Search Results (618)

Background and Aims: Multiple genetic variants have been associated with disease prevalence and outcomes in middle-aged people with metabolic dysfunction-associated fatty liver disease (MAFLD). However, genetic studies in older adults have been lacking. We aimed to understand their clinical relevance in healthy older persons. Methods: A secondary analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized trial involving community-dwelling older adults ≥ 70 years without prior cardiovascular disease events or life-limiting illness at enrolment. The Fatty Liver Index (FLI) was used to identify MAFLD at baseline. We assessed the associations between six previously reported MAFLD-associated genetic variants with prevalent MAFLD at baseline, and the associations of these variants with cardiovascular disease events and all-cause mortality. Results: A total of 8756 participants with genetic data were stratified according to the FLI, with 3310 having MAFLD at baseline. The follow-up was for a median of 8.4 (IQR 7.3–9.5) years. Variants in two genes (GCKR and HSD17B13) were associated with prevalent MAFLD (p < 0.05); PNPLA3, TM6SF2, LYPLAL1, and MBOAT7 were not. PNPLA3, TM6SF2, HSD17B13, GCKR, and LYPLAL1 were not associated with major adverse cardiovascular events (MACEs) or mortality in the overall cohort or in participants with MAFLD during the follow-up (all p > 0.05). Within the MAFLD group, homozygosity for the rs641738 C > T variant in the MBOAT7 gene was associated with a reduced risk of MACEs (HR 0.68 [95% CI 0.48–0.97]), but not all-cause mortality (HR 1.14 [95% CI 0.89–1.47]). This protective association remained significant after adjusting for multiple key covariates (aHR 0.64 [95% CI 0.44–0.92]). The results were similar when using the metabolic dysfunction-associated steatotic liver disease definition rather than MAFLD. Conclusions: The rs641738 C > T variant in MBOAT7 may confer protection against MACEs in older adults with MAFLD, independent of other clinical risk factors. Further validation using external cohorts is needed. Full article

The liver’s susceptibility to age-related diseases, including hepatocellular carcinoma (HCC), is increasingly linked to progressive epigenetic alterations that disrupt gene regulation, promote fibrosis, and impair regeneration. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) are well-established in the treatment of type 2 diabetes and obesity, emerging evidence suggests they may also exert protective effects on the liver through the modulation of epigenetic pathways. In this perspective, we explore the hypothesis that GLP-1RAs may help restore a healthier epigenetic state in the aging liver by influencing mechanisms such as DNA methylation, histone modification, and non-coding RNA activity. These effects could reduce chronic inflammation, hepatic stellate cell activation, and fibrotic remodeling, key steps in the path to HCC. Preclinical studies have shown GLP-1RAs can affect transcriptional regulation and fibrotic markers, and early clinical data support improvements in liver function and structure in patients with metabolic liver disease. We highlight the need for further research to clarify these mechanisms in aging populations and propose that GLP-1RAs hold potential as a novel therapeutic strategy to reduce liver cancer risk by targeting the epigenetic contributors to disease progression. Full article

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is strongly associated with metabolic syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD). IH exacerbates MASLD progression through oxidative stress, inflammation, and lipid accumulation. This study aims to investigate the impact of oxygen normalization on metabolic dysfunction in OSA patients using continuous positive airway pressure (CPAP) therapy, and in mice exposed to IH followed by a reoxygenation period. In the clinical study, 76 participants (44 OSA patients and 32 controls) were analyzed. OSA patients had higher insulin resistance, triglycerides, very low density lipoprotein (VLDL) content, and liver enzyme levels, along with a higher prevalence of liver steatosis. After 18 months of CPAP therapy, OSA patients showed significant improvements in insulin resistance, lipid profiles (total cholesterol and VLDL), liver function markers (AST and albumin), and steatosis risk scores (Fatty Liver Index and OWLiver test). In the experimental study, IH induced hepatic lipid accumulation, oxidative stress, and inflammation, and reoxygenation reversed these deleterious effects in mice. At the molecular level, IH downregulated fatty acid oxidation (FAO)-related genes, thus impairing the FAO process. Reoxygenation maintained elevated levels of lipogenic genes but restored FAO gene expression and activity, suggesting enhanced lipid clearance despite ongoing lipogenesis. Indeed, serum β hydroxybutyrate, a key marker of hepatic FAO in patients, was impaired in OSA patients but normalized after CPAP therapy, supporting improved FAO function. CPAP therapy improves lipid profiles, liver function, and MASLD progression in OSA patients. Experimental findings highlight the therapeutic potential of oxygen normalization in reversing IH-induced liver damage by FAO pathway restoration, indicating a metabolic reprogramming in the liver. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) begins with hepatic lipid accumulation and triggers insulin resistance. Hibiscus leaf extract exhibits antioxidant and anti-atherosclerotic activities, and is rich in (−)-epicatechin gallate (ECG). Despite ECG’s well-known pharmacological activities and its total antioxidant capacity being stronger than that of other catechins, its regulatory effects on MASLD have not been fully described previously. Therefore, this study attempted to evaluate the anti-MASLD potential of ECG isolated from Hibiscus leaves on abnormal lipid and glucose metabolism in hepatocytes. First, oleic acid (OA) was used as an experimental model to induce lipid dysmetabolism in human primary hepatocytes. Treatment with ECG can significantly (p < 0.05) reduce the OA-induced cellular lipid accumulation. Nile red staining revealed, compared to the OA group, the inhibition percentages of 29, 61, and 82% at the tested doses of ECG, respectively. The beneficial effects of ECG were associated with the downregulation of SREBPs/HMGCR and upregulation of PPARα/CPT1 through targeting AMPK. Also, ECG at 0.4 µM produced a significant (p < 0.01) decrease in oxidative stress by 83%, and a marked (p < 0.05) increase in glycogen synthesis by 145% on the OA-exposed hepatocytes with insulin signaling blockade. Mechanistic assays indicated lipid and glucose metabolic homeostasis of ECG might be mediated via regulation of lipogenesis, fatty acid β-oxidation, and insulin resistance, as confirmed by an AMPK inhibitor. These results suggest ECG is a dual modulator of lipid and carbohydrate dysmetabolism in hepatocytes. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a significant comorbidity in individuals with type 1 diabetes (T1D), despite its historical association with type 2 diabetes. This review focuses on summarizing current findings regarding the role of insulin resistance in the development of MASLD in T1D, as well as examining the relationship between MASLD and diabetes-related complications. We will also briefly discuss the prevalence, diagnostic challenges, associated complications, and potential mechanisms underlying MASLD in T1D. Although insulin resistance is well established in MASLD among those with type 2 diabetes, its role in T1D requires further clarification. Emerging markers, such as the estimated glucose disposal rate, offer early insight into this relationship. MASLD in T1D is linked to both microvascular and macrovascular complications, including nephropathy, retinopathy, neuropathy, and cardiovascular disease. Variability in prevalence estimates reflects inconsistencies among imaging modalities, emphasizing the need for standardized, non-invasive diagnostic approaches. Recognizing and addressing MASLD and its links to insulin resistance and diabetes complications in T1D is vital for mitigating long-term complications and enhancing clinical outcomes. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder associated with metabolic risk factors such as obesity, type 2 diabetes, and cardiovascular disease. If left untreated, the accumulation of excess hepatic fat can lead to inflammation, fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately liver failure. Capsaicin (CAP), the primary pungent compound in chili peppers, has previously been shown to prevent weight gain in high-fat diet (HFD)-induced obesity models. In this study, we investigated the potential of dietary CAP to prevent HFD-induced MASLD. Methods: C57BL/6 mice were fed an HFD (60% kcal from fat) with or without 0.01% CAP supplementation for 26 weeks. We evaluated CAP’s effects on hepatic fat accumulation, inflammation, and mitochondrial function to determine its role in preventing MASLD. Results: CAP acts as a potent and selective agonist of the transient receptor potential vanilloid 1 (TRPV1) channel. We confirmed TRPV1 expression in the liver and demonstrated that CAP activates hepatic TRPV1, thereby preventing steatosis, improving insulin sensitivity, reducing inflammation, and enhancing fatty acid oxidation. These beneficial effects were observed in wild-type but not in TRPV1 knockout mice. Mechanistically, CAP-induced TRPV1 activation promotes calcium influx and activates AMPK, which leads to SIRT1-dependent upregulation of PPARα and PGC-1α, enhancing mitochondrial biogenesis and lipid metabolism. Conclusions: Our findings suggest that dietary CAP prevents MASLD through TRPV1 activation. TRPV1 signaling represents a promising therapeutic target for the prevention and management of MASLD in individuals with metabolic disorders. Full article

Understanding the components of the diet, food groups, and nutritional strategies that help prevent MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) is essential for identifying dietary behaviors that can stop the progression of this condition, which currently affects over one-quarter of the global population. This review highlights the importance of including antioxidant nutrients in the diet, such as vitamins C and E, CoQ10, and polyphenolic compounds. It also emphasizes substances that support lipid metabolism, including choline, alpha-lipoic acid, and berberine. Among food groups, it is crucial to choose those that help prevent metabolic disturbances. Among carbohydrate-rich foods, vegetables, fruits, and high-fiber products are recommended. For protein sources, eggs, fish, and white meat are preferred. Among fat sources, plant oils and fatty fish are advised due to their content of omega-3 and omega-6 fatty acids. Various dietary strategies aimed at preventing MASLD should include elements of the Mediterranean diet or be personalized to provide anti-inflammatory compounds and substances that inhibit fat accumulation in liver cells. Other recommended dietary models include the DASH diet, the flexitarian diet, intermittent fasting, and diets that limit fructose and simple sugars. Additionally, supplementing the diet with spirulina or chlorella, berberine, probiotics, or omega-3 fatty acids, as well as drinking several cups of coffee per day, may be beneficial. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease. It has known multifactorial pathophysiology, but the impact of social determinants of health (SDOH) on the rising prevalence of MASLD is poorly understood. We conducted a retrospective cross-sectional study to examine the influence of SDOH on MASLD using nationwide data from the 2017–2018 National Health and Nutrition Examination Survey (NHANES) study. Methods: We identified participants with MASLD based on liver ultrasound-based controlled attenuation parameter measurements consistent with diagnostic guidelines. We then used logistic regression models to examine associations between SDOH variables and MASLD, with a pre-specified focus on education and income, sequentially adjusting for sociodemographic factors, medical comorbidities, and other SDOH. Results: Our study found that higher education (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.62–0.97, p = 0.024) but not higher income (OR 1.12, 95% CI 0.91–1.37, p = 0.3) was associated with lower odds of MASLD in multivariable adjusted models. We also identified a significant interaction between education level and food security, as well as interactions between food security and other significant SDOH. In the stratified analyses, higher education was significantly associated with lower odds of MASLD among participants with food security (OR 0.71, 95% CI 0.55–0.91, p = 0.007) but not among those with food insecurity (OR 1.26, 95% CI 0.76–2.11, p = 0.4). Conclusions: Our findings identify the potential impact of SDOH on odds of MASLD and suggest increased importance of food security relative to other SDOH. Full article

A dietary supplement, trans-resveratrol and hesperetin (tRES+HESP)—also known as GlucoRegulate—induces increased expression of glyoxalase 1 (Glo1) by activation of transcription factor Nrf2, countering accumulation of the reactive dicarbonyl glycating agent, methylglyoxal. tRES+HESP corrected insulin resistance and decreased fasting and postprandial plasma glucose and low-grade inflammation in overweight and obese subjects in a clinical trial. The aim of this study was to explore, for the first time, health-beneficial gene expression other than Glo1 induced by tRES+HESP in human endothelial cells and fibroblasts in primary culture and HepG2 hepatoma cell line and activity of cis-resveratrol (cRES) as a Glo1 inducer. We measured antioxidant response element-linked gene expression in these cells in response to 5 µM tRES+HESP by the NanoString method. tRES+HESP increases gene expression linked to the prevention of dicarbonyl stress, lipid peroxidation, oxidative stress, proteotoxicity and hyperglycemia-linked glycolytic overload. Downstream benefits were improved regulation of glucose and lipid metabolism and decreased inflammation, extracellular matrix remodeling and senescence markers. The median effective concentration of tRES was ninefold lower than cRES in the Glo1 inducer luciferase reporter assay. The GlucoRegulate supplement provides a new treatment option for the prevention of type 2 diabetes and metabolic dysfunction–associated steatotic liver disease and supports healthy aging. Full article

Background/Objectives: Primary liver cancer (PLC), encompassing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), constitutes a growing global health concern. Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) and Type 2 diabetes mellitus (T2DM) represent a recurrent epidemiological overlap. Individuals with MASLD and T2DM (MASLD-T2DM) are at a higher risk of PLC. This scoping review highlights the epidemiological burden, the classic and novel pathogenetic frontiers, and the potential strategies optimizing the management of PLC in MASLD-T2DM. Methods: A systematic search of the PubMed, Medline, and SCOPUS electronic databases was conducted to identify evidence investigating the pathogenetic mechanisms linking MASLD and T2DM to hepatic carcinogenesis, highlighting the most relevant targets and the relatively emerging therapeutic strategies. The search algorithm included in sequence the filter words: “MASLD”, “liver steatosis”, “obesity”, “metabolic syndrome”, “body composition”, “insulin resistance”, “inflammation”, “oxidative stress”, “metabolic dysfunction”, “microbiota”, “glucose”, “immunometabolism”, “trained immunity”. Results: In the MASD-T2DM setting, insulin resistance (IR) and IR-induced mechanisms (including chronic inflammation, insulin/IGF-1 axis dysregulation, and autophagy), simultaneously with the alterations of gut microbiota composition and functioning, represent crucial pathogenetic factors in hepatocarcinogenesis. Besides, the glucose-related metabolic reprogramming emerged as a crucial pathogenetic moment contributing to cancer progression and immune evasion. In this scenario, lifestyle changes, simultaneously with antidiabetic drugs targeting IR-related effects and gut-liver axis, in parallel with novel approaches modulating immunometabolic pathways, represent promising strategies. Conclusions: Metabolic dysfunction, classically featuring MASLD-T2DM, constitutes a continuously expanding global issue, as well as a critical driver in PLC progression, demanding integrated and personalized interventions to reduce the future burden of disease. Full article

Background/objectives: Polycystic ovary syndrome (PCOS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are common co-morbidities in women of reproductive age. PCOS is highly heterogeneous and is, therefore, divided into four phenotypes. MASLD leads to numerous systemic complications. Studies to date have shown an association between PCOS and MASLD. This study was designed to compare the FIB-4 score (based on age, alanine aminotransferase, aspartate aminotransferase and platelet count) and the results of shear wave elastography in assessing the risk of developing MASLD by patients with PCOS divided by phenotypes. Methods: The study enrolled 242 women age 18–35 years with PCOS diagnosed according to Rotterdam criteria, hospitalized at the Department of Gynaecological Endocrinology of the University Clinical Centre in Katowice. The study subjects were assigned to phenotypes A to D. Clinical and biochemical assessments were performed (including androgens and metabolic parameters), and the FIB-4 index was calculated. Liver fibrosis was evaluated by shear wave elastography. To balance the group sizes of phenotypes, oversampling with replacement was applied (PROC SURVEYSELECT, SAS), increasing the number of observations for phenotypes B, C, and D fivefold. Statistical analyses were performed based on data distribution (Shapiro–Wilk test), using ANOVA or the Kruskal–Wallis test with Dunn’s correction. Statistical significance was set at p < 0.05. Results: The FIB-4 score was the highest in phenotype B patients (0.50 ± 0.15), and the lowest in phenotypes A and C (0.42 ± 0.14). The highest rate of positive elastography findings was recorded in phenotype A patients (34.7%) and the lowest in phenotype C group (13.5%). Significant differences between the phenotypes were also found in terms of androgen levels, insulin, HOMA-IR, and the lipid profile. Among patients with positive elastography, the highest FIB-4 scores were recorded in phenotype C group (0.44 ± 0.06), but the differences between the phenotypes were not statistically significant. Conclusions: The FIB-4 score was the highest in phenotype B patients and differed significantly from phenotypes A, C and D. In the elastography exam, the fibrosis index was statistically significantly higher in phenotype A compared to other phenotypes. No correlation was detected between the FIB-4 index and positive elastography. The findings suggest that the FIB-4 index may be used for MASLD screening, but its usefulness as a predictor of eligibility for elastography requires more research. Full article

Cholesterol accumulation plays a significant role in the pathogenesis of metabolic-dysfunction-associated steatotic liver disease (MASLD), yet changes in cholesterol homeostasis in MASLD remain insufficiently investigated. This study aimed to examine alterations in cholesterol synthesis and absorption by measuring plasma levels of endogenous cholesterol precursors (as markers of synthesis) and phytosterols (as indicators of absorption). A total of 124 MASLD patients and 43 healthy individuals were included. Our results showed higher plasma concentrations of lathosterol in the MASLD group (p = 0.006), in parallel with comparable concentrations of desmosterol (p = 0.472) and all analyzed phytosterols in both groups. Correlation analysis showed that both lathosterol and desmosterol were positively associated with non-invasive hepatic steatosis indices: FLI, HSI, and TyG index (p < 0.01, p < 0.01, and p < 0.05, respectively). Multivariate linear regression further confirmed that these synthesis markers remained significant predictors of FLI (p = 0.010), HSI (p = 0.013), and TyG index (p = 0.002), even after adjusting for other relevant variables. These findings indicate that MASLD is associated with a shift in cholesterol homeostasis towards enhanced endogenous cholesterol synthesis. Full article

Background: This study aimed to determine the association between PNPLA3 rs738409, rs2896019, and FTO rs9939609, rs17817449 single-nucleotide polymorphisms and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in Mongolian individuals. Methods: We conducted a case-control study, enrolling 100 MASLD patients and 50 subjects without MASLD. We used the PCR-RFLP technique on three genotype SNPs (rs738409, rs2896019 in PNPLA3, and rs9939609 in FTO). We analyzed liver function and lipid metabolism parameters in the peripheral blood of study participants. A p-value below 0.05 was considered a statistically significant result. Results: This study, which included 150 participants aged 23 to 75, had a mean age of 46.73 ± 11.45 years, with 40% of participants being male (60 individuals). We observed the rs738409 (G), rs2896019 (G), and rs9939609 (A) alleles at a statistically significantly enhanced frequency in the case group (32.5%, 33%, and 21%) compared to the control group (19%, 25%, and 19%), indicating an increased risk of MASLD. The FTO rs17817449 SNP did not show a significant difference between groups. PNPLA3 rs738409 GC/GG genotype (OR = 2.39, p = 0.019) and FTO rs9939609 AT/AA (OR = 2.55, p = 0.025) genotype showed a significant association with MASLD. In the evaluation of the FTO rs9939609, rs17817449, and PNPLA3 rs738409, rs2896019 single-nucleotide polymorphisms among the research individuals, 18.7% had no SNPs, 15.3% had one SNP, 29.3% had two SNPs, 25.3% had three SNPs, and 11.3% had four SNPs. The risk of MASLD increased significantly for individuals having four SNPs (OR = 4.23, p = 0.007). Conclusions: We found that PNPLA3 rs738409 GC/GG genotype and FTO rs9939609 AT/AA genotype are strongly associated with an increased risk of MASLD. Notably, individuals with a higher rate of SNP number, had a significantly higher risk of MASLD. Full article

Background: Transient elastography (TE), using Fibroscan^® and point shear wave elastography (pSWE), are two techniques used to estimate liver fibrosis. The aim of our study was to compare, for the first time, these two techniques in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), stratifying the analysis on the basis of the grades of steatosis. Methods: We recruited 85 consecutive MAFLD patients who underwent liver stiffness (LS) measurement performed by Fibroscan^® and pSWE on the same day. Severity of steatosis was estimated by Fibroscan^® and expressed as controlled attenuation parameter (CAP), ranging from S0 to S3. Spearman’s “r” coefficient was used to calculate the correlation and Bland–Altman graphs was used to evaluate the agreement. Results: In general, the correlation and agreement between Fibroscan^® and pSWE were substantial (r = 0.66, p < 0.001 and bias= −0.64 ± 2.48, respectively). When data were analyzed according to the grade of steatosis, an increasing significant correlation was observed going from S0 to S2 (r = 0.79, r = 0.81, and r = 0.85, respectively), whereas a low correlation and agreement were observed for S3 patients (r = 0.48, p = 0.003, bias= −0.95 ± 2.51). Conclusions: Fibroscan^® and pSWE are equivalent techniques to estimate liver fibrosis in patients with mild to moderate steatosis, while in presence of severe steatosis their agreement is low. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a prevalent, multisystem disease affecting approximately 30% of adults worldwide. Obesity, along with dyslipidemia, type 2 diabetes mellitus, and hypertension, are closely intertwined with MASLD. In people with obesity, MASLD prevalence is estimated to be about 75%. Despite various approaches to MASLD treatment, dietary changes remain the most accessible and safe interventions in MASLD, especially in obese and overweight patients. Whey proteins are rich in bioactive compounds, essential amino acids with antioxidant properties, offering potential benefits for MASLD prevention and management. This state-of-the-art review summarizes whey protein impacts on a spectrum of MASLD-related manifestations, such as obesity, impaired glucose and lipid metabolism, hypertension, liver injury, oxidative stress, and inflammation. The results obtained in clinical environments, with a focus on meta-analysis, propose whey protein supplementation as a promising strategy aimed at managing multifaced MASLD disorders. Well-designed cohort studies are needed for validation of the efficacy and long-term safety of whey proteins in MASLD patients. Full article