alcohol intake [MetALD] and MASLD with other combined aetiology). Brain age was estimated using machine learning by 1079 brain MRI phenotypes. Brain age gap (BAG) was calculated as the difference between brain age and chronological age. Low-grade inflammation (INFLA) was calculated based on white blood cell count, platelet, neutrophil granulocyte to lymphocyte ratio and C-reactive protein. Data were analysed using linear regression and structural equation models.

At baseline, 7360 (24.2%) participants had MASLD/related SLD. Compared to participants with no MASLD/related SLD, those with MASLD/related SLD had significantly larger BAG (β = 0.86, 95% CI = 0.70, 1.02), as well as those with MASLD (β = 0.59, 95% CI = 0.41, 0.77) or MetALD (β = 1.57, 95% CI = 1.31, 1.83). The association between MASLD/related SLD and larger BAG was significant across middle-aged (< 60) and older (≥ 60) adults, males and females, and APOE ɛ4 carriers and non-carriers. INFLA mediated 13.53% of the association between MASLD/related SLD and larger BAG (p < 0.001).

MASLD/related SLD, as well as MASLD and MetALD, is associated with accelerated brain ageing, even among middle-aged adults and APOE ɛ4 non-carriers. Low-grade systemic inflammation may partially mediate this association.

Metabolic dysfunction-associated steatohepatitis (MASH) is a human health-threatening hepatic disease with limited treatment strategies. As a clinical Traditional Chinese Medicine compound for MASH, Shugan Xiaozhi (SGXZ) decoction has a definite effect, but its mechanism in treating MASH is still not very clear.

Exploring the potential mechanism of SGXZ decoction in treating MASH through multiomics and animal experimental validation.

UPLC-ESI-MS method was used to identify the main components of SGXZ decoction. Periodic acid-schiff (PAS), picrosirius red (PSR), and oil red o staining were used to assess the effect of SGXZ decoction on MCD-induced MASH mouse model. The mechanism of SGXZ decoction on MASH was analyzed using multiomics techniques. TUNEL staining, western blot (WB), immunohistochemistry (IHC), kits, transmission electron microscopy (TEM), and immunofluorescence (IF) were used to validate the mechanism of SGXZ decoction on MASH. Finally, molecular docking and molecular dynamics simulation were used to verify the targeting between key components of SGXZ decoction and important targets for intervention.

Through UPLC-ESI-MS analysis, 30 main active ingredients were obtained from SGXZ decoction. SGXZ decoction improved MASH, as evidenced by the improvement in histopathology, hepatic function indexes, lipid and fibrosis indicators. Both proteomic and transcriptomic results suggested an important role for ferroptosis in SGXZ decoction intervention in MASH, ferroptosis-related pathways were the main significant pathways obtained from these analyses. In addition, SGXZ decoction treatment reduced cell death, inflammation, and oxidative stress levels and restored impaired mitochondrial morphology in MCD-induced MASH mice. Furthermore, Mechanism experiments proved that SGXZ decoction treatment improved iron metabolism and lipid peroxidation imbalance and activated the Xc- system in MASH mice.

SGXZ decoction does have a therapeutic effect on MASH, and its mechanism may be related to its regulation of p53/ SLC7A11/GPX4 pathway to reduce ferroptosis.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder with no approved pharmacological therapies. Linghe granules, a hospital-based formulation derived from a classic prescription, have demonstrated potential in reducing hepatic fat accumulation and improving metabolic health. This study provides a novel, comprehensive assessment of Linghe granules, integrating clinical, preclinical, and molecular analyses for NAFLD management.

This study aims to evaluate the therapeutic efficacy of Linghe granules in alleviating NAFLD through an integrated approach.

A clinical trial involving 40 patients with NAFLD was conducted, with participants divided into a control group (lifestyle interventions) and a treatment group (lifestyle interventions plus oral Linghe granules). Various metabolic and liver function indicators were assessed before and after treatment. Additionally, a high-fat diet (HFD) was used to induce a NAFLD model in rat, followed by treatment with different doses of Linghe granules. In vitro studies on HepG2 and L02 cells were performed to the effects of the granules on lipid metabolism. Transcriptomic profiling, Weighted Gene Co-expression Network Analysis (WGCNA), Dynamic Network Biomarkers (DNB) analysis, and molecular docking were employed to explore the underlying mechanisms.

Linghe granules led to significant reductions in BMI, liver enzymes (AST, ALT), triglycerides, LDL-C, and GGT in patients with NAFLD, accompanied by a notable decrease in hepatic fat accumulation. In the rat model, treatment improved liver weight, liver function, and lipid metabolism. In vitro, Linghe granules decreased lipid accumulation and regulated key lipid metabolism markers, including sterol regulatory element-binding protein 1 (SREBP-1), stearoyl-CoA desaturase 1 (SCD1), and fatty acid-binding protein 5 (FABP5). Mechanistic analyses revealed that Linghe granules modulated oxidative stress-related pathways and genes involved in lipid metabolism.

This study represents the first integrated evaluation of Linghe granules' efficacy and mechanisms in treating NAFLD, demonstrating their potential to improve liver function, reduce lipid accumulation, and modulate key metabolic markers. These results suggest that Linghe granules may serve as an effective adjunctive treatment for NAFLD.

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.

This study investigates the intricate relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and depression, emphasizing the mediating role of body fat distribution, particularly in female.

We analyzed the pairwise relationship among body fat distribution (android fat and gynoid fat), MASLD, and depression within a robust, ethnically diverse sample (n = 3332) drawn from the National Health and Nutrition Examination Survey (NHANES).

Studies have indicated that individuals with depression or MASLD exhibit significantly higher levels of android fat compared to those without these health issues. Even after controlling for confounding factors, MASLD maintained significant correlations with both depression and body fat distribution (android fat and gynoid fat). Notably, sex moderated the relationship between MASLD, depression, and body fat distribution. Among the potential mediators of the effect of MASLD on depression, android fat emerged as a significant mediator, accounting for 16.6 % of the variance and yielding statistically significant results (p < 0.05). This mediating effect was particularly pronounced in female subjects, with a mediating proportion of 17.83 %, which was also statistically significant (p < 0.05). However, it was not observed in males.

This study reveals an important association between MASLD and depression, and android fat distribution is a potential mediator in this relationship, with a particularly pronounced effect on the female population.

Exposure to metabolism-disrupting chemicals (MDCs), compounds largely belonging to the group of endocrine-disrupting chemicals (EDCs), is associated with metabolic dysfunctions such as dyslipidemia, insulin resistance and hepatic steatosis. Steroid hormone receptors (SHRs) are known targets for MDCs but their regulatory environment in the presence of environmental chemicals remains elusive. Here, we studied the activation and molecular interactions of SHRs exposed to 17 suspected MDCs including pesticides, plasticizers, pharmaceuticals, flame retardants, industrial chemicals and their metabolites by combining in vitro and in silico approaches. We first established and pre-validated reporter gene assays in HepG2 hepatoma cells to assess the activation of estrogen (ER), androgen (AR), glucocorticoid (GR) and progesterone (PR) receptors. Next, using RNA-seq and publicly available protein interaction data, we identified relevant SHR-interacting coregulators expressed in hepatic cells and measured their MDC-dependent interactions with SHRs using the Microarray Assay for Real-time Coregulator-Nuclear receptor Interaction (MARCoNI) technology. Finally, we examined MDC binding to ER and GR using molecular dynamics simulations. These combined approaches lead to identification of MDCs capable of SHR activation at picomolar-to-low micromolar concentrations and paralleled with their ability to induce recruitment of multiple coregulators. MDCs induced distinct SHR-coregulator binding patterns involving multiple coactivators, corepressors and other modulatory proteins. Our results have broadened the test battery to detect MDCs and indicate that the activation of SHRs by MDCs is driven by diverse molecular interactions.

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.

Non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction associated steatotic liver disease (MASLD), has reached epidemic levels in multiple regions worldwide and contributes to cirrhosis and hepatocellular carcinoma. We have previously reported that the CC motif chemokine ligand 11 (CCL11) is a key regulator of MASLD. Expression of interferon regulatory factor 1 (IRF1) can be up-regulated by CCL11 treatment in hepatocytes, the relevance of which is not clear. In the present study we investigated the role of IRF1 in NAFLD pathogenesis.

MASLD was investigated in mice fed a high-fat high carbohydrate (HFHC) diet or in the genetically predisposed obese mice (db/db).

Hepatocytes from CCL11 knockout mice displayed a less severe MASLD phenotype, when treated with palmitic acid (PA), compared to wild type hepatocytes, which could be normalized by IRF1 over-expression. On the contrary, IRF1 knockdown in hepatocytes significantly down-regulated expression of pro-inflammatory mediators and dampened lipid accumulation induced by PA treatment. More importantly, IRF1 knockdown in hepatocytes led to amelioration of MASLD in mice. RNA-seq and CUT&Tag-seq identified pro-MASLD genes, including Osbpl3, Ddit4, and Ccl2, as potential targets for IRF1 in hepatocytes.

Our data reveal a novel regulatory role of IRF1 in MASLD pathogenesis. Targeting IRF1 can be considered as a reasonable approach for MASLD intervention.

Excessive hepatic lipid accumulation is the hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), yet its underlying mechanisms still not fully understood. In this study, we identified RNA binding motif protein 39 (Rbm39) as a key modulator of hepatic lipid homeostasis during MASLD progression. To establish in vivo MASLD model, mice were fed either a high-fat diet (HFD) or a Gubra-Amylin NASH (GAN) diet. We employed adeno-associated virus to manipulate Rbm39 expression levels to assess its role in MASLD. Transcriptome analysis was conducted to pinpoint the genes targeted by Rbm39. Western blot, RT-PCR, dual-luciferase reporter gene assays, and alternative splicing analysis were utilized to delve into the molecular mechanisms. Our results showed that Rbm39 expression was notably decreased in the livers of MASLD mice. Knockdown of hepatic Rbm39 aggravated HFD-induced hepatic steatosis and GAN diet-induced MASH, along with a notable decrease in serum lipid levels. Conversely, overexpression of Rbm39 attenuated MASLD development and progression. RNA sequencing data analysis indicated that Rbm39 regulated the expression of apolipoprotein B (Apob) and fatty acid-binding protein 4 (Fabp4), both of which are crucial for lipid transport. Mechanistically, Rbm39 enhanced the transcription of Apob by upregulating hepatocyte nuclear factor 4α (Hnf4α), while it suppressed Fabp4 transcription by regulating alternative splicing of hypoxia inducible factor-1α (Hif-1α). These findings highlight the pivotal role of Rbm39 in maintaining hepatic lipid homeostasis and suggest its potential as a therapeutic target for MASLD.

Emerging evidence has linked metabolic dysfunction-associated steatotic liver disease (MASLD) with accelerated cognitive decline and dementia. We aimed to investigate the associations of MASLD with volumes of total brain tissue and subcortical grey matter, and white matter microstructures in the UK Biobank.

This cross-sectional study included 29,195 individuals (aged 45-82 years) from the UK Biobank who undertook a magnetic resonance imaging (MRI) sub-study between 2014 and 2022. The brain MRI covers three modalities (T1, T2 FLAIR, and diffusion). Volumes of grey matter, subcortical grey matter structures, and regional cortex were derived from T1-weighted images. Fractional anisotropy (FA) and mean diffusivity (MD) were derived from diffusion tensor imaging (DTI) to assess global and tract-specific microstructure. MASLD was defined as the MRI-derived proton density fat fraction (MRI-PDFF) ≥5% and the presence of at least one cardiometabolic criterion. Data were analysed using multiple linear regression models.

MASLD was significantly associated with smaller volumes of total grey matter and subcortical grey matter (p < 0.05) and reduced Alzheimer's disease (AD)-signature cortical thickness (multivariable-adjusted β = -0.04; 95% confidence interval [CI]: -0.07, -0.01). Having MASLD was associated with higher total white matter hyperintensity (WMH) volume (multivariable-adjusted β = 0.12; 95% CI: 0.10, 0.15). For white matter microstructure, MASLD was associated with increased global FA (multivariable-adjusted β = 0.05; 95% CI: 0.03, 0.08) and reduced global MD (multivariable-adjusted β = -0.04; 95% CI: -0.07, -0.01).

Brain morphology associated with MASLD is characterized by smaller subcortical grey matter volume and higher coherence but lower magnitudes of white matter microstructure.

Despite increasing evidence linking triglyceride-glucose (TyG) related indices with metabolic and cardiovascular outcomes, the associations with severe infection in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear.

We analyzed data from a large population-based cohort, which included participants who were diagnosed with MASLD and enrolled in 2016 and 2017, with follow-up until December 2022. Severe infections were defined as those requiring hospital admission or resulting in mortality. Multivariate Cox and restricted cubic spline (RCS) regression models were used to evaluate the associations between TyG-related indices and severe infection among participants with MASLD. Additionally, we examined these associations within subgroups defined by age, sex, hypertension, diabetes, obesity, and hyperlipidemia.

Among the 11,782 eligible participants with MASLD (mean age 57.02 years; 34.36 % male), a total of 898 (7.62 %) severe infections occurred during the median follow-up of 5.71 years. The multivariate Cox regression analyses revealed that high levels of TyG (HR = 1.175, 95%CI = 1.049-1.315), TyG-BMI (HR = 1.004, 95%CI = 1.001-1.006), and TyG-WC (HR = 1.002, 95%CI = 1.001-1.003) indices were significantly associated with the severe infection in patients with MASLD. The RCS curves showed positive linear correlations between three TyG-related indices with severe infection in MASLD. Subgroup analyses showed these associations were more pronounced among MASLD patients without obesity. Additionally, incorporating TyG-related indices into the basic model considerably improved the predictive ability for severe infection.

Our study indicated that a high TyG-related indices are associated with an increased risk of severe infection in MASLD patients. TyG-related indices would be the surrogate biomarkers for the follow-up of the MASLD population.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global public health and economic burden worldwide in the past few decades. Epidemiological studies have shown that MASLD is a multisystem disease that is associated not only with liver-related complications but also with an increased risk of developing extrahepatic cancers. MASLD is a sexually dimorphic disease with sex hormones playing an important role in the development and progression of MASLD, especially by the levels and ratios of circulating estrogens and androgens. MASLD is associated with hormone-sensitive cancers including breast and gynecological cancer. The risk of breast and gynecological cancer is elevated in individuals with MASLD driven by shared metabolic risk factors including obesity and insulin resistance. Multiple potential mechanisms underline these associations including metabolic dysfunction, gut dysbiosis, chronic inflammation and dysregulated release of hepatokines. However, the effect of hormone therapy including hormone replacement therapy and anti-estrogen treatment on MASLD and female-specific cancers remains debatable at this time. This synopsis will review the associations between MASLD and breast and gynecological cancer, their underlying mechanisms, implications of hormonal therapies, and their future directions.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become a major health risk and a serious worldwide issue. MAFLD typically arises from aberrant lipid metabolism, insulin resistance, oxidative stress, and inflammation. However, subjacent causes are multifactorial. The gut has been proposed as a major factor in health and disease, and over the last decade, bacterial strains with potentially beneficial effects on the host have been identified. In vitro cell models have been commonly used as an early step before in vivo drug assessment and can confer complementary advantages in gut and liver health research. In this study, several selected strains of the order Bacteroidales were used in a three-cell line in vitro analysis (HT-29, Caco-2, and HepG2 cell lines) to investigate their potential as new-generation probiotics and microbiota therapeutics. Antimicrobial activity, a potentially useful trait, was studied, and the results showed that Bacteroidales can be a source of either wide- or narrow-spectrum antimicrobials targeting other closely related strains. Moreover, Bacteroides sp. 4_1_36 induced a significant decrease in gut permeability, as evidenced by the high TEER values in the Caco-2 monolayer assay, as well as a reduction in free fatty acid accumulation and improved fatty acid clearance in a steatosis HepG2 model. These results suggest that Bacteroidales may spearhead the next generation of probiotics to prevent or diminish MAFLD.

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

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

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

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

Metabolic dysfunction-associated steatotic liver disease (MASLD), considered as the hepatic manifestation of metabolic syndrome, can increase the risk for cardiometabolic diseases. Accumulating reports have implicated the central nervous system in MASLD pathogenesis, specifically endoplasmic reticulum (ER) stress in subfornical organ (SFO) to hypothalamic paraventricular nucleus (PVN) projecting neurons (SFO→PVN). Here, we investigated how ER stress in this neural circuit influences hepatic lipid regulatory pathways that may contribute to MASLD development during obesity. Hepatic steatosis was elicited by feeding C57BL/6J male mice a high-fat diet for 11 wk. Intersectional viral targeting was used to inhibit ER stress in SFO→PVN neurons to examine the contribution of ER stress in this circuit to hepatic lipid acquisition and disposal genes during obesity. Inhibition of ER stress in SFO→PVN neurons of obese mice resulted in a reduction in hepatic triglycerides and lipid acquisition genes that was paralleled by a reduction in liver tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. Moreover, hepatic tyrosine hydroxylase expression was positively correlated with lipid acquisition but not disposal pathways. These results indicate that ER stress in SFO→PVN neurons may contribute to MASLD through sympathetic nervous system influences, primarily on hepatic lipid acquisition.NEW & NOTEWORTHY Endoplasmic reticulum stress in SFO→PVN neurons modulates hepatic lipid acquisition and disposal pathways during obesity-induced hepatic steatosis. Hepatic tyrosine hydroxylase levels are positively correlated with liver triglyceride levels and lipid acquisition pathway-related genes in diet-induced obese animals.

Insulin resistance (IR) is strongly related to non-alcoholic fatty liver disease (NAFLD). Triglyceride-glucose (TyG) index serves as a novel substitute indicator for IR. However, research on the effect of TyG index on NAFLD remains sparse. This study aims to investigate the causal association between TyG index and incident NAFLD.

The primary cohort consisted of 27,052 participants from the Beijing Health Management Cohort, while the external validation cohort included 75,023 participants from the Taiwan MJ Cohort. Entropy balancing for continuous treatments (EBCT) combined with logistic regression and targeted maximum likelihood estimation (TMLE) were used to evaluate the causal association between the TyG index and incident NAFLD.

During a median follow-up of 2.49 years in the primary cohort, 6,168 participants (median age: 36.0 years) developed incident NAFLD. EBCT combined with logistic regression revealed the odds ratio (95 % CI) of NAFLD risk was 1.742 (1.478-2.054) for each 1-unit increase in the baseline TyG index. In the TMLE model, the risk ratio (95 % CI) for NAFLD was 1.540 (1.406-1.687) in the Q4 (quartile 4) group compared with the Q1 group. These findings were consistent with those from the external validation cohort, reinforcing the robustness of the causal relationship between the TyG index and NAFLD incidence.

The advanced double-robust estimation method suggests that a higher baseline TyG index may be causally associated with an increased NAFLD risk, providing more reliable evidence for its role as a simple biomarker and demonstrating the utility of double-robust estimation causal inference models in epidemiology.

Adherence to plant-based diets has significantly increased in popularity recently, with claims that they reduce the risk of non-communicable diseases. This study investigated whether high adherence to plant-based diets can reduce the risk of hepatic steatosis and fibrosis. In this study, 8516 participants from the Ravansar Noncommunicable Disease cohort completed a validated food frequency questionnaire (FFQ) to assess their plant-based diet scores. The study used the fatty liver index and fibrosis-4 index to predict hepatic steatosis and fibrosis. The plant-based diet index (PDI) was used to measure the overall quality of diets from healthy and unhealthy plant-derived foods and animal-derived foods. Associations were determined using binary logistic regression, considering potential confounders. Participants in the highest tertiles of plant-based diet scores had higher energy-adjusted intakes of fructose than those in the lowest tertiles (16.09 ± 12.11 vs. 26.65 ± 12; P-value < 0.001). In multivariable-adjusted models, participants in the highest tertile of PDI had lower odds of hepatic fibrosis than those in the lowest tertile (OR: 0.59; 95%CI: 0.43-0.81). There was no significant association between adherence to PDI and hepatic steatosis after adjustment for potential confounders (OR: 0.989; 95%CI 0.78 - 1.25). The odds of hepatic fibrosis decreased by 6% for each unit increase in healthy plant-based foods (OR: 0.94; 95%CI: 0.91-0.97). The odds of hepatic steatosis increased by 14% for each 1 SD increase in fructose intake (OR: 1.14; 95% CI: 1.02-1.28). This study highlights the potential benefits of high adherence to plant-based diets in reducing the risk of hepatic fibrosis, but high fructose content in some plant-based foods may have an unfavorable role in hepatic steatosis. These findings highlight the importance of selecting whole, fiber-rich plant foods and minimizing intake of fructose-dense products in plant-based diets to promote liver health. Therefore, selecting low-fructose food items in plant-based diets is recommended, though further research is needed to confirm these findings.

The clinical manifestations of Cushing syndrome are variable, but an important number of patients present a metabolic syndrome, strongly associated with hepatic steatosis.

The aim of this study was to determine the prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) at the diagnosis of Cushing syndrome.

We conducted a single-center retrospective study at Angers Hospital (France) between 2010 and 2020. Forty-nine patients followed for Cushing syndrome with available abdominal imaging at diagnosis were included. A mean liver/spleen density ratio < 1 on computed tomography was diagnostic of hepatic steatosis. Simple clinico-biological scores predictive of hepatic fibrosis (FIB-4, NAFLD Fibrosis Score, and eLIFT) were calculated for patients with hepatic steatosis.

Of the 49 patients, 13 (26.5%) had hepatic steatosis at diagnosis of Cushing syndrome. All 13 had MASLD. These patients had a higher prevalence of type 2 diabetes and higher triglyceride levels in multivariate analysis. There was no difference according to the intensity or duration of Cushing syndrome. Among the 13 patients with MASLD, 2 (15.4%) had a significant fibrosis predictive score. Of the 4 patients with follow-up imaging after remission of Cushing syndrome, 3 had remission of steatosis between 1 and 5 years after remission of Cushing syndrome. No patient without MASLD at diagnosis had a worsening liver/spleen ratio after remission.

We estimated the prevalence of hepatic steatosis at the diagnosis of Cushing syndrome at 26.5%. The presence of metabolic factors was associated with the occurrence of hepatic steatosis.

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

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

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern. MASLD is strongly linked to obesity, sedentary lifestyles, and metabolic syndrome. In India, the prevalence of MASLD exhibits regional variations because of genetic, dietary, and socioeconomic factors. Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) are standardized non-invasive tools for assessing fibrosis and steatosis in MASLD. This study aimed to determine the prevalence and severity of MASLD across different Indian regions and examine regional disparities in MASLD burden.

This retrospective, multicenter, cross-sectional study analyzed the data of 13,750 adults from 105 diabetes and endocrine clinics across six geographic zones in India between May 2023 and February 2024. Participants underwent LSM and CAP assessment using FibroScan™. Based on LSM, liver fibrosis was categorized as F0-F1 (2-7 kPa), F2 (7-10 kPa), F3 (10-14 kPa), and F4 (≥ 14 kPa). Based on CAP, MASLD was classified as mild (238-260 dB/m), moderate (261-292 dB/m), and severe (≥ 293 dB/m).

The prevalence of MASLD was 68.2% (CAP ≥ 238 dB/m), and the prevalence of fibrosis was 33.7% (LSM ≥ 7 kPa). The highest MASLD burden was observed in North India (73.3%), particularly in Uttarakhand (80.0%). Severe fibrosis (F4) was highly prevalent in Kerala (20.0%), whereas severe steatosis (S3) was highly prevalent in Jammu and Kashmir (50.3%). The prevalence of MASLD was significantly associated with regional variations (P < 0.001) but not with age.

This study highlights significant regional disparities in MASLD burden. The high burden in North India calls for region-specific public health interventions, standardized screening, and preventive strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease, with other fat-liver diseases potentially progressing to cirrhosis and hepatocellular carcinoma. Our study aimed to alleviate MASLD by EGCG inhibiting oxidative stress-mediated pyroptosis in zebrafish.

The one month old wild-type zebrafh larval (50 per group) and three months old adult male zebrafish (15 per group) were treated with high-fat diet (HFD) feeding (powdered egg yolk) following by treatment with 25 μM EGCG for 15 days. Indicators related to liver damage, oxidative stress, inflammation, pyroptosis and aging were assessed using Oil Red O staining, H&E staining, commercial assay kits, enzyme-linked immunosorbent assay (ELISA) kits, and Western blot analysis.

The results suggest that EGCG significantly reduced fatness, severe lipid deposition, triglyceride (TG), total cholesterol (TC) and free fatty acid (FFA) levels (p < 0.05). EGCG markedly reduced serum ALT, AST and ameliorated liver injury in zebrafish (p < 0.05). EGCG also showed an antioxidant effect by reducing reactive oxygen species (ROS) production malondialdehyde (MDA) and increasing superoxide dismutase (SOD) levels (p < 0.05). Moreover, EGCG obviously down-regulated the pro-inflammatory factors like tumor necrosis factor-a (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-18 (IL-18) levels (p < 0.05). EGCG indicated a significant upregulation involved in pyroptosis pathway, such as nuclear factor erythroid 2-related factor 2 (NRF2) and downregulated the expressions of nuclear factor-κB (NF-κB), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), as well as gasdermin D (GSDMD) (p < 0.01). Moreover, EGCG significantly improved aging-related markers induced by a HFD, including the level of senescence-associated β-Galactosidase (SA β-Gal) and expression of p53, p16, and p21 (p < 0.05), while ameliorating liver function in zebrafish.

These results suggest that EGCG may attenuate MASLD in larval and adult zebrafish induced by 15 consecutive days HFD, which is potentially mediated by modulating the Nrf2/NF-κB/NLRP3 signaling pathway which relieve pyroptosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) remains the most common chronic liver disease worldwide, and appropriate in vitro models are of great significance for investigating pathogenesis and drug screening of MASLD. In this study, human expandable cholangiocyte organoids were derived from adult stem cells of normal liver tissue. After differentiation, liver organoids (LOs) exhibited the functional characteristics and genomic features of mature hepatocytes. To induce steatosis, LOs were incubated with a gradient concentration oleic acid, and it was found that the model could recapitulate the development of lipid accumulation and inflammation. In addition, the drug sensitivity of the hepatic steatosis model was further verified through anti-steatosis drug testing. In summary, LOs have great potential for disease modeling, and the results indicate that the hepatic steatosis model may serve as a useful tool for exploring the molecular mechanisms and drug screening of MASLD.

Hepatocellular carcinoma (HCC) is a major global health issue, in which the underlying liver disease aetiology has shifted towards non-viral causes, particularly metabolic (dysfunction)-associated fatty liver disease (MAFLD). While traditionally associated with cirrhosis, a subset of HCC cases arises in patients with MAFLD but without cirrhosis, whose characteristics remain poorly understood.

The study aims to explore the clinical, tumour and genetic characteristics of non-cirrhotic MAFLD-related HCC when compared to those that develop in the context of cirrhosis.

A multi-centre, retrospective study of 89 MAFLD-related HCC patients enrolled between 2009 and 2023 was performed.

We conducted a study of well-defined MAFLD-related HCC patients to explore their MAFLD-related clinical and genetic associations. Statistical analysis was undertaken to compare the underlying cirrhosis and non-cirrhosis groups for HCC features, adjusting for relevant confounders.

Patients with HCC arising in cases of MAFLD without cirrhosis exhibited a lower body mass index, higher triglyceride levels and increased smoking prevalence compared to their counterparts with cirrhosis. Despite arising in the absence of cirrhosis, these patients had more aggressive tumour features, including larger tumour size, multifocality and portal vein thrombosis. Logistic regression confirmed non-cirrhosis status to be an independent predictor of larger tumour size and increased lesion number.

Non-cirrhotic MAFLD-related HCC presents with distinct clinical and tumour characteristics, suggesting the existence of unique disease drivers that are yet to be discovered.

Metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosis and management have evolved rapidly alongside the increasing prevalence of obesity and related complications. Hepatology has expanded its focus beyond late-stage cirrhosis and portal hypertension to earlier, complex MASLD cases in younger patients, necessitating closer collaboration with endocrinology. The renaming of nonalcoholic fatty liver disease (NAFLD) to MASLD reflects its pathophysiology, reduces stigma, and has prompted new research directions. Noninvasive tests such as liver stiffness measurement now play a crucial role in diagnosis, reducing reliance on invasive liver biopsies. However, advanced omics technologies, despite their potential to enhance diagnostic precision and patient stratification, remain underutilized in routine clinical practice. Behavioral factors, including posttraumatic stress disorder (PTSD) and lifestyle choices, influence disease outcomes and must be integrated into patient management strategies. Primary care settings are critical for early screening to prevent progression to advanced disease, yet sizable challenges remain in implementing effective screening protocols. This Review explores these evolving aspects of MASLD diagnosis and management, emphasizing the need for improved diagnostic tools, multidisciplinary collaboration, and holistic care approaches to address existing gaps and ensure comprehensive patient care across all healthcare levels.

The THR-β agonist resmetirom is the first treatment approved for metabolic dysfunction-associated steatohepatitis (MASH) in the US so far. It can be prescribed given MASH and F2/F3-fibrosis ("at-risk MASH").We analyzed how many patients qualify for resmetirom in a recently recruited Steatotic Liver Disease-cohort involving both tertiary and secondary care centers, the German SLD-Registry.Indication for resmetirom was assessed by three different approaches: (i) biopsy-proven MASH with F2/3 fibrosis and NAS-score ≥ 4; (ii) FibroScan-AST (FAST) score ≥ 0.67 and vibration controlled transient elastography (VCTE) < 15 kPa; (iii) US expert recommendations with VCTE 10-15 kPa and platelets ≥ 140×109/L or VCTE 8-15 kPa.1113 patients were recruited across 8 tertiary and 12 secondary care centers. NAS grading and staging were available for 180 cases (16%) with 179/180 conducted at tertiary care level. Of these, 61 (34%) qualified for resmetirom. FAST score without histologic assessment was available for 638 cases (57.3%), of which 612 (87%) were from tertiary and 26 (11%) from secondary care centers. Based on approach (ii), 41 (6%) of these individuals qualified for resmetirom compared to 117 (18.3%) using approach (iii). Combining approach (iii) with FAST ≥ 0.67 leads to 191 (30.0%) eligible patients. Using VCTE 8-15 kPa results in 182 (28.5%) eligible patients.Eligibility for resmetirom treatment depends on the available method used to identify "at-risk MASH". Availability of VCTE was highest among different levels of care.

The rising incidence of nonalcoholic fatty liver disease (NAFLD) poses a great socioeconomic burden worldwide. Also, periodontitis is the most common chronic inflammatory disease caused by a group of oral pathogens, affecting both oral health and systemic conditions, especially liver disease. Although accumulating evidence has elucidated an association between periodontal pathogens and NAFLD, the role of periodontal pathogen-derived outer membrane vesicles (OMVs) has not yet been clarified. In this comprehensive review, we aim to address this gap by summarising the progression and pathogenesis of NAFLD and revealing the relationship between periodontal disease and NAFLD multidimensionally. Additionally, this review sheds light on the multifunctional roles of periodontal pathogens OMVs and emphasises that periodontal pathogen-derived OMVs promote the development of NAFLD by stimulating Kupffer cells to produce inflammatory factors and inducing the activation of Hepatic stellate cells. However, it is still controversial whether periodontal pathogen-derived OMVs can be transferred to the liver through the bloodstream route or the oral-gut-liver axis. This highlights the pressing need for continued research efforts to develop new and optimised research schemes to observe the formation of the systemic distribution pathway of periodontal pathogen-derived OMVs. Finally, it is notable that there are currently no relevant clinical treatment guidelines to make specific provisions on controlling the level of periodontal pathogen-derived OMVs in patients with NAFLD. Guidelines developed based on our findings may contribute to the standardisation of practices. It can also provide effective strategies and potential therapeutic targets for NAFLD patients with periodontitis to alleviate the development of NAFLD diseases by inhibiting periodontal pathogens OMVs.

Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder of the liver with an increasing global prevalence. Despite significant advancements in understanding NAFLD, effective therapeutic strategies remain limited. Mitochondria-associated membranes (MAMs) are specialized domains of the endoplasmic reticulum (ER) that closely interact with mitochondria and play a crucial role in regulating Ca2+ homeostasis. Our previous research demonstrated that dimethyl fumarate (DMF) alleviates NAFLD by modulating hepatic Ca2+ homeostasis. However, the precise mechanisms remain unclear. In this study, we found that DMF significantly alleviated lipid accumulation in NAFLD mice by inhibiting excessive MAMs enrichment. Mechanistically, DMF improved mitochondrial function by reducing mitochondrial Ca2+ overload and oxidative stress caused by MAMs over-enrichment. Furthermore, our results demonstrated that protective effects of DMF against NAFLD are dependent on Sirtuin-1 (SIRT1) regulation. Inhibition of SIRT1 markedly reversed the ability of DMF to suppress MAMs over-enrichment in both in vitro and in vivo models. Moreover, the beneficial effects of DMF on oxidative stress, mitochondrial dysfunction, and hepatic steatosis were abrogated by co-administration of EX527, a selective SIRT1 inhibitor. In summary, our findings demonstrate that DMF alleviates mitochondrial Ca2+ dysregulation caused by aberrant MAMs enrichment, thereby reducing oxidative stress and mitochondrial dysfunction, ultimately inhibiting lipid accumulation in hepatocytes. These results provide new insights into the therapeutic potential of DMF for NAFLD treatment.

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.

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.

Most forms of obesity are associated with chronic diseases that remain a global public health challenge.

Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation.

This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood.

The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies.

The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity.

This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.