Search Results (1,256)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disorder shaped by interorgan crosstalk: dynamic, bidirectional communication through which the liver and endocrine organs, gut, adipose tissue, brain, kidney, skeletal muscle, bone, and heart exchange signals to coordinate metabolism, immunity, and tissue homeostasis. Across these axes, neural circuits, hormones, cytokines, adipokines, hepatokines, myokines, osteokines, bile acids, microbial metabolites, lipids, extracellular vesicles, and microRNAs integrate nutrient handling, insulin action, immunity, mitochondrial function, and tissue remodeling. Perturbation of these networks converts physiological homeostasis into self-reinforcing loops of substrate overflow, endocrine dysregulation, dysbiosis, inflammation, and fibrogenesis, while hepatic dysfunction propagates renal, neurocognitive, cardiometabolic, and musculoskeletal complications. This framework helps explain why individuals with comparable steatosis show divergent trajectories of metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, extrahepatic disease, and treatment response. It also highlights tractable points of intervention, including restoration of adipose buffering, modulation of gut microbial and bile-acid signaling, correction of endocrine drivers, preservation of muscle and bone, and integrated cardio–kidney–liver risk reduction across different disease stages and clinical phenotypes. We argue that precision hepatology should move beyond isolated assessment of liver fat and fibrosis towards multidimensional phenotyping of dominant crosstalk mechanisms. Longitudinal multi-omic studies and trials incorporating outcomes across organs are now required to distinguish causal signals from disease correlates, define clinically actionable endotypes, and test whether targeting one node can restore durable metabolic and functional resilience throughout the interconnected MASLD network, while improving patient-centered outcomes across the disease course. Full article

Background/Objectives: Insulin clearance is a key determinant of circulating insulin availability, but its diurnal variation and relationship with circadian metabolic programs in metabolic dysfunction associated steatotic liver disease (MASLD) remain unclear. This study aimed to explore diurnal insulin clearance in humans and examine associated metabolic gene signatures in MASLD. Methods: A single-subject pilot assessment was performed to explore daytime-nighttime differences in insulin clearance rate (ICR) surrogate index, followed by evaluation using public hyperinsulinemic-euglycemic clamp datasets from healthy individuals and patients with MASLD. Public circadian transcriptomic datasets, spatial transcriptomic data, and a time course high-fat diet (HFD)-induced mouse dataset were integrated. A predefined panel of insulin clearance-related and circadian genes, including carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), insulin receptor (INSR), insulin-degrading enzyme (IDE), clock circadian regulator (CLOCK), basic helix-loop-helix ARNT like 1 (BMAL1), nuclear receptor subfamily 1 group D member 1/2 (NR1D1/2), period circadian regulator 1/2 (PER1/2), and cryptochrome 1/2 (CRY1/2), was analyzed. Results: The pilot assessment showed higher nighttime than daytime ICR, and independent clamp datasets showed a similar pattern in healthy individuals. In MASLD, nighttime ICR remained relatively higher, whereas overall insulin clearance was reduced compared with controls. Human blood-based circadian transcriptomic datasets identified rhythmic expression patterns of selected genes involved in insulin clearance and circadian regulation, including CEACAM1, CLOCK, NR1D1, CRY1, PER1, and PER2. MASLD liver datasets showed reduced expression of insulin clearance-related and circadian genes, while spatial transcriptomics suggested altered lobular distribution of these signatures. In HFD mouse model, rhythmic expression of selected genes was attenuated. Conclusions: These integrative findings suggest that insulin clearance may exhibit diurnal variation and may be linked to circadian metabolic gene signatures across systemic and hepatic datasets in MASLD. Larger controlled human studies are needed to validate the temporal regulation of insulin clearance and its metabolic relevance. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and heart failure (HF) frequently coexist within a shared cardiometabolic environment, yet their mitochondrial abnormalities are stage- and phenotype-dependent rather than uniform. In MASLD, mitochondrial adaptation evolves from increased oxidative metabolism in early steatosis toward impaired respiratory flexibility, oxidative stress, and defective quality control with disease progression, whereas the failing myocardium develops reduced energetic reserve and altered substrate utilization. These organ-specific disturbances can modify mitochondria-linked metabolites, mitochondrial damage-associated molecular patterns, stress-responsive endocrine mediators, and extracellular vesicle-associated mitochondrial cargo. However, similar mitochondrial abnormalities or circulating signals in the liver and heart do not by themselves establish direct inter-organ communication. This review distinguishes shared systemic drivers and organ-intrinsic mitochondrial stress from source-resolved cardio-hepatic signaling, highlighting hepatic ketogenesis, fibroblast growth factor 21 (FGF21), mitochondrial DNA (mtDNA)-dependent inflammatory pathways, and extracellular vesicle-mediated cargo transfer as mechanistically distinct examples with different levels of evidence. We further discuss biomarker limitations, HF-related hemodynamic liver injury, and therapeutic strategies ranging from established cardiometabolic unloading to emerging mitochondria-centered interventions. A stage-, phenotype-, and source-resolved framework may improve interpretation of mitochondrial signals and guide future mechanistic and translational studies in the MASLD–HF overlap. Full article

Background/Objectives: Aerobic exercise is widely recognized as an effective non-pharmacological strategy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effects of different aerobic exercise loads on MASLD-associated hepatic iron dyshomeostasis and ferroptosis, as well as the underlying mechanisms, remain unclear. This study aimed to compare the effects of different aerobic exercise loads on HFD-induced MASLD and to explore whether exercise-induced improvements in hepatic lipid accumulation are associated with changes in iron homeostasis and ferroptosis-related markers. Methods: Forty male Sprague-Dawley rats were randomly assigned to a normal-fat diet group (NFD, n = 8) or a high-fat diet group (HFD, n = 32). After 8 weeks of HFD feeding, HFD-fed rats were further allocated to four groups: HFD control, low-load aerobic exercise (LEH), moderate-load aerobic exercise (MEH), and high-load aerobic exercise (HEH) (n = 8 per group). The exercise intervention lasted for 8 weeks. At the end of the intervention, blood and liver samples were collected to assess metabolic parameters, hepatic steatosis, iron homeostasis, oxidative stress, ferroptosis-related markers, and the IL-6/JAK2/STAT3-hepcidin pathway. Results: All three exercise regimens partially improved hepatic lipid metabolic abnormalities, iron accumulation, and oxidative stress-related liver injury in MASLD rats. These effects were accompanied by suppression of the IL-6/JAK2/STAT3-hepcidin pathway, increased hepatic FPN1 mRNA expression and decreased DMT1 mRNA expression, increased GPX4 expression, reduced PTGS2 expression, and improved antioxidant capacity. MEH and HEH generally produced larger changes than LEH, with HEH showing the most consistent overall response across the measured outcomes. Conclusions: Aerobic exercise attenuated HFD-induced MASLD in association with improved hepatic iron handling and a lower burden of ferroptosis-related molecular alterations. Because ferroptosis-specific rescue experiments and pathway inhibitors were not used, these findings are associative. Within the tested conditions, the 90-min protocol produced the most consistent response, but further dose–response studies are required before translation to humans. Full article

Objectives: This study focuses on exploring the mechanism by which Schisandrin B (Sch B) regulates metabolic dysfunction-associated steatotic liver disease (MASLD) mice induced by a high-fat methionine–choline-deficient (MCD) diet through the activation of peroxisome proliferator-activated receptor γ (PPARγ). Methods: Male C57BL/6 mice were fed a high-fat MCD diet for 8 weeks to establish a mouse MASLD model, and the effects of Sch B on MASLD and the mechanisms were investigated. PPARγ overexpression (OE) was induced by adeno-associated virus (AAV) administration via intrahepatic portal vein injection in mice, and a negative control (NC-OE) was also established. Body weight; wet liver weight; hepatic index; serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β); and hepatic triglyceride (TG) levels were measured in the mice. The histopathology and lipid deposition were observed by hematoxylin and eosin (H&E) staining and Oil Red O staining, while the fibrosis was assessed using Masson staining. Western blot was employed to detect the expression levels of PPARγ, sterol regulatory element-binding protein 1c (SREBP-1c), carnitine palmitoyltransferase 1A (CPT1A), transforming growth factor β1 (TGF-β1), α-smooth muscle actin (α-SMA), collagen type I (collagen I), Smad family members 2/3 (Smad2/3), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase 1/2 (ERK1/2), along with the phosphorylation activation status of these kinases. Results: It was confirmed that Sch B caused effects similar to those induced by PPARγ overexpression, reducing the hepatic index, AST, and ALT levels while alleviating lipid accumulation and fibrosis; and upregulating PPARγ and CPT1A while inhibiting SREBP-1c; and the phosphorylation of the TGF-β/Smad and MAPK pathways were involved in the mechanisms. Conclusions: Sch B can alleviate high-fat MCD-induced MASLD by activating PPARγ in mice. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive liver lipids and metabolic imbalance. Thyroid hormone receptor alpha (THRA) is essential for liver lipolysis; however, its transcription function is dependent on successful nuclear localization. Since natural polyphenols are known to modulate THRA activity, making them potential candidates for MASLD management, their roles in THRA nuclear trafficking have not been elucidated. In this study, an integrative computational method was utilized to investigate the impact of polyphenol binding on THRA nuclear import. Protein–protein docking simulations suggested that polyphenol binding may augment the interaction of THRA and importin-α, while importin-7 was predicted to be essential for basal transport. In conclusion, our findings showed that polyphenol binding could potentially support THRA nuclear import, thus potentially implicating a new process in MASLD. Full article

Background: Coronary artery disease (CAD) frequently coexists with cardiometabolic and hepatic dysfunction, yet accessible biomarkers capturing this convergence remain limited. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been proposed as an integrative marker of endothelial and metabolic impairment. This study aimed to evaluate the diagnostic value of ADMA as a unified biomarker of endothelial dysfunction (ED), cardiometabolic burden, and metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with stable CAD. Methods: In this cross-sectional study, 298 patients with stable CAD (functional class I–II) were enrolled at two centers in Tashkent, Uzbekistan. Serum ADMA was measured by ELISA; endothelial function was assessed by flow-mediated dilation (FMD). Associations between ADMA, metabolic indices, MASLD, and CAD severity were analyzed. Results: MASLD was present in 48.3% of CAD patients and metabolic syndrome (MetS) in 62.4%. Patients with MASLD had more severe angina, reduced exercise tolerance, and greater ischemic burden than those without. ADMA correlated positively with BMI, waist circumference, TyG index, and TG/HDL-C ratio (all p < 0.001), with the TyG index showing the strongest predictive value for elevated ADMA (AUC 0.76). A dose–response relationship linked rising ADMA to worsening FMD; concentrations >160 ng/mL conferred markedly increased odds of overt ED (OR 114.8, 95% CI 6.8–1935.0) and were disproportionately prevalent in patients with MASLD (93.1% vs. 61.0%, p < 0.001). Conclusions: ADMA is markedly elevated in stable CAD and closely tracks endothelial, metabolic, and hepatic dysfunction. These cross-sectional associations position ADMA as a promising, hypothesis-generating integrative biomarker; prospective longitudinal studies are needed before its use for risk stratification in primary and cardiovascular care can be recommended. Full article

Background: Endoscopic sleeve gastroplasty (ESG) is a minimally invasive option for weight reduction, but its effect on metabolic syndrome (MetS) and metabolic dysfunction-associated steatotic liver disease (MASLD) is less well characterized. Methods: Following PRISMA, we searched five databases to November 2025 (PROSPERO CRD420261283041) for adults with obesity undergoing ESG with ≥6-month follow-up. Continuous outcomes were pooled as mean differences (MDs) using DerSimonian–Laird random-effects models with Hartung–Knapp–Sidik–Jonkman sensitivity analysis. As MetS resolution was inconsistently defined, the primary outcome was post hoc operationalised as change in individual MetS components. Results: Of 858 records, 12 studies (4452 patients; two randomised) were included. At 12 months, ESG was associated with lower glycated haemoglobin (MD −0.33%), HOMA-IR (MD −3.52), triglycerides (MD −25.56 mg/dL), low-density lipoprotein cholesterol (MD −6.94 mg/dL), alanine aminotransferase, and non-invasive steatosis/fibrosis indices; aspartate aminotransferase did not change significantly. Total body weight loss was 16.54% at 12 months and 14.21% at 36 months. Liver stiffness (two studies, differing windows) is described narratively, not pooled. Heterogeneity was often substantial; certainty was low to very low. Conclusions: ESG was associated with metabolic and hepatic improvements alongside substantial weight loss; a weight-independent hepatic effect cannot be established, and randomised trials with histological endpoints are needed. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become an important public health burden. However, the association of food insecurity with MASLD remains understudied. Accordingly, this study analyzed the association between food insecurity and MASLD in Korean adults. Methods: We used data from 12,697 adults drawn from a nationally representative survey. Food insecurity was determined using the Household Food Security Survey Module. Food insecurity was categorized into no, mild, and moderate-to-severe. MASLD was determined by a hepatic steatosis index >36 in conjunction with at least one metabolic abnormality. The association was analyzed using logistic regression. Results: Among the participants, 95.5%, 3.7%, and 0.8% were classified as having no, mild, and moderate-to-severe food insecurity, respectively. Compared to no food insecurity, the odds ratios (ORs) (95% CIs [confidence intervals]) for MASLD were 1.40 (1.09–1.81) for mild food insecurity and 1.76 (1.06–2.90) for moderate-to-severe food insecurity. Additionally, the continuous HFSSM score was directly associated with MASLD (OR: 1.07; 95% CI: 1.02–1.12). Conclusions: This nationally representative study showed that, compared with no food insecurity, mild and moderate-to-severe food insecurity were associated with MASLD. Full article

Background: Early detection of hepatocellular carcinoma (HCC) is critical for improving patient outcomes; however, ultrasound-based surveillance has limited sensitivity and variable performance across patient populations. We evaluated the performance of a multitarget HCC blood test (mt-HBT), incorporating methylated DNA markers, alpha-fetoprotein (AFP), and patient sex, across clinically relevant subgroups. Methods: We performed a subgroup analysis of a multicenter, prospective case-control study that included 159 patients with early-stage HCC (Barcelona Clinic Liver Cancer Stage 0/A) and 649 control patients with cirrhosis or chronic hepatitis B without HCC. The mt-HBT combined methylated HOXA1, TSPYL5, and B3GALT6 markers with AFP and sex. Sensitivity and specificity were evaluated overall and according to age, sex, obesity, liver disease etiology, Child Pugh class, and tumor size. Performance was compared with AFP and GALAD. Results: Overall sensitivity and specificity of mt-HBT for early-stage HCC detection were 76.7% (95% CI, 69.6–82.6) and 87.5% (95% CI, 84.8–89.8), respectively. Sensitivity was significantly higher than that of AFP (35.2%, p < 0.001) and comparable to that of GALAD (78.6%, p = 0.56), whereas specificity was lower than that of AFP (98.5%, p < 0.001) but higher than that of GALAD (76.9%, p < 0.001). Sensitivity was maintained across key subgroups, including patients with obesity (68.9%), Child Pugh B cirrhosis (75.0%), hepatitis C (80.0%), hepatitis B (72.2%), alcohol-associated liver disease (80.5%), and metabolic dysfunction-associated steatotic disease (69.0%) (all p > 0.05 between subgroups). Specificity exceeded 80% in all examined populations and was significantly higher in women than in men (92.5% vs. 83.9%, p < 0.001). Sensitivity increased with tumor size, ranging from 60.0% for tumors < 2 cm to 100% for tumors > 5 cm. Conclusions: The mt-HBT demonstrated robust, consistent performance for early-stage HCC detection across diverse patient populations, including subgroups in which ultrasound surveillance commonly underperforms. These findings support the prospective validation of mt-HBT as a blood-based surveillance strategy for HCC. Full article

Glucose and lipid metabolism disorders are closely associated with type 2 diabetes mellitus (T2DM), obesity, hyperlipidemia, and metabolic dysfunction-associated steatotic liver disease (MASLD). Gynura divaricata (L.) DC., traditionally consumed as both a food and folk medicine, has attracted increasing attention for its potential regulatory effects on glucose and lipid metabolism. Existing in vitro and in vivo studies suggest that G. divaricata extracts and candidate bioactive constituents, including flavonoids, polysaccharides, phenolic acids, and peptides, may improve metabolic phenotypes such as hyperglycemia, dyslipidemia, and insulin resistance. These effects may involve the regulation of intestinal carbohydrate hydrolysis, insulin signaling, gut microbial homeostasis, pancreatic β-cell function, lipid metabolism, oxidative stress, and chronic inflammation. However, human evidence remains limited, and most studies have investigated compound formulations or combined interventions, which are insufficient to establish the clinical efficacy of G. divaricata as a standalone preparation. This review summarizes the major bioactive constituents of G. divaricata, reviews the current evidence for its glucose-lowering and lipid-regulating effects and related antioxidant and anti-inflammatory mechanisms, and discusses the limitations of existing research. This study aimed to provide a reference for elucidating the mechanisms by which G. divaricata regulates glucose and lipid metabolism and for its future clinical translation. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2DM) have been associated with dyslipidemia. This study aimed to investigate the association between lipid values and markers of hepatic steatosis and fibrosis in patients with T2DM. Methods: This is a post hoc analysis of the AleCardio randomized controlled trial in patients with T2DM and recent acute coronary syndrome. Risk of liver steatosis was estimated with the Hepatic Steatosis Index (HSI), risk of liver fibrosis with the NAFLD Fibrosis Score (NFS). Results: Of 7226 participants, 526 were untreated with lipid-lowering medication and formed the analysis cohort. Mean age was 61 ± 10 years, and body mass index (BMI) was 28.5 ± 5.8 kg/m². A total of 75% of individuals had an HSI score > 36, associated with high risk of liver steatosis, elevated NFS scores > 0.67, associated with high risk of liver fibrosis, were present in 15%. Patients with elevated HSI scores had higher BMI, HOMA IR, triglycerides, remnant cholesterol, and lower high-density lipoprotein compared to those with lower scores. Patients with elevated NFS scores had greater BMI and HOMA IR, and had lower triglycerides, remnant cholesterol, and apolipoprotein B in linear regression analyses. Conclusion: Patients with T2DM, cardiovascular disease, and blood-based indices suggesting liver steatosis or fibrosis differed significantly with respect to the lipid profile. An elevated HSI score, suggesting steatosis, was associated with dyslipidemia, an elevated NFS score, suggesting fibrosis, was not. A possible explanation for the latter findings is reduced very-low-density lipoprotein (VLDL-C) synthesis or secretion accompanying advanced hepatocellular dysfunction. Full article

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated steatotic liver disease, affects approximately 3–5% of the global population and lacks effective therapies. This study examined the impact of near-thermoneutral housing on MASH progression in mice fed a fast-food diet (FFD) enriched in fat, sucrose, and cholesterol. Male C57BL/6J mice were housed under standard (22 °C) or near-thermoneutral (27 °C) conditions and fed chow or FFD for 20 weeks. Body weight, composition, liver pathology, hepatic gene expression, plasma lipids, and adipose thermogenic and inflammatory markers were assessed. FFD increased body weight, fat mass, and lean mass at both temperatures. Near-thermoneutral housing markedly exacerbated MASH in FFD-fed mice, with increased steatosis, fibrosis, inflammation, and elevated liver enzymes. Hepatic lipogenic and fibrosis-related gene expression was upregulated, alongside higher plasma total cholesterol and very-low-density lipoprotein levels. Near-thermoneutral housing also impaired brown adipose tissue thermogenesis, reducing uncoupling protein 1 and other thermogenic genes, and modestly altered inguinal white adipose tissue inflammation and thermogenic signaling. These findings demonstrate that near-thermoneutral housing accelerates MASH progression, accompanied by increased hepatic lipid accumulation, fibrosis, and inflammation and reduced adipose thermogenic signatures. These findings identify environmental temperature as a critical modifier of MASH pathophysiology and suggest that enhancing adipose thermogenesis may offer therapeutic potential. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) requires practical and inexpensive tools for risk stratification. We investigated whether the red cell distribution width (RDW), a routinely available hematologic parameter, predicts adverse clinical outcomes, using data from 352,623 UK Biobank participants, including 165,700 individuals with MASLD. RDW was analyzed as both a continuous and categorical variable using Cox proportional hazards models, restricted cubic splines, inverse probability treatment weighting, landmark, competing risk, and mediation analyses. Over a median follow-up of 13.6 years, each 1% increase in RDW was independently associated with higher risks of all-cause mortality (hazard ratio [HR] 1.14), cardiovascular disease (HR 1.07), cerebrovascular disease (HR 1.07), and chronic kidney disease (HR 1.09) (all p < 0.001). These associations remained consistent across multiple sensitivity analyses, and conventional biomarkers explained a modest proportion of the observed associations. Oxidative stress, together with other systemic processes affecting erythrocyte homeostasis, represents one potential mechanism underlying these associations. Higher RDW was independently associated with adverse clinical outcomes after adjustment for routine liver and metabolic biomarkers, supporting its potential value as a readily available prognostic marker in MASLD. Full article