Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, with a range of manifestations, such as hepatic steatosis. Our previous study showed that Kaili Sour Soup (KSS) significantly attenuated hepatic steatosis in rats. This study explored the main components of KSS and the mechanisms by which it exerts its protective effects against NAFLD.

Twenty-four 6-week-old male Sprague-Dowley (SD) rats were randomly assigned to three treatments: feeding a normal standard diet, a high-fat diet, or a high-fat diet plus gavage KSS. The effects of KSS treatment on hepatic lipid accumulation were assessed using biochemical, histological, and molecular experiments. The amounts of KSS ingredients were measured using biochemical assays. Network pharmacology analyses were performed to identify the hub genes of KSS targets and enriched pathways. CCK-8 assay was used to determine the effect of free fatty acids (FFA), lycopene, and estrogen on HepG2 viability. Quantitative Real-Time polymerase chain reaction (qRT-PCR) and Western blot assays were performed to determine the effect of KSS or lycopene on estrogen signaling and expression of lipid metabolism-related molecules. Statistical analyses were performed using GraphPad Prism and SPSS.

KSS alleviated fat deposition in rat liver tissue and affected the expression of hepatic lipid synthesis, catabolism, and oxidative molecules. Lycopene was identified as the ingredient with the highest amount in KSS. Network pharmacology analyses showed that the hub genes were enriched in the estrogen signaling pathway. Cellular experiments showed that lycopene increased the expression of Estrogen Receptor α (ERα), Carnitine palmitoyltransferase 1 A (CPT1A), Peroxisome proliferator-activated receptor α (PPARα) (all p < 0.01), and Hormone sensitive lipase (HSL) (p < 0.05), and reduced the expression of lipid metabolism-related factors 1c(SREBP-1c) (p < 0.01), Acetyl-CoA carboxylase 1 (ACC) and Lipoprotein lipase (LPL) (all p < 0.05).

KSS ameliorated abnormal lipid metabolism in patients with NAFLD. Lycopene was the major component of KSS, and it affected estrogen signaling and the expression of lipid metabolism molecules. In short, both KSS and LYC could change lipid metabolism by lowering lipid accumulation and raising lipolysis.

Exercise effectively treats metabolic dysfunction-associated steatotic liver disease (MASLD) by enhancing hepatic mitochondria energy metabolism. However, the efficiency of exercise in treating MASLD in postmenopausal women may be reduced. Previously, we showed acute treadmill exercise activates hepatic mitophagy, the selective degradation of low-functioning mitochondria. Mitophagic flux is differentially regulated in female mice compared with males, possibly by estrogen. Here, we tested if loss of ovarian function via ovariectomy (OVX), which reduces estrogen, drives MASLD, and compromised hepatic mitochondrial energetics, would blunt activation of hepatic mitophagy induced by exercise. Following OVX, 12- to 15-wk-old female mice were placed on a low-fat diet (LFD) or high-fat diet (HFD) for 4 wk to induce MASLD, after which half of the mice performed a single acute bout of treadmill exercise to exhaustion or remained sedentary. Two hours post exercise, isolated hepatic mitochondria were examined via Western blotting and proteomics for accumulation of known mitophagy proteins. After exercise, reduced basal mitophagic flux in LFD-fed OVX was restored to levels found in sham mice. However, exercise possessed blunted capacity to promote mitochondrial recruitment of DRP1 (regulator of fission) and accumulation mitophagy-associated proteins (E3-ubiquitin ligase, ubiquitin, autophagy adaptor proteins, and autophagosome cargo receptors) in OVX versus sham mice on HFD. Mitochondrial H2O2 production, which putatively activates mitophagy, was elevated following exercise in all conditions except OVX + HFD. In summary, OVX reduces mitophagic flux, blunting the stimulatory effects of exercise on these factors. The impaired regulation of mitophagy following the cessation of ovarian function likely contributes to the pathogenesis of MASLD post menopause.NEW & NOTEWORTHY Loss of ovarian function reduces hepatic mitochondrial respiratory capacity, but mechanisms are unknown. Here, we leverage exercise-induced hepatic mitophagy activation to determine if loss of ovarian function impairs mitochondrial quality control mechanisms. Our data reveal that loss of ovarian function reduces both ubiquitin-mediated hepatic mitophagy and mitochondrial recruitment of Drp1 (mitochondrial fission protein) following acute exercise. These impairments to hepatic mitophagy coincided with alterations in hepatic mitochondrial respiratory capacity and mitochondrial-derived H2O2 production.

In recent years, we have witnessed a sharp growth of metabolic dysfunction associated steatotic liver disease (MASLD). How to achieve early prevention of MASLD is imminent. We aimed to determine the dietary pattern and other factors influencing MASLD, to explore whether it mediated by serum uric acid (SUA) or not.

A total of 4,038 adults attending the Health Management Center of the Second Affiliated Hospital of Dalian Medical University between October 2018 and May 2019 were surveyed using a questionnaire and underwent physical measurements. Structural equation model (SEM) was used to verify the risk factors and determine the path affecting MASLD.

A total of 3,589 participants were studied. The standardized prevalence of MASLD was 47.8%. Three dietary patterns were identified using factor analysis. The SEM showed that SUA was positively associated with MASLD (standardization coefficient 0.285). In rank order, sex, SUA, dyslipidemia, age, a high-protein diet, and a fast-food diet were risk factors for MASLD. Sex, dyslipidemia, and a fast-food diet had positive and indirect effects on NAFLD through SUA, while age and a high-protein diet had negative and indirect effects on MAFLD through SUA.

SUA may be an important mediator of the risk of MASLD. People with abnormal SUA, especially men, should limit their intake of fried and cured foods and desserts; have their blood lipid profiles monitored carefully; appropriately increase their consumption of high-quality protein sources, such as eggs, milk, and beans; and be aware of their MASLD risk.

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.

The long-term association between total energy intake and clinical outcomes in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. The present study aimed to explore the associations between total energy intake and mortality in MASLD patients and to evaluate whether the associations differ by sex. A total of 2,466 MASLD patients from the Third National Health and Nutrition Examination Survey was included. Total energy intake was assessed using 24-hour dietary recall. Mortality was ascertained by linkage to National Death Index records through 31 December 2019. Multivariable Cox proportional hazards model was used to estimate the association between total energy intake and mortality. In MASLD patients, both low and high total energy intake were significantly associated with elevated risk of all-cause mortality. Compared with moderate total energy intake (2,000-3,000 kcal/day for males and 1,600-2,400 kcal/day for females), the HRs (95% CIs) for low and high total energy intake were 1.27 (1.05-1.53; P = 0.01) and 1.40 (1.03-1.92; P = 0.03), respectively. A significant interaction was demonstrated between sex and total energy intake for all-cause mortality (P value for interaction = 0.03). In males, both low and high total energy intake were significantly associated with elevated risk of all-cause mortality. The HRs (95% CIs) for low and high total energy intake were 1.35 (1.02-1.80; P = 0.04) and 1.54 (1.05-2.28; P = 0.03), respectively. However, no significant association was observed in females. The HRs (95% CIs) for low and high total energy intake were 1.14 (0.86-1.52; P = 0.34) and 1.14 (0.81-1.61; P = 0.46), respectively. These findings provide novel evidence supporting sex-specific dietary guidelines for MASLD, with particular emphasis on maintaining moderate energy intake to mitigate mortality risk in male patients.

Micro/nanoplastics (MNPs), as emerging environmental pollutants, are widely present in environments that are essential for human survival. They exist in vast quantities and possess stable properties, making them challenging to manage. Some reports indicated that there is a positive correlation between the production of MNPs and the incidence of obesity. The liver serves as both the central hub for lipid metabolism and a prime target for MNPs toxicity. These studies revealed that MNPs can lead to increased hepatic lipid accumulation, suggesting that they may be potential obesogens. However, the specific metabolic changes and possible mechanisms involved remain to be elucidated.

This study focuses on the impact of nanoplastics (NPs) on liver lipid metabolism, using C57BL/6J mice (hereinafter referred to as C57 mice) as the research subjects, and exposing them to 100 nm NPs at 1000 µg/L continuously for 12 weeks.

The study revealed that (1) NPs led to nondietary weight gain together with an increase in fat volume and mass in mice. (2) NPs significantly increased serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, with notable differences between groups. Notably, NPs exposure induced opposing effects on serum lipid profiles, elevating high-density lipoprotein cholesterol (HDL-C) concentrations while suppressing triglyceride (TG) levels, though intergroup differences failed to reach statistical significance. (3) NPs caused multiple inflammatory responses in the liver, with significant lipid deposition. (4) Untargeted metabolomics analysis indicated that NPs exposure led to significant alterations in various lipid metabolites, particularly glycerophospholipids. Additionally, transcriptomics reveals that differentially expressed genes (DEGs) triggered by NPs exposure are predominantly involved in metabolic routes including lipid metabolism and cytochrome P450 (CYP). Taken together, these findings suggested that alterations in lipid metabolism resulting from NPs exposure may involve arachidonic acid metabolism. Phosphatidylcholine (PC) could be the key substance, and the CYP gene family (Cyp2c23, Cyp2c40) might be the critical genes regulating liver lipid metabolism during NPs exposure.

This study has demonstrated that NPs exposure induced obesity and hepatic lipid accumulation in male mice independently of food intake. The integrated omics data identified dysregulated PC metabolism and CYP gene family expression, suggesting their involvement in arachidonic acid-associated pathways. These findings provided preliminary mechanistic clues linking NP exposure to hepatic lipid metabolism dysregulation and helped to elucidate the adverse effects of NPs on liver lipid metabolism.

Manganese (Mn) is an essential nutrient that plays a crucial role in maintaining normal physiological functions of the human body. However, overexposure to Mn often leads to adverse health outcomes and contributes to the development of a variety of diseases. Several studies have explored the relationship between dietary Mn and metabolic dysfunction-associated steatotic liver disease (MASLD) risk. Two UK Biobank (UKB)-based studies suggested that Mn, as a key nutrient, may be associated with a reduced risk of MASLD. Another study found an association between the dietary antioxidant index and the onset of non-alcoholic fatty liver disease (NAFLD), highlighting the importance of nutritional factors (including Mn) in liver health. However, the relationship between dietary Mn intake and MASLD in the Chinese population remains unexplored, and further research is needed to elucidate its underlying mechanisms.

This prospective multi-cohort study had 1,137 adults from the Guangzhou Nutrition and Health Study (GNHS) cohort and 17,649 people from the Tianjin Chronic Low-grade Systemic Inflammation and Health (TCLSIH) cohort. We measured dietary intake using a validated and standardized food frequency questionnaire. Annual abdominal ultrasound was used to diagnose new-onset MASLD. We used multivariable Cox regression models to assess the relationship between dietary Mn intake and the risk of MASLD.

In the TCLSIH cohort, 3640 MASLD cases were observed with a follow-up time of 60,190 person-years. After taking into account possible confounding factors, the multivariable HRs (95% CIs) for MASLD across the quartiles of dietary Mn intake in males were 1.00 (reference), 1.08 (0.96-1.21), 1.12 (0.99-1.26), and 1.16 (1.02-1.31), with a P for trend = 0.02; for females, the HRs (95% CIs) for MASLD across the quartiles of dietary Mn intake were 1.00, 1.11 (0.95-1.31), 1.08 (0.91-1.28), and 0.97 (0.81-1.16), with a P for trend = 0.58. After adjustment for proteins, lipids, and carbohydrates, the HRs (95% CIs) for MASLD across the quartiles of dietary Mn intake in males were 1.00 (reference), 1.11 (0.97-1.26), 1.14 (1.00-1.31), and 1.16 (1.00-1.34), with a P for trend = 0.045. For females, the HRs (95% CIs) for MASLD across the quartiles of dietary Mn intake were 1.00 (reference), 1.08 (0.91-1.30), 1.06 (0.88-1.27), and 0.93 (0.76-1.13), with a P for trend = 0.39. In the GNHS cohort, 624 MASLD cases were observed with a follow-up time of 6454 person-years. After adjusting for relevant confounders, the HRs (95% CIs) for males comparing T3 versus T1 of dietary Mn intake were 1.04 (0.65-1.60); the HRs (95% CIs) for females comparing T3 versus T1 of dietary Mn intake were 1.00 (0.78-1.29).

In males, higher dietary Mn intake is associated with a higher incidence of MASLD.

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

Fatty liver disease (FLD), characterized by hepatic lipid accumulation, impairs quality of life and can progress to cirrhosis and hepatocellular carcinoma, imposing a healthcare burden. This study investigates the association between the aggregate index of systemic inflammation (AISI) and FLD prevalence, evaluating AISI's potential as an early biomarker for risk assessment.

Data were obtained from the National Health and Nutrition Examination Survey (NHANES) database, which encompasses the years 2017 through 2020. Participants were chosen based on the availability of controlled attenuation parameter (CAP) scores derived from transient elastography (TE), a technique utilized for assessing liver steatosis. The formula employed to compute the AISI is as follows: AISI = N × P × M / L, where N, P, M, and L refer to neutrophils, platelets, monocytes, and lymphocytes, respectively. Additionally, demographic, socioeconomic, dietary, and health-related information was gathered. Logistic regression models were utilized to pinpoint risk factors associated with FLD, and a nomogram was created to forecast FLD risk.

Of the 3,961 participants, 2,377 (60.0%) were diagnosed with FLD based on a CAP score ≥ 248 dB/m. Elevated AISI was significantly associated with FLD (P = 0.021). Other significant risk factors included sex, age, BMI, race, marital status, hypertension, and diabetes. The nomogram demonstrated excellent discriminatory performance with an AUC of 0.814 (95% CI: 0.800, 0.827) and good calibration.

This study reveals a significant, independent association between elevated AISI and increased FLD risk in the U.S. population, even after adjusting for confounders. AISI demonstrated good discriminative performance for FLD, but its effect size suggests it should supplement, not replace, existing clinical risk assessment tools. AISI, a cost-effective biomarker, holds potential for enhancing FLD screening, particularly in resource-limited settings.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease worldwide. The liver communicates with the intestine, in large part through the gut microbiota. Microbial enzymes are key mediators that affect the progression of MASLD and the more severe metabolic dysfunction-associated steatohepatitis (MASH). These enzymes contribute to the metabolism or biosynthesis of steroids, fatty acids, amino acids, ethanol, choline, and intestinal hormones that contribute to disease progression. Additionally, dysbiosis and functional alterations in the microbiota compromise the intestinal barrier, increasing its permeability to bacterial metabolites and liver exposure to microbial-associated molecular patterns (MAMPs), thereby exacerbating liver inflammation and fibrosis. Furthermore, functional alterations in the gut microbiota can modulate intestinal signaling pathways through metabolites or gut hormones, subsequently affecting hepatic metabolism. A deeper understanding of the roles of the gut microbiota and microbial enzymes in MASH will facilitate the development of personalized treatments targeting specific gut microbes or functional enzymes.

To describe and understand differences between U.S. rural and urban populations with respect to outcomes of hospitalization and related epidemiology of Non-alcoholic fatty liver disease (NAFLD).

We analyzed data from the Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (NIS) from 2007 to 2019, identifying 847,165 NAFLD cases, of which 370,131 met inclusion criteria. Statistical analyses included Pearson's chi-square, independent samples t-tests, Mann-Whitney U tests, and multivariate logistic regression models to examine factors associated with NAFLD.

Hospitalizations due to NAFLD significantly increased over time from 2007 - 2019 with urban cases constituting 84.9% while rural cases represented 15.1%. Differences in demographics, hospital characteristics, insurance, income, and outcomes were significant between the two groups. Multivariate analysis showed higher odds of NAFLD diagnosis in fringe metro areas (adjusted odds ratio [a.O.R.]=1.074, 95% CI=1.044-1.105), medium metro counties ((a.O. R.=1.146, 95% CI=1.114-1.179), small metro counties (a.O. R.=1.182, 95% CI=1.140-1.226), and rural regions (a.O. R.=1.279, 95% CI=1.233-1.327) compared to central metro areas. NAFLD was more prevalent in females, those aged 35-49 or 50-64 years, and White patients, particularly among those with diabetes, metabolic syndrome, and obesity.

The increasing prevalence of NAFLD suggests a strong association with metabolic and cardiovascular diseases. With increasing closure of rural hospitals, we may see more rural patients with NAFLD admitted to urban centers. Early detection and diagnosis should help prevent long-term complications of NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with heart failure (HF), independent of shared risk factors. Our aim was to describe the incidence of HF in patients with biopsy-proven MASLD.

We followed patients with biopsy-proven MASLD from the prospective Duke NAFLD Biorepository and Clinical Database from liver biopsy (2007-2013) until death or 5 January 2023. Clinical and echocardiographic data were abstracted via manual chart review. Incident HF was defined as one of the following: (1) hospitalization for HF, (2) medical record diagnosis of HF, (3) ≥1 sign/symptom of HF and elevated natriuretic peptide, or (4) diastolic dysfunction on transthoracic echocardiography with ≥1 sign/symptom of HF. Univariable and multivariable logistic regression models were evaluated. Overall, 570 patients with biopsy-proven MASLD were included. The mean age was 49.5 years, 42.5% were male and 87.0% were non-Hispanic White. Ten patients (1.8%) had baseline HF, leaving 560 patients to assess for incident HF. Over a median follow up of 4009 days (11.0 years) (interquartile range 2270-4672 days), 100 (17.9%) patients developed incident HF while 268 (47.9%) met criteria for HF suspicion. In a multivariable model, increasing age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02-1.08, p < 0.001) and female sex (OR 1.85, 95% CI 1.12-3.04, p = 0.02) were associated with incident HF.

We found a high incidence of HF in patients with biopsy-proven MASLD. Despite nearly half of patients having suspected HF, very few carried a chart diagnosis. Screening for HF in high-risk patients and establishment of formal care pathways to address early HF may reduce morbidity and mortality.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with insulin resistance (IR). However, the prognostic value of different alternative IR surrogates in patients with MASLD remains unclear. This study aimed to evaluate the association between various IR indices and all-cause mortality and cardiovascular mortality in MASLD patients.

A total of 8,753 adults aged ≥ 20 years with MASLD from the National Health and Nutrition Examination Survey (NHANES, 2003-2018) were included, and their mortality data were obtained from the National Death Index (NDI). Insulin resistance surrogates [including the triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference index, TyG-waist-to-height ratio index, and Homeostatic Model Assessment for IR] were stratified into quartiles. Cox proportional hazards models, receiver operating characteristic (ROC) curve analysis, restricted cubic spline (RCS), mediation analyses, and subgroup analyses were used to explore the associations between these indices and all-cause mortality as well as cardiovascular mortality in MASLD patients.

During a median follow-up of 98 months, 1,234 deaths were observed, including 409 cardiovascular disease (CVD)-related deaths. In the fully adjusted model, higher quartiles of TyG-related indices were significantly associated with an increased risk of all-cause mortality in MASLD patients. Furthermore, the TyG-BMI index was associated with both all-cause mortality and CVD mortality [all-cause mortality: HR (95% CI) 2.84 (1.73-4.67), P < 0.001; CVD mortality: HR (95% CI) 5.32 (2.26-12.49), P < 0.001]. The RCS analyses indicated a U-shaped relationship between TyG-BMI and mortality, with a threshold value of 270.49. Subgroup analyses demonstrated that TyG-related indices had stronger associations with mortality in elderly MASLD patients.

Our findings highlight the prognostic value of IR indices, particularly TyG-BMI index, in predicting all-cause mortality and CVD mortality in MASLD patients.

Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent worldwide. This study aimed to analyze the risk factors associated with NAFLD progression by collecting and evaluating clinical data of NAFLD patients, providing a scientific basis for its prevention and treatment.

Clinical data of NAFLD patients from June 2015 to June 2016 were retrospectively collected, including gender, age, alanine aminotransferase (ALT), aspartate aminotransferase(AST), alkaline phosphatase(ALP),γ-glutamyltranspeptidase (GGT), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), fasting blood glucose (FBG), and visceral fat area (VFA). All patients were stratified by gender and age, and logistic regression analysis was used to explore the risk factors for NAFLD disease progression.

ALT, TG, FBG, and VFA were identified as independent risk factors for NAFLD progression. Stratified analysis showed that in male patients, ALT, TG, and VFA were independent risk factors, whereas in female patients, TG, FBG, and VFA were identified as independent risk factors. Age-stratified analysis revealed that ALT, TG, and VFA were significant risk factors for progression in young and middle-aged patients. At the same time, age, ALT, TG, and FBG were substantial in elderly patients.

Different risk factors should be closely monitored in sex- and age-specific populations to prevent NAFLD progression effectively.

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

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

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

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

Inbred mouse strains are critical tools for studying immune regulation of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Here, we profiled mouse strain-associated hepatic immune differences, and performed mice-human cross-species immune comparisons.

Immune landscapes of C57BL/6, BALB/c, and FVB/N mice were compared under healthy, MASH, or HCC state using high-dimensional spectral flow cytometry (n = 4 per condition). MASH was induced by feeding methionine- and choline-deficient or Western diet + carbon tetrachloride. HCC was caused by hydrodynamic plasmid injection of MYC/sg-p53. Public mouse and human scRNA-seq datasets were used for validation and cross-species comparisons.

In healthy mice, liver CD4+ T (24% vs. 14% vs. 34%, p <0.05) and B cells (36.5% vs. 35% vs.18%, p <0.05) varied the most among three strains. C57BL/6 mice showed TH1 dominance, whereas BALB/c and FVB/N mice had TH2 dominance (log[TH1:TH2] = 0.17, -0.31, -0.17). In MASH mice, expansion of liver myeloid cells and innate lymphocytes were commonly found, but changes of B cells (log(fold-change) = -0.38, -0.28, -0.58, p <0.05) and T subsets (e.g. CD4+ T log(fold-change) = -0.21, -0.07, -0.15, p <0.05) varied greatly among strains. MYC/sg-p53 HCC induced a consistent expansion of liver Tregs and CD8+ T cells (p <0.05), but differential shifts of liver immune landscape were seen among strains. The flow cytometry data was supported by public scRNA-seq datasets matching C57BL/6 background. Further cross-species comparison in MASH condition confirmed shared changes of adaptive lymphocytes between mice and humans. In two MASH models, BALB/c or C57BL/6 mice were more consistent to recapture loss of CD4+ T or B cells, respectively (p <0.05).

Substantial liver immune differences exist among common mouse strains. Mice can recapitulate certain human liver immune changes with strain variations.

Our immune cell profiling study revealed that the liver immune environment can be quite different among common mouse strains both under healthy and pathologic states, such as steatohepatitis or neoplastic processes. Our results serve as a data resource for studies investigating liver immunology and provide valuable insights for the design of studies on various immune cells in the livers of mice.

Sucrose intake is a potential risk factor for non-alcoholic fatty liver disease (NAFLD). Individual characteristics such as sex, play arole in the biological variation of the disease, potentially related to genetic regulation. This research evaluated sex differences in biochemical, histopathological, and gene expression responses associated with NAFLD in C57bl/6N mice on a high sucrose diet. Female and male mice were assigned to control or high sucrose diets (50% sucrose solution) for 20 weeks. After sacrifice, blood and hepatic tissue were collected for analysis. Female mice revealed moderate-to-high NAFLD, whereas male mice showed mild-to-moderate NAFLD. Sex-specific variations were observed in Cd36 gene expression, an upregulation in females compared with the male group, and Adipor1 gene expression showed significant downregulation in the female group in response to high sucrose diet compared with the control group. These findings highlight the importance of considering gender disparities in the treatment and management of NAFLD.

We aimed to investigate the association of healthy diet scores (HDS), comprising major components (fruits and vegetables, soybean, fish, and sugar-sweetened beverages), with non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). In this cross-sectional study of 2,404 T2DM individuals aged 35-70 years, individuals with higher HDS (≥3 components) had a lower odds of NAFLD (adjusted odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.48, 0.84) and lower fatty liver index (FLI) levels (β: -4.70; 95% CI: -7.61, -1.79). Each one-component increase in HDS was associated with a 14% reduction in the odds of NAFLD (OR: 0.86; 95% CI: 0.75, 0.98) and a 1.95-unit reduction in FLI levels (β: -1.95; 95% CI: -3.21, -0.70). These results suggest that adherence to a higher HDS pattern may be protective against NAFLD in T2DM.

Although premenopausal women are at lower risk for metabolic dysfunction-associated steatotic liver disease than men within the same age group, the sex advantage becomes minimal after menopause, suggesting a role for female hormones.

This study aimed to elucidate the role of reproductive factors in the development of female metabolic dysfunction-associated steatotic liver disease, using an integrated analysis.

Up to 269,607 women without metabolic dysfunction-associated steatotic liver disease during baseline recruitment (2006-2010) of the UK Biobank were included. Among these, 21,017 women did not develop metabolic dysfunction-associated steatotic liver disease across the follow-up period (through December 2021) and had the measure of liver proton density fat fraction quantified by magnetic resonance imaging since 2014. Multivariable Cox regression models were applied to assess the prospective relationships of various reproductive factors with incident metabolic dysfunction-associated steatotic liver disease. Multiple linear regression models were used to explore the relationships of reproductive factors with liver proton density fat fraction. A 2-sample Mendelian randomization analysis was conducted to investigate causality in the relationships of certain reproductive factors with metabolic dysfunction-associated steatotic liver disease.

During a median of 12.65 years of follow-up, 3077 incident cases of metabolic dysfunction-associated steatotic liver disease were identified. Early menarche, a greater number of live births, younger age at first live birth, and oral contraceptives or hormone replacement therapy initiated at a young age were associated with an elevated risk of metabolic dysfunction-associated steatotic liver disease and higher levels of liver proton density fat fraction. Several other reproductive factors (ie, a greater number of miscarriages, surgical menopause at a young age, and prolonged use of hormone replacement therapy) were associated with incident metabolic dysfunction-associated steatotic liver disease but not with liver proton density fat fraction. In the Mendelian randomization analysis, genetically determined earlier age at menarche and younger age at first live birth were substantially associated with increased risk of metabolic dysfunction-associated steatotic liver disease.

Several reproductive factors were associated with the risk of and histologic features of metabolic dysfunction-associated steatotic liver disease, supporting the role of female hormones in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.

Chronic Hepatitis C (CHC) often results in liver fibrosis. Therefore, an important benefit of CHC treatment with direct-acting antiviral (DAA) medication is liver fibrosis regression. However, it is unclear how concurrent liver steatosis affects fibrosis regression following DAA therapy. Recent guidelines have defined liver steatosis associated with metabolic syndrome as metabolic dysfunction-associated steatotic liver disease (MASLD). We sought to examine the association of MASLD with the fibrosis regression benefits of DAA treatment for CHC.

We conducted an observational retrospective analysis using electronic health records of patients aged 18-65 who completed DAA therapy for CHC from 2016 through 2022. FIB-4 scores were calculated during three time periods: just prior to DAA initiation, within 6 months post-DAA completion, and within 6-12 months post-DAA completion. These scores categorized liver fibrosis as high risk (>3.25), intermediate risk (1.45-3.25), or low risk (<1.45). An ordinal logistic regression model assessed the degree of fibrosis regression across these periods in CHC patients with and without MASLD.

We identified 845 patients with CHC who received DAA therapy, of whom 225 met MASLD criteria. Both CHC patients with and without MASLD exhibited a decrease in FIB-4 category (coefficient = -0.361, P < 0.001) within the year following DAA therapy. The reduction in FIB-4 category post-treatment was more pronounced in the MASLD group compared to the non-MASLD group, as evidenced by a significant interaction between group and time period (coefficient = -0.439, P = 0.004).

In our cohort, MASLD was associated with greater liver fibrosis regression in the year following DAA therapy for CHC. This suggests that the concurrent presence of MASLD is not associated with diminished fibrosis regression from DAA therapy. Additional research is needed to determine the exact mechanism responsible for DAA-associated fibrosis regression in patients with MASLD.

Cancer-associated cachexia (CAC), also known as wasting syndrome, is a systemic condition that affects multiple tissues and organs via a variety of metabolic pathways. Systemic inflammation, progressive weight loss, depletion of adipose tissue, and skeletal muscle impairment are some of the hallmark features of cachexia. Despite various studies on the clinical features of CAC, the complexity of the syndrome continues to pose significant challenges in clinical practice, leading to late diagnoses and the absence of a standardised treatment. Men and women respond differently to CAC, which may be prompted by the pre-existing physiologic sex differences. This review presents the sexual dimorphism associated with the hallmark pathways involved in CAC. A comprehensive understanding of sexual dimorphism in these pathways could drive research on cachexia to prioritise the inclusion of more females in related studies in order to achieve personalised sex-based therapeutic approaches and, consequently, enhance treatment efficacy and better patient outcomes.

The mammalian liver plays a critical role in maintaining metabolic homeostasis during fasting and feeding. Liver function is further shaped by sex dimorphism and zonation of hepatocytes. To explore how these factors interact, we performed deep RNA-sequencing and label-free proteomics on periportal and pericentral hepatocytes isolated from male and female mice under fed and starved conditions. We developed a classification system to assess protein-mRNA relationship and found that gene products (mRNA or protein) for most zonation markers showed strong concordance between mRNA and protein. Although classical growth hormone regulated sex-biased gene products also exhibited concordance, ∼60% of sex-biased gene products showed protein-level enrichment without corresponding mRNA differences. In contrast, transition between feeding and starvation triggered widespread changes in mRNA expression without significantly affecting protein levels. In particular, key lipogenic mRNAs (e.g. Acly , Acaca , and Fasn ) were dramatically induced by feeding, but their corresponding proteins (ACLY, ACC1, and FAS) showed little to no change even as functional de novo lipogenic activity increased ∼28-fold in the fed state. To facilitate further exploration of these findings, we developed Discorda ( https://shinoda-lab.shinyapps.io/discorda/ ), a web database for interactive analysis. Our findings reinforce the principle that mRNA changes do not reliably predict corresponding protein levels (and vice versa), particularly in the context of sex and acute metabolic regulation of hepatocytes, and that de novo lipogenesis activity can be completely uncoupled from changes in protein expression.

The higher prevalence of non-alcoholic fatty liver disease (NAFLD) in men than women before menopause and the reduced difference post-menopause suggest that sex hormones may influence liver lipid accumulation. This study compared the effects of sex hormones on lipid droplet (LD) accumulation in palmitate/ oleate-treated HepG2 cells.

The MTT method was used to determine effective doses of palmitic and oleic acids in HepG2 cells, followed by a combined dose for inducing LD formation. Changes in LD content after treatment with various doses of β-estradiol and testosterone were evaluated qualitatively and semi-quantitatively using Oil Red O staining and light microscopy. The effects of these hormones on gene expression related to LD formation and lipogenesis, including PLIN2, ATGL, CGI-58, and CIDEB, were assessed using quantitative PCR.

Treatment of HepG2 cells with palmitate and oleate increased LD accumulation and the expression of PLIN2 and CIDE while elevating ATGL expression without affecting CGI-58. With no significant difference, both β-estradiol and testosterone significantly reduced LD accumulation in steatotic HepG2 cells. Gene analysis indicated that both hormones decreased PLIN2 and increased CGI-58 expression. Testosterone did not affect CIDE, while β-estradiol reduced it at low doses. Combined treatment showed no significant changes in gene expression compared to individual hormone effects, but LD accumulation was synergistically reduced.

This study demonstrates that β-estradiol and testosterone significantly modulate LD content and the expression of key regulatory genes in HepG2 cells, with β-estradiol showing a somewhat dominant role in enhancing lipid turnover and mitigating lipid accumulation.

Metabolic-dysfunction associated steatotic liver disease (MASLD) is associated with prevalent cardiovascular disease. More favorable cardiovascular health (CVH) profiles are associated with a lower prevalence of MASLD in cross-sectional studies. The relationship between long-term CVH patterns and MASLD prevalence in midlife remains unknown.

Participants (aged 18-30 years at baseline) of the CARDIA (Coronary Artery Risk Development in Young Adults) study who had individual CVH components measured at 7 examinations over 20 years and liver fat assessed by noncontrast computed tomography at year 25 follow-up were included. CVH score was defined using published American Heart Association definitions. Group-based trajectory modeling was used to identify CVH trajectories. MASLD was defined as liver attenuation of ≤51 Hounsfield units with at least 1 metabolic risk factor after excluding other causes of liver fat. Logistic regression was used to examine associations of CVH trajectory groups and MASLD prevalence. At baseline, 39% of 2529 participants had high and 5% had low CVH, respectively. MASLD prevalence at year 25 was 23% (n=587). Five distinct CVH trajectories were identified. Between the 2 groups that started at similar CVH scores, those whose CVH declined over time had a higher prevalence of MASLD at year 25 (7.0% in high-stable versus 23.0% high-decreasing; 24.4% in moderate-stable versus 35.7% in moderate-decreasing). Lower and decreasing trajectories were associated with higher year-25 MASLD prevalence compared with the high-stable trajectory.

Achieving and maintaining high CVH scores starting in young adulthood lowers the risk of prevalent MASLD in midlife.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver disease and represents a significant public health issue. Nevertheless, current risk stratification methods remain inadequate. The study aimed to use machine learning in the identification of significant features and the development of a predictive model to determine its usefulness in discrimination of MAFLD's risk stratification (low, moderate, and high) in adults.

The data of the 2021-2023 NHANES database were analyzed. Vibration-controlled transient elastography measurements, including controlled attenuation parameter for the evaluation of steatosis and liver stiffness for the evaluation of fibrosis, were used for risk stratification. The participants were grouped into low-risk, moderate-risk, and high-risk groups based on specific criteria. Feature selection was conducted through Least Absolute Shrinkage and Selection Operator (LASSO) regression and random forest classification.

A total of 4,227 participants were included in the study. There were 16 significant predictors identified by LASSO regression, among which the top 10 predictors were demographic (age, gender, race, hypertension history), clinical (body mass index, waist circumference, hemoglobin, glycohemoglobin, lymphocyte count), and education level. The area under the receiver operating characteristic curve (AUC) of the random forest model in the validation set was 0.80, and the individual AUC was 0.83, 0.66 and 0.79 for the low-, moderate-, and high-risk groups, respectively.

Our machine learning model has excellent performance in stratification of risk for MAFLD with readily available clinical and demographic parameters. This model could be employed as a valuable screening tool to refer high-risk patients for further hepatological evaluation.

Objectives: Obesity is a significant public health concern, as it is associated with the development of numerous chronic diseases. The prevalence of obesity and attendant diseases has been increasing over recent years. This study attempted to ascertain the frequency of chronic diseases in obese patients in Türkiye for the first time on this scale. Methods: A retrospective study was conducted, with patients admitted to the internal medicine outpatient clinics or obesity centers between December 2023 and December 2024 included in this study. Participants were recruited from seven regions, 20 provinces, and 28 centers, and the inclusion criteria were met by those aged 18 years and over with a body mass index (BMI) of 30 kg per square meter (kg/m2) or above. Their status, with respect to chronic diseases, and their anthropometric parameters were documented. Results: The total number of patients was 10,121, with a mean age of 45.2 ± 13.92. Of these, 7222 (71.35%) were female. The prevalence of type 2 diabetes mellitus (T2DM), hypertension (HT), dyslipidemia (DL), coronary artery disease (CAD), obstructive pulmonary disease (OPD), obstructive sleep apnea syndrome (OSAS), and fatty liver disease (FLD) was found to be 35.01%, 78.19%, 12.37%, 10.32%, 5.88%, and 75.12%, respectively. A subsequent analysis of the prevalence of these diseases by region revealed a statistically significant variation between regions (p < 0.001 for all regions). Conclusions: This study represents a substantial contribution to the existing body of knowledge in this field, particularly with regard to the identification of the current chronic disease rate of obese patients in Türkiye.

Pyruvate kinase is a key regulator in hepatic glucose metabolism, encoded by the gene pyruvate kinase liver/red blood cells (PKLR). Systems biology-based approaches, including metabolic and gene co-expression networks analyses, as well as genome-wide association studies (GWAS), have led to the identification of PKLR as a pivotal gene influencing liver metabolism in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). Here, we review the critical role of PKLR in MASLD and HCC progression and examine the effects of PKLR modulation both in vitro and in vivo. We also discuss the development of therapeutic strategies for patients with MASLD and HCC by modulating PKLR, highlighting its promising future in a broader range of liver diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver dysfunction worldwide, characterized by hepatic steatosis that may progress to nonalcoholic steatohepatitis and cirrhosis. Owing to its strong association with metabolic disorders, current management focuses on weight reduction via lifestyle modifications. Recently, the very-low-calorie ketogenic diet (VLCKD) has emerged as a promising intervention due to its potential for rapid weight loss and reduction in liver fat. This review aims to evaluate the clinical evidence regarding the impact of ketogenic diets on hepatic steatosis. We conducted an extensive MEDLINE literature search in databases including PubMed, Scopus, and Web of Science up to December 2024. Studies assessing the effects of ketogenic or low-carbohydrate high-fat diets on liver fat, evaluated by imaging, histology, or biochemical markers, were included. The analysis indicates that ketogenic diets significantly reduce hepatic fat content and improve metabolic parameters, including insulin sensitivity and liver enzyme levels. Evidence further suggests that substituting saturated fats with unsaturated fats or replacing carbohydrates with proteins may enhance these benefits. However, considerable variability exists among studies and long-term data remain limited. Although short-term outcomes are encouraging, potential adverse effects such as dyslipidaemia, gastrointestinal disturbances, and transient 'keto flu' symptoms require careful clinical monitoring. Future research should focus on elucidating underlying mechanisms, optimizing dietary composition, and assessing long-term safety to establish ketogenic diets as a robust strategy for managing MASLD.

Nonalcoholic fatty liver disease (NAFLD) was clinically documented to be accompanied by iron homeostasis imbalances, however, the causal relationship between them remains unclear. Therefore, this study aimed to examine the relationship between iron homeostasis indicators (serum iron, ferritin, transferrin, total iron binding capacity (TIBC), and transferrin saturation (TSAT)) and NAFLD risk.

We applied two-sample Mendelian randomization (MR) to assess the effects of genetic liability to iron homeostasis indicators (N = 43,220-246,139) on NAFLD risk (N = 377,988) in individuals of European ancestry. Reverse direction MR, multivariable MR, and two-step MR were performed to estimate reverse association, causal effects independent of smoking or drinking, and the mediating effect of lipid metabolism, respectively. Smoking and drinking as confounders were considered confounders.

Genetically predicted serum iron, ferritin, and TSAT were significantly associated with a higher risk of NAFLD (odds ratio (OR): 1.286, 95% confidence interval (CI): 1.075-1.539; p = 0.0059; OR: 1.260, 95% CI: 1.050-1.500, p = 0.0195; and OR: 1.223, 95% CI: 1.067-1.402; p = 0.0039, respectively). Reverse direction MR analysis suggested that genetic liability to NAFLD had no significant causal effect on iron homeostasis. Sex-specific MR exhibited a stronger effect size for the association of elevated ferritin with NAFLD risk in males (OR: 1.723, 95% CI: 1.338-2.219; p = 2.48 × 10-5). Two-step MR revealed that elevated triglycerides (TGs) mediated approximately 3%-5% of the observed effect of serum iron and TSAT on NAFLD risk, while decreased low-density lipoprotein cholesterol (LDL-C) mediated 9%-10%.

Genetic liability to iron status imbalance may causally affect NAFLD. This evidence may support the clinical treatment of NAFLD in the target population.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease influenced by genetic, lifestyle, and environmental factors. While MASLD is more prevalent in men, women are at increased risk after menopause, highlighting the critical pathogenetic role of sex hormones. The complex interplay between estrogen deficiency, visceral fat accumulation, metabolic syndrome (MetS), and inflammation accelerates disease progression, increases cardiovascular (CV) risk, and triggers a cycle of worsening adiposity, metabolic dysfunction, and psychological problems, including eating disorders. Weight loss in postmenopausal women can significantly improve both metabolic and psychological outcomes, helping to prevent MASLD and related conditions. This review examines the prevalence of MASLD, its comorbidities (type 2 diabetes T2D, CV, mental disorders), pathogenetic mechanisms, and pharmacological treatment with GLP-1 receptor agonists (GLP1-RAs), with a focus on postmenopausal women. Given the use of GLP1-RAs in the treatment of obesity and T2D in MASLD patients, and the increase in MetS and MASLD after menopause, this review analyzes the potential of a stable GLP-1-estrogen conjugate as a therapeutic approach in this subgroup. By combining the synergistic effects of both hormones, this dual agonist has been shown to increase food intake and food reward suppression, resulting in greater weight loss and improved insulin sensitivity, glucose, and lipid metabolism. Therefore, we hypothesize that this pharmacotherapy may provide more targeted therapeutic benefits than either hormone alone by protecting the liver, β-cells, and overall metabolic health. As these effects are only supported by preclinical data, this review highlights the critical need for future research to evaluate and confirm the mechanisms and efficacy in clinical settings, particularly in postmenopausal women.

The global prevalence of Metabolic Dysfunction-Associated Liver Disease is dramatically increasing with the diffusion of cardiometabolic risk factors (CMRFs). The aim of the present study was to assess the natural course of liver cirrhosis, in terms of decompensation, development of hepatocellular carcinoma and mortality, in relation to the presence of CMRFs (type 2 diabetes mellitus, obesity, arterial hypertension, low HDL levels, hypertriglyceridemia).

667 patients with liver cirrhosis (50 with CMRFs and without non-metabolic aetiological factors, 167 with non-metabolic aetiological factors and without CMRFs, and 450 with both non-metabolic aetiological factors and at least one CMRF) followed at the University and General Hospital of Padua, Italy, from 1998 to 2022, were included.

No difference in the occurrence of cirrhosis decompensating events and development of hepatocellular carcinoma was observed, whereas patients in the metabolic or mixed group had 4-3-fold higher all-cause mortality and significantly lower 3-years survival compared to patients in the non-metabolic group, despite a better liver function at enrolment. Hypertriglyceridemia and low HDL levels were the less prevalent CMRFs, but those associated with the highest risk of cirrhosis decompensation. Hypertriglyceridemia was also associated with an increased risk of mortality. Arterial hypertension was associated with a reduced risk of cirrhosis decompensation, but a higher risk of mortality.

Compared to patients without CMRFs, those with CMRFs had similar rates of liver cirrhosis decompensation but higher overall mortality. Hypertriglyceridemia was associated with a high risk of both liver decompensation and death.

Liver-kidney-metabolic health (LKMH) depends on complex interactions between metabolic dysfunction-associated steatotic liver disease (MASLD), chronic kidney disease (CKD), sex, and reproductive status. This study evaluates in a holistic manner how LKMH, sex, and menopause influence coronary artery calcification (CAC) burden.

Patients without previous cardiovascular disease were prospectively recruited. Liver fat was assessed via ultrasonography and categorized as mild or moderate-to-severe. CKD was classified using estimated glomerular filtration rate (eGFR). CAC burden was quantified as 0, 1-299, ≥ 300, single-vessel, or multivessel with coronary computed tomography. Stepwise backward multinomial logistic regression was applied for analysis.

A total of 446 patients (59.2% female, average age 52.9 years) were included. Moderate-to-severe MASLD was independently associated with an increased risk of CAC 1-299 [OR 2.30 (1.21-4.36)], CAC ≥ 300 [OR 4.93 (1.46-16.59)], and single-vessel CAC [OR 2.03 (1.03-4.00)]. Mild MASLD [OR 2.47 (1.20-4.21)], moderate-to-severe MASLD [OR 3.74 (1.76-7.93)], and CKD stage 2 [OR 2.27 (1.26-4.08)] were independently associated with increased multivessel CAC risk. Liver fat content showed a dose-response association with CAC burden. Subgroup analysis revealed that MASLD and CKD increased CAC risk in male but not female patients, with menopause significantly modifying LKMH's effect.

LKMH's impact on CAC burden is significantly influenced by liver fat content, eGFR, sex, and menopause, suggesting that MASLD, CKD, sex, and reproductive status should be integrated into CAC risk prediction models.

Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of liver disease with adverse outcomes. Manipulating interorgan communication is considered a promising strategy for managing metabolic disease, including steatohepatitis. Here, we report that remote limb ischemic conditioning (RIC), a clinically validated therapy for distant organ protection by transient muscle ischemia, significantly alleviated steatohepatitis in different mouse models. The beneficial effect of limb ischemic conditioning was mediated by muscle-to-liver transfer of small extracellular vesicles (sEVs) and their cargo microRNAs, leading to elevation of miR-181d-5p in the liver. Hepatic miR-181d-5p overexpression faithfully mirrored the molecular and histological benefits of limb ischemic conditioning by suppressing nuclear receptor 4A3 (NR4A3). Furthermore, circulating EVs from human volunteers undergoing limb ischemic conditioning improved steatohepatitis and transcriptomic perturbations in primary human hepatocytes and animal models. Our data underscore the translational potential of limb ischemic conditioning for steatohepatitis management and extend our understanding of muscle-liver crosstalk.

Previous research studies have linked the systemic immune inflammation index (SII), derived from a complete blood count, to metabolic dysfunction-associated steatotic liver disease (MASLD). However, evidence on the relationship between longitudinal changes in SII and MASLD remains limited. This study aimed to explore distinct SII trajectories and their association with MASLD incidence.

A longitudinal study analyzed 25,600 individuals who underwent periodic health assessments at a Dalian City hospital between 2014 and 2023. MASLD was diagnosed via ultrasound. The SII was calculated using the formula SII = (platelet count × neutrophil count) / lymphocyte count. Group-based trajectory modeling was used to identify SII trajectories, and restricted cubic spline (RCS) analysis was employed to assesse the dose-response relationship. Stratified analyses and sensitivity analyses were also conducted.

Three SII trajectories were identified: "low stable" (50.6%), "moderate stable" (35.1%), and "high stable" (8.9%). After adjustments, the hazard ratios (HR) for MASLD incidence were 1.118 (95% CI: 1.057-1.182, P<0.001) for the "moderate stable" group and 1.284 (95% CI: 1.172-1.408, P<0.001) for the "high stable" group. These associations persisted after adjusting for lifestyle factors. A significant non-linear relationship between SII and MASLD risk was found in both the overall population and among different genders. Subgroup and sensitivity analyses consistently confirmed these findings.

Elevated SII levels are significantly associated with an increased risk of MASLD, particularly among individuals under 45 and women. Regular SII monitoring may improve risk stratification and facilitate targeted prevention strategies for those at higher risk of MASLD.

Fatty liver hemorrhage syndrome (FLHS) has become one of the major factors leading to the death of laying hen in caged egg production. FLHS is commonly associated with lipid peroxidation, hepatocyte injury, decreased antioxidant capacity, and inflammation. However, there are limited evidences regarding the preventive effect of Lactiplantibacillus plantarum on FLHS in laying hens and its mechanisms. Our previous results showed that Lp. plantarum FRT4 alleviated FLHS by regulating lipid metabolism, but did not focus on its antioxidant and anti-inflammatory functions and mechanisms. Therefore, this study aimed to investigate the preventive mechanisms of Lp. plantarum FRT4 in alleviating FLHS, with a focus on its role in antioxidant activity and inflammation regulation.

Supplementation with Lp. plantarum FRT4 enhanced the levels of T-AOC, T-SOD, and GSH-Px, while reducing the levels of TNF-α, IL-1β, IL-8, and NLRP3 in the liver and ovary of laying hens. Additionally, Lp. plantarum FRT4 upregulated the mRNA expressions of SOD1, SOD2, CAT, and GPX1, downregulated the mRNA expressions of pro-inflammatory factors IL-1β, IL-6, and NLRP3, and upregulated the mRNA expressions of anti-inflammatory factors IL-4 and IL-10. Lp. plantarum FRT4 improved the structure and metabolic functions of gut microbiota, and regulated the relative abundances of dominant phyla (Bacteroidetes, Firmicute, and Proteobacteria) and genera (Prevotella and Alistipes). Additionally, it influenced key KEGG pathways, including tryptophan metabolism, amino sugar and nucleotide sugar metabolism, insulin signaling pathway, FoxO signaling pathway. Spearman analysis revealed that the abundance of microbiota at different taxonomic levels was closely related to antioxidant enzymes and inflammatory factors. Furthermore, Lp. plantarum FRT4 modulated the mRNA expressions of related factors in the FoxO/TLR-4/NF-κB signaling pathway by regulating gut microbiota. Moreover, the levels of E2, FSH, and VTG were significantly increased in the ovary after Lp. plantarum FRT4 intervention.

Lp. plantarum FRT4 effectively ameliorates FLHS in laying hens. This efficacy is attributed to its antioxidant and anti-inflammatory properties, which are mediated by modulating the structure and function of gut microbiota, and further intervening in the FoxO/TLR-4/NF-κB signaling pathway. These actions enhance hepatic and ovarian function and increase estrogen levels. Video Abstract.

The steatosis, activity, and fibrosis (SAF) score is a histological scoring system developed by the European Association for the Study of the Liver to evaluate liver biopsy samples in cases of non-alcoholic fatty liver disease (NAFLD). Based on histopathological results and SAF scores, NAFLD patients were categorized into mild, moderate, and severe groups. We compared the differences between these groups and identified the risk factors influencing lesion severity.

We gathered data from 539 NAFLD patients who underwent percutaneous liver biopsy confirmation at Beijing Ditan Hospital between January 2018 and December 2022. All biopsies were graded according to the SAF scoring system, and the severity of the disease was classified as mild, moderate, or severe. We compared the differences in gender, age, BMI, history of diabetes, history of hypertension, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum cholesterol levels, and other factors among NAFLD patients with varying degrees of disease severity. Additionally, we explored the risk factors that influenced the severity of lesions.

A total of 539 patients were enrolled in this study, with ages ranging from 6 to 79 years. Among them, there were 325 men and 214 women in an average age of 39 ± 13 years. The patients were divided into three groups based on disease severity: mild NAFLD group (162 cases), moderate NAFLD group (210 cases), and severe NAFLD group (167 cases). The results showed significant differences between the three groups in terms of age composition, high-calorie diet, family history of hypertension, ALT, AST, GGT, total bile acids, cholinesterase, glycosylated albumin, blood glucose, uric acid, type III procollagen, serum human laminin, liver stiffness, and hepatic steatosis.

BMI, uric acid, AST, type III procollagen, liver stiffness, and hepatic steatosis play critical roles in the progression of NAFLD and contribute to high pathological SAF scores in NAFLD patients.