Search Results (4,264)

Objectives: The FibroScan–aspartate transaminase (AST) score (FAST score) is a hybrid biomarker combining ultrasound and blood test data for identifying nonalcoholic steatohepatitis (NASH). This study aimed to assess the feasibility of using quantitative ultrasound (QUS) biomarkers related to hepatic steatosis for NASH detection and to compare their diagnostic performance with the FAST score. Methods: A total of 137 participants, comprising 71 individuals with NASH and 66 with non-NASH (including 49 normal controls), underwent FibroScan and ultrasound exams. QUS imaging features (Nakagami parameter m, homodyned-K parameter μ, entropy H, and attenuation coefficient α) were extracted from backscattered radiofrequency data. A weighted QUS parameter based on m, μ, H, and α was derived via linear discriminant analysis. NASH was diagnosed based on liver biopsy findings using the nonalcoholic fatty liver disease activity score (NAS). Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUROC) and compared with the FAST score using the DeLong test. Separation metrics, including the complement of overlap coefficient, Bhattacharyya distance, Kullback–Leibler divergence, and silhouette score, were used to assess inter-group separability. Results: All QUS parameters were significantly elevated in NASH patients (p < 0.05). AUROC values for individual QUS features ranged from 0.82 to 0.91, with the weighted QUS parameter achieving 0.91. The FAST score had the highest AUROC (0.96), though differences with the weighted QUS and homodyned-K parameters were not statistically significant (p > 0.05). Separation metrics ranked the FAST score highest, closely followed by the weighted QUS parameter. Conclusions: QUS biomarkers can be repurposed for NASH detection, with the weighted QUS parameter offering diagnostic accuracy comparable to the FAST score and serving as a promising, blood-free alternative. Full article

RNA-binding proteins (RBPs) play essential roles in all major steps of RNA processing. Genetic studies in human and mouse models support that many RBPs are crucial for maintaining homeostasis in key tissues/organs, but to what extent the function of RBPs is conserved between humans and mice is not clear. Our recent study using a chimeric humanized liver mouse model found that knocking down human HuR in human hepatocytes resulted in a broad upregulation of human genes involved in fatty acid catabolism. This regulation is human-specific, as the knocking down of mouse HuR in the liver of traditional mouse models did not show these effects. To further study this human-specific role of HuR, we co-overexpressed HuR with PPARα, a master transcription factor that promotes fatty acid catabolism, in cultured cells. We found that HuR suppressed the expression of PPARα-induced fatty acid catabolism genes in human cells but not in mouse cells. We provide evidence supporting that the human-specific suppressive effect of HuR is independent of PPARα expression or location. The regulatory effects of HuR are also independent of its role in regulating mRNA stability. Using the human HMGCS2 gene as an example, we found that the suppressive effect of HuR cannot be explained by decreased promoter activity. We further provide evidence supporting that HuR suppresses the pre-mRNA processing of HMGCS2 gene, leading to accumulated intron/pre-mRNA expression of HMGCS2 gene. Furthermore, overexpression of HuR blocked and knocking down of HuR sensitized PPARα agonist-induced gene expression. By analyzing published RNA-seq data, we found compromised pre-mRNA processing for fatty acid catabolism genes in patients with fatty liver diseases, which was not observed in mouse fatty liver disease models. Our study supports the model that HuR suppresses the expression of fatty acid catabolism genes by blocking their pre-mRNA processing, which may partially explain the mild effects of PPARα agonists in treating fatty liver diseases in humans as compared with studies in mice. Full article

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a major global health concern associated with insulin resistance, metabolic syndrome, and cardiovascular morbidity. Early identification of at-risk individuals through simple, non-invasive methods is essential, particularly in working populations. Objectives: This study aimed to assess and compare the diagnostic accuracy of four widely used anthropometric and metabolic indicators—body mass index (BMI), waist-to-height ratio (WtHR), triglyceride–glucose index (TyG), and waist–triglyceride index (WTI)—in identifying individuals at risk of metabolic-dysfunction-associated steatotic liver disease (MASLD), as determined by the Fatty Liver Index (FLI) and the Lipid Accumulation Product (LAP), within a large sample of Spanish workers. Methods: A cross-sectional analysis was performed on data from 386,924 Spanish employees aged between 18 and 69 years. Standardized anthropometric and laboratory measurements were obtained as part of routine occupational medical examinations conducted from 2021 to 2023. The presence of NAFLD was inferred using two validated surrogate markers: FLI and LAP. Receiver operating characteristic (ROC) curves and area under the curve (AUC) values were used to assess the discriminatory ability of each index, stratified by sex. Results: WTI and TyG demonstrated the highest diagnostic accuracy for both FLI- and LAP-defined NAFLD, with AUC values >0.95 in both sexes. WTI showed the best overall performance, followed closely by TyG. WtHR outperformed BMI but was less accurate than the metabolic indices. Sex-stratified analyses confirmed consistent patterns, with slightly higher AUCs for TyG and WTI in women. BMI consistently yielded the lowest discriminatory performance. Conclusions: WTI and TyG are superior to BMI and WtHR for non-invasive screening of MASLD in occupational settings. Their simplicity, low cost, and strong predictive value support their integration into routine workplace health surveillance. Sex-specific thresholds and prospective validation are warranted to enhance clinical application. Full article

Lean metabolic dysfunction-associated steatotic liver disease (lean MASLD) challenges longstanding views that link hepatic steatosis primarily to obesity. Emerging as a distinct and under-recognized clinical entity, lean MASLD affects individuals with a normal body mass index (BMI), yet carries risks of cardiovascular disease, hepatocellular carcinoma, and liver-related mortality comparable to obesity-associated MASLD. The absence of overt metabolic dysfunction complicates diagnosis, revealing critical limitations in current screening frameworks centered on BMI. This review synthesizes evolving clinical insights and epidemiological trends in lean MASLD, and delineates its unique pathophysiological mechanisms. Recent advances in metabolomics have uncovered disease-specific disruptions in lipid and amino acid metabolism, bile acid signaling, and gut microbiota-derived metabolites. By integrating evidence from metabolic, genetic, and epigenetic domains, we identified promising biomarkers, and therapeutic targets that may support earlier detection and precision-guided treatment strategies. Full article

Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant metabolic disorder in modern poultry production, particularly affecting high-yielding laying hens. This condition compromises bird welfare, productivity, and economic sustainability within commercial farming systems. This narrative review provides a comprehensive overview of the underlying mechanisms through which hepatic lipid accumulation, metabolic dysfunctions, hormonal imbalances, genetic susceptibilities, and environmental stress contribute to the development of NAFLD. The multifactorial nature of NAFLD is explored through a critical assessment of the literature, highlighting the influence of diet composition, management practices, and physiological demands associated with intensive egg production. Emphasis is placed on recent advancements in nutritional modulation, selective breeding, and housing improvements aimed at prevention and mitigation of NAFLD. Furthermore, the review identifies key research gaps, including limited understanding of epigenetic influences and the long-term efficacy of intervention strategies. An integrative framework is advocated, synergizing genetics, nutrition, and environmental optimization to effectively address the complexity of NAFLD in poultry and supports the development of resilient production systems. The insights presented aims to inform both future research and practical applications for enhancing poultry health and performance. Full article

Background: Fetuin-A, a hepatokine implicated in metabolic regulation, has been associated with both metabolic syndrome and cardiovascular disease. However, its specific role in type 2 diabetes mellitus (T2DM) remains incompletely understood. Objective: This study aimed to investigate the relationship between fetuin-A levels and key components of metabolic syndrome (abdominal obesity, arterial hypertension, hyperglycemia, hypertriglyceridemia and low high-density lipoprotein cholesterol) as well as other cardiovascular risk markers, including metabolic dysfunction-associated fatty liver disease (MAFLD), carotid intima-media thickness (CIMT), and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Methods: A total of 51 patients with T2DM not receiving insulin therapy were enrolled. Participants underwent clinical, biochemical, and imaging evaluations. Hepatic steatosis was assessed via abdominal ultrasonography, and subclinical atherosclerosis was evaluated using CIMT measured with Doppler ultrasonography. Serum fetuin-A was quantified by ELISA. Results: Hepatic steatosis was significantly associated with metabolic syndrome, increased CIMT, and dyslipidemia (elevated total cholesterol, triglycerides, and reduced HDL cholesterol). Although no direct correlation was found between fetuin-A levels and hepatic steatosis, multivariate analysis revealed that fetuin-A concentrations were significantly influenced by total cholesterol and LDL cholesterol levels. Conclusions: Fetuin-A appears to be linked to lipid abnormalities in T2DM and may contribute to cardiovascular risk in this population. These findings support the potential utility of fetuin-A as a biomarker and possible therapeutic target for dyslipidemia management in diabetic patients. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM) share overlapping pathophysiological mechanisms, including insulin resistance and chronic inflammation. Recent evidence suggests that Orosomucoid-2 (ORM2), an acute-phase immunomodulatory protein, may play a role in metabolic regulation; however, its specific involvement in MAFLD remains unclear. This study examined the association between circulating ORM2 levels and the severity of hepatic steatosis, insulin resistance, and T2DM in a cohort of 449 adults. MAFLD was assessed using FibroScan^® with hepatic steatosis categorized by Controlled Attenuation Parameter (CAP) scores, while plasma ORM2 levels were measured via ELISA. Statistical analyses using Spearman correlation and multiple logistic regression revealed that elevated ORM2 levels were significantly correlated with greater hepatic steatosis, insulin resistance, triglycerides, ALT, and hip circumference (p < 0.001). Individuals with severe steatosis (CAP > 290 dB/m) had markedly higher ORM2 levels (312.3 ng/mL) compared to those with normal CAP scores (210.4 ng/mL; p < 0.001). ORM2 was identified as an independent predictor of steatosis severity and after adjusting for several metabolic variables (AOR = 1.005; 95% CI: 1.002–1.007). ROC analysis incorporating ORM2 and metabolic variables demonstrated strong predictive capability for MAFLD (AUC = 0.864, 95% CI: 0.825–0.902). These findings support ORM2 as a promising non-invasive diagnosis for MAFLD, involving only blood sampling without direct invasion of the liver and associated metabolic dysfunction. Full article

Specialized herbivores like giant pandas (Ailuropoda melanoleuca), red pandas (Ailurus fulgens), and bamboo rats, which primarily consume bamboo, are at risk of nutrient deficiencies, particularly vitamin B12 (VB12), potentially leading to cardiovascular diseases. This study explored the effects of VB12 supplementation on cardiovascular health in silver star bamboo rats (Rhizomys pruinosus). We first conducted a comprehensive genome annotation of R. pruinosus, laying the foundation for in-depth evolutionary studies. Comparative transcriptomic analysis revealed that genes related to cardiovascular disease (e.g., Sgcb, Adcy2, Itga1, Itgb8, Ifng, and Gpc1) were upregulated in the livers of R. pruinosus compared to carnivorous and omnivorous rodents, indicating a higher cardiovascular disease risk. After 60 days of VB12 supplementation, liver transcriptome analysis revealed significant improvements in cardiovascular health markers, including reduced cholesterol synthesis and enhanced fatty acid metabolism. Serum biochemical assays indicated that VB12 supplementation led to reduced homocysteine levels, decreased low-density lipoprotein (LDL)-to-high-density lipoprotein (HDL) ratios, and increased the apolipoprotein A-to-apolipoprotein B ratio. These findings suggest that VB12 may mitigate cardiovascular disease risk and could be considered in the dietary management of specialized bamboo-eating species. Our study provides valuable insights into disease prevention strategies for these species with similar dietary habits. Full article

Background/Objectives: The incidence of metabolic-dysfunction-associated steatotic liver disease (MASLD) is on the rise worldwide. The purpose of this paper is to review the current and emerging trends in the management and treatment of this condition. Methods: A comprehensive literature review was conducted using PubMed and GoogleScholar, focusing on articles published within the last ten years. Results: As the incidence of MASLD rises worldwide, it is becoming ever more important to call attention to disease prevention and progression. Although weight loss, diet, and exercise play a major role, certain therapies including GLP-1 receptor agonists, resmetirom, lanifibranor, and FGF-3 analogs are showing promise when treating patients with MASLD. As more drugs become available, it will be important to note how these medications change the global outlook of this disease. Conclusions: Overall, the treatment landscape of MASLD is rapidly changing. Several phase 3 trials have revealed promising data when it comes to improving liver fibrosis and histology. This shift in treatment will provide new hope for patients and clinicians when treating this challenging disease. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a significant global public health issue, affecting approximately 25% of the population and currently offering limited treatment options. Trimetazidine (TMZ) serves as a metabolic modulator that shifts cellular energy metabolism from fatty acid oxidation to glucose oxidation, thereby providing a novel therapeutic strategy aimed at addressing the underlying metabolic dysfunctions that contribute to the pathogenesis of MASLD. Our study aims to assess the efficacy of trimetazidine in improving hepatic steatosis, inflammation, and various metabolic parameters. Methods: In this double-masked, randomized controlled trial, 60 patients with confirmed MASLD diagnoses were randomly assigned in a 1:1 ratio to receive either trimetazidine 20 mg three times daily or a placebo, alongside lifestyle modifications, for 24 weeks. The trial was conducted in accordance with the Declaration of Helsinki and approved by the ethics committees of both participating institutions. We measured changes in hepatic steatosis, non-invasive fibrosis scores, inflammatory markers (including interleukin-6, tumor necrosis factor-alpha, and highly sensitive C-reactive protein), liver enzymes, and lipid profiles at baseline and at the end of the 24 weeks. Results: Hepatic steatosis decreased significantly, with controlled attenuation parameter scores from 352.5 to 302 dB/m in the TMZ group compared to the control (p < 0.001). TNF-α was reduced significantly in the TMZ group compared to the control group (p = 0.001). Fibrosis to AST score decreased from 0.49 to 0.25 in the TMZ group (p < 0.001). Aspartate aminotransferase decreased significantly compared to the control group (p 0.032). Notably, TMZ also imparted cardioprotective benefits, reducing total cholesterol by 14%, LDL by 17% (both p < 0.05), and triglycerides by 16% (p = 0.176). Conclusions: This groundbreaking trial supports the potential of trimetazidine as a promising therapeutic agent for MASLD, indicating substantial improvements in hepatic steatosis, inflammation, and metabolic disturbances. These findings underscore the urgency and importance of further multicenter trials to validate trimetazidine’s efficacy as a disease-modifying therapy for MASLD. Full article

Peroxisomes are cellular organelles involved in multiple metabolic processes, including lipid oxidation, lipid synthesis, and the metabolism of reactive oxygen species. Peroxisomal disorders arise from defects in peroxisomal biogenesis or peroxisomal enzymes. Patients with severe peroxisomal disorders often present with a range of distinctive physical features and congenital malformations, such as neuronal migration defects, renal cysts, and bony stippling in the patellae and long bones. Liver disease has also been reported in some patients with peroxisomal biogenesis disorders, although the exact molecular mechanisms underlying its development remain unclear. Metabolic dysfunction-associated steatotic liver disease (MASLD) is now recognised as one of the most prevalent causes of chronic liver disease globally, due to its widespread incidence and potential for serious complications. This review aims to highlight the possible involvement of peroxisomal defects in the pathogenesis of MASLD. Full article

Background/Objectives: Acetyl-CoA carboxylase (ACC) inhibitors block the initial step of de novo lipogenesis and potentially ameliorate liver pathology in nonalcoholic fatty liver disease (NAFLD). However, increased expression of glycerol-3-phosphate acyltransferase 1 resulting from reduced PUFA may cause hypertriglyceridemia. This systematic review and meta-analysis assessed the efficacy and safety of dual ACC 1/2 inhibitors in adult NAFLD patients, either with or without metabolic dysfunction. Methods: Six databases were searched for randomized controlled trials (RCTs). The primary outcomes were changes in liver fat and fibrosis. Study quality was assessed using the RoB 2 tool. Pooled mean differences (MDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a fixed-effects model. Results: Six RCTs comprising 655 participants were included; most had low risk of bias. Interventions included firsocostat, clesacostat, and combined regimens with semaglutide, selonsertib, and cilofexor or ervogastat. Compared with placeo, ACC inhibitor monotherapy significantly reduced liver fat (mean difference [MD]: −48.38; 95% CI: −58.54 to −38.22; p < 0.00001) and ALT (MD: −16.07; 95% CI: −24.97 to −7.17; p = 0.0004) but increased ALP (MD: 11.95; 95% CI: 6.98, to 16.92; p < 0.00001) and GGT levels (MD: 23.90; 95% CI: 12.58 to 35.23; p < 0.0001). Hypertriglyceridemia risk was markedly elevated (odds ratio [OR]: 10.33; 95% CI: 4.93 to 21.65; p < 0.00001). No significant improvement in fibrosis was observed by magnetic resonance elastography. Serious adverse events were infrequent, and overall treatment-emergent adverse events were comparable between groups; however, the incidence of hypertriglyceridemia was consistently more frequent with ACC inhibitors. Conclusions: Dual ACC 1/2 inhibitors reduce hepatic steatosis and ALT levels but do not improve fibrosis. Their consistent association with hypertriglyceridemia raises concerns regarding potential long-term cardiometabolic risks, particularly in NAFLD patients with metabolic dysfunction. Full article

Background/Objectives: Metabolic (dysfunction)-associated steatotic liver disease (MASLD), the hepatic consequence of metabolic syndrome, affects 30% of the global population. Studies in animals and humans investigating the effect of fructose on MASLD present conflicting findings, while in vitro methods often fail to add meaningful evidence due to acute exposures (<72 h) and non-physiological concentrations. This study aimed to determine the effect of fructose on triglyceride (TG) accumulation in HepG2 cells following acute and chronic exposures and assess its effect on the expression of genes related to de novo lipogenesis (DNL). Methods: TG concentration was measured after 48 h in response to fructose (20 mM) or glucose (20 mM), with or without a fatty acid mixture (oleic acid/palmitic acid 110 µM/55 µM), in low (5.5 mM)- and high (25.5 mM)-glucose media. To model chronic exposure, cells were maintained in fructose, glucose, or fatty acids for 28 days and the TG concentration was determined every 7 days. The effect of fructose on DNL regulators (SREBPF1, NR1H3, FASN, and ACACA) was determined using qPCR. Results: Neither fructose nor glucose, with or without fatty acids, changed the TG levels in cells at 48 h and the media glucose concentration had no effect on this result. Similarly, fructose did not increase TG levels after 28 days. While fructose and glucose did not affect key DNL genes at 6 h, the fatty acid mixture reduced FASN by 41%. Conclusions: This study shows that fructose did not significantly impact TG synthesis or DNL gene expression in the HepG2 cell model. Future studies should consider using primary human hepatocytes or more complex in vitro models. Full article

Background/Objectives: Gut microbiota has been implicated in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease (CVD). This study aimed to identify associations between gut dysbiosis and MASLD, regarding body mass index (BMI) and subclinical coronary atherosclerosis (SCA). Methods: We conducted a cross-sectional study of 202 patients with MASLD who had no previous history of CVD. The severity of MASLD was evaluated using a magnetic resonance imaging-based method, and SCA was measured by assessing coronary artery calcification (CAC). Gut microbiota was assessed in fecal specimens using sequencing targeting the V4 region of the 16S rRNA gene. Results: Our results demonstrated that gut microbial profiles between low- and high-BMI groups (<30 vs. ≥30 kg/m²) differed significantly in beta-diversity, but not in alpha-diversity indices. At the genus level, we identified Megamonas, Sutterella, Catenibacterium, and Odoribacter, enriched in the high BMI group. Compared to the low CAC group (<100 AU), MASLD patients with high CAC scores (≥100 AU) exhibited enrichment in Ruminococcus gnavus, Bacteroides, and Lachnoclostridium, along with depletion of several short-chain fatty acid (SCFA)-producing bacteria, such as Faecalibacterium. Multivariate analysis demonstrated that older age, the presence of diabetes, high BMI, fibrosis stage F3-F4, and high plasma trimethylamine oxide (TMAO) levels were independently associated with a high CAC score in patients with MASLD. Conclusions: These data indicated that gut dysbiosis and related metabolites, in association with advanced liver disease, were potential contributors to the progression of SCA in obese patients with MASLD. Full article

Alcohol abuse and alcoholic liver diseases (ALD) are globally prevalent, with alcohol-induced gut microbiota dysbiosis playing a key role in ALD pathogenesis. Synbiotic (combinations of probiotics and prebiotics) are recognized as effective in reducing inflammation in ALD. Bacillus coagulans, a probiotic with favorable industrial and functional traits (e.g., sporulation, lactic acid production), shows potential in treating intestinal diseases. Here, we investigated the effects of B. coagulans, alone or combined with pectin, on ethanol-induced ALD in mice. Synbiotic supplementation (B. coagulans + pectin) more significantly alleviated ethanol-induced ALD severity than B. coagulans or pectin alone. Relative to the ethanol group, synbiotic treatment significantly reduced hepatic inflammatory injury and lipid accumulation, downregulated proinflammatory factors (TNF-α, IL-1β, myeloperoxidase [MPO]), and upregulated tight junction proteins and mucins—enhancing intestinal barrier function. Moreover, these supplements modulated gut microbiota composition and enhanced short-chain fatty acids (SCFAs) production by increasing the abundance of beneficial SCFA-producing bacteria (Muribaculaceae, Akkermansia). In summary, changes in tight junction proteins, cytokines and hepatic injury markers indicate that the synbiotic alleviated overall inflammation in the experimental ALD model and exerted a greater therapeutic effect than B. coagulans or pectin alone. Full article