Search Results (177)

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

Metabolic dysfunction-associated fatty liver disease (MASLD) is a chronic, non-communicable spectrum of diseases characterized by lipid accumulation. It is often asymptomatic, and its prevalence varies by region, age, gender, and economic status. It is estimated that 25% of the world’s population currently suffer from MAFLD, and 20 million patients will die from MAFLD-related diseases. In the last 20 years, tea and anti-obesity research have indicated that regularly consuming tea decreases the risk of cardiovascular disease, stroke, obesity, diabetes, and metabolic syndrome (MeS). In this review, we aimed to present studies concerning the influence of matcha extracts and epigallocatechin-3 gallate (EGCG) supplements on metabolic functions in the context of MAFLD in human and animal studies. The published data show promise. In both human and animal studies, the beneficial effects on body weight, cholesterol levels, and liver metabolism and function were noted, even in short-period experiments. The safety levels for EGCG and green tea extract consumption are marked. More experiments are needed to confirm the results observed in animal studies and to show the mechanisms by which green tea exerts its effects. The preliminary data from research concerning microbiota or epigenetic changes observed after polyphenols and green tea consumption need to be expanded. To improve the efficiency and availability of green tea or supplement consumption as a treatment for MAFLD patients, more research with larger groups and longer study durations is needed. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD), a recently proposed term to replace non-alcoholic fatty liver disease (NAFLD), emphasizes the critical role of metabolic dysfunction and applies broader diagnostic criteria. Diagnosis of MAFLD requires evidence of hepatic steatosis combined with obesity, type 2 diabetes mellitus, or other metabolic dysregulation conditions, all of which significantly elevate the risk of chronic kidney disease (CKD). This review discusses the pathological mechanisms of lipid accumulation and insulin resistance in MAFLD and CKD, highlighting their mechanistic connections. Specifically, ectopic fat accumulation triggered by metabolic reprogramming, oxidative stress and inflammation induced by energy overload, modified lipids, uremic toxins, and senescence, as well as insulin resistance pathways activated by pro-inflammatory factors and lipotoxic products, collectively exacerbate simultaneous hepatic and renal injury. Moreover, interactions among hyperinsulinemia, the sympathetic nervous system, the renin–angiotensin system (RAS), and altered adipokine and hepatokine profiles further amplify insulin resistance, ectopic lipid deposition, and systemic damage. Finally, the review explores potential therapeutic strategies targeting lipid metabolism, insulin sensitivity, and RAS activity, which offer promise for dual-organ protection and improved outcomes in both hepatic and renal systems. Full article

Background/Objective: Metabolic dysfunction-associated fatty liver disease (MAFLD) is defined by the presence of hepatic steatosis, and is associated with obesity, diabetes, and other metabolic alterations. Feeding rats with a high-fat high-fructose (HFHF) diet is a reproducible experimental model of obesity/metabolic syndrome and the related MAFLD. Aronia melanocarpa, Rosa canina, and Alchemilla vulgaris are polyphenol-rich plants with proven health benefits. The aim of this study was to reveal the effects of four Aronia melanocarpa-based fruit juices (AMBFJs) in HFHF-fed rats. Methods: The AMBFJs were AM20 and AM60 (produced from aronia berries at 20 °C and 60 °C, respectively), AMRC (aronia juice with Rosa canina), and AMAV (aronia juice with Alchemilla vulgaris). Male Wistar rats were allocated to 6 groups. Except for the Control, the rest of the groups were fed an HFHF diet for 60 days. Throughout the experiment, each of the AMBFJs was administered to one HFHF-fed group. Results: HFHF-fed rats had an increased calorie intake on the background of increased liquid and decreased food consumption. At the end of the experiment, they had similar body weights, slightly increased fat indices, increased levels of blood lipids and liver enzymes, as well as typical histopathological changes in liver and adipose tissue. AMBFJs-treated animals showed improvement in most of these parameters, especially in triglyceride levels, liver enzymes, and the histopathological changes in the liver and fat. AMAV, the juice with the highest polyphenolic content, had the highest effect on adiposity. Conclusion: In HFHF-fed rats, AMBFJs exerted beneficial effects on MAFLD probably due to their polyphenolic ingredients. Full article

Hypertension and metabolic dysfunction-associated fatty liver disease (MAFLD) are both common chronic diseases globally. Nearly half of patients with hypertension are complicated by MAFLD. The mechanisms of the bidirectional promotion between the two remain unclear. The (pro) renin receptor ((P)RR) is one of the classic members of the renin–angiotensin system (RAS) and serves as the receptor for prorenin. Although the role of (P)RR in the induction and progression of hypertension has been extensively studied, its role and underlying mechanisms in MAFLD remain underreported. In this study, we aim to investigate the role of (P)RR in the pathogenesis of hypertension combined with MAFLD. In this study, SHRs were used for the model for hypertension combined with MAFLD. Liver lipid content analysis, liver H&E staining, the detection of (P)RR, ERK and downstream proteins related to fatty acid synthesis and transport, and RNA sequencing and data analysis were performed. In the in vitro experiments, we activated (P)RR using renin and established the lipid deposition model of HepG2 cells induced by renin for the first time. (P)RR was specifically blocked using handle region peptide (HRP), and Nile red fluorescence staining, (P)RR/ERK/PPARγ protein expression analysis, and immunofluorescence were performed to further verify the role of (P)RR in the pathogenesis of hypertension combined with MAFLD. Our results demonstrate that (P)RR plays a role in the development and progression of hypertension combined with MAFLD. The hepatic TG and FFA levels in the SHRs were increased, and the protein expression of the (P)RR/ERK/PPARγ pathway and downstream proteins related to fatty acid synthesis and transport were upregulated. HRP reversed the activation of these proteins and reduced intracellular lipid accumulation. In conclusion, our study first reveals that (P)RR is a potential therapeutic target for hypertension combined with MAFLD. And we found the (P)RR/ERK/PPARγ axis for the first time, which plays an important role in the progression of spontaneous hypertension combined with MAFLD. Full article

Changes in hepatic lipoprotein metabolism are responsible for the majority of metabolic dysfunction-associated disorders, including familial hypercholesterolemia (FH), metabolic syndrome (MetS), metabolic dysfunction-associated fatty liver disease (MAFLD), and age-related diseases such as atherosclerosis, a major health burden in modern society. This review aims to advance the understanding of state-of-the-art mechanistic concepts in lipoprotein metabolism, with a particular focus on lipoprotein uptake and secretion and their dysregulation in disease, and to provide a comprehensive overview of experimental models used to study these processes. Human lipoprotein research faces several challenges. First, significant differences in lipoprotein metabolism between humans and other species hinder the reliability of non-human model systems. Additionally, ethical constraints often limit studies on human lipoprotein metabolism using tracers. Lastly, while 2D hepatocyte cell culture systems are widely used, they are commonly of cancerous origins, limiting their physiological relevance and necessitating the use of more physiologically representative models. In this review, we will elaborate on key findings in lipoprotein metabolism, as well as limitations and challenges of currently available study tools, highlighting mechanistic insights throughout discussion of these models. These include human tracer studies, animal studies, 2D tissue culture-based systems derived from cancerous tissue as well as from induced pluripotent stem cells (iPSCs)/embryonic stem cells (ESCs). Finally, we will discuss precision-cut liver slices, liver-on-a-chip models, and, particularly, improved 3D models: (i) spheroids generated from either hepatoma cancer cell lines or primary human hepatocytes and (ii) organoids generated from liver tissues or iPSCs/ESCs. In the last section, we will explore future perspectives on liver-in-a-dish models in studying mechanisms of liver diseases, treatment options, and their applicability in precision medicine approaches. By comparing traditional and advanced models, this review will highlight the future directions of lipoprotein metabolism research, with a focus on the growing potential of 3D liver organoid models. Full article

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is linked to cardiovascular complications, including atrial fibrillation. P-wave indices (PWIs) reflect atrial conduction heterogeneity but have not been fully evaluated in MAFLD. To compare PWIs in MAFLD patients versus controls, assess their association with fibrosis severity, and evaluate their diagnostic performance for MAFLD and fibrosis. Methods: In this retrospective single-center study, 447 subjects were included (noMAFLD: Fatty Liver Index (FLI) < 30 without metabolic dysfunction, n = 205; MAFLD: FLI ≥ 60+ ≥ 1 metabolic risk factor, n = 242). Among MAFLD subjects, the non-alcoholic fatty liver disease (NAFLD) Fibrosis Score (NFS) stratified lower (NFS ≤ −1.455; n = 170), and there was a higher fibrosis risk (NFS > −1.455; n = 72). Standard 12-lead ECGs were digitized for offline PWI measurement. Statistical analyzes included group comparisons, multivariable logistic regression, and ROC curve analysis. Results: MAFLD patients exhibited a longer PWPT-D2 (63 ± 12 vs. 52 ± 10 ms, p = 0.003), PWPT-V1 (68 ± 14 vs. 60 ± 13 ms, p = 0.005), PWdis (55 ± 13 vs. 46 ± 11 ms, p = 0.010), and PTFV₁ (38 [31–46] vs. 28 [22–34] mm·ms, p = 0.021) compared with controls. Within MAFLD, a higher fibrosis risk was associated with a further PWI prolongation (all p < 0.015). Multivariate analysis identified PWPT-D2 (OR 1.05 per ms; 95% CI 1.02–1.08; p = 0.002) and PWDIS (OR 1.03 per ms; 95% CI 1.00–1.06; p = 0.048) as independent MAFLD predictors. ROC curves showed PWPT-D2 had the highest AUC for MAFLD detection (0.78; 95% CI 0.72–0.84) and fibrosis (0.82; 95% CI 0.76–0.88). Combining PWPT-D2 with BMI and waist circumference improved MAFLD discrimination (AUC 0.89; 95% CI 0.85–0.93; p < 0.001 vs. PWPT-D2 alone). Conclusions: PWPT-D2 and PWdis are significantly prolonged in MAFLD and more so with advanced fibrosis. PWPT-D2 may be a simple, noninvasive ECG marker for MAFLD screening and fibrosis staging, particularly when combined with anthropometric measures. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a growing health concern worldwide. Human cell-based in vitro culture models that retain disease-relevant phenotypic pathways and responses to assess the efficacy and liability of new therapeutics are needed. Obeticholic Acid (OCA), a Farnesoid X Receptor agonist, has been identified for MAFLD treatment, and clinically shown to have anti-inflammatory and anti-fibrotic effects. In this study, healthy and disease-origin primary human hepatocytes (PHHs) were cultured in TruVivo^®, an all-human hepatic system for 14 days and treated with OCA to determine its’ effects on lipogenic, inflammatory, and fibrogenic pathways. Decreases in lipogenesis and triglyceride levels were measured in OCA treated healthy and diseased PHHs. Significant decreases in CYP3A4 activity and gene expression were quantified. Macrophage marker expression, pro-inflammatory cytokines and fibrotic markers were lowered in OCA treated diseased PHHs. CYP7A1 gene expression decreased, while BSEP gene expression increased in OCA treated healthy and diseased PHHs. Overall, OCA treatment reduced lipogenic, inflammatory, and fibrogenic markers in diseased PHHs. Differences in the potency and efficacy of OCA against different disease-relevant pathways were observed in healthy and diseased PHHs indicating divergence of key regulatory mechanisms between healthy versus diseased phenotypes. Full article

Non-alcoholic fatty liver disease (NAFLD) is characterized by an accumulation of fat in hepatocytes, and it may progress, under additional triggering factors, to non-alcoholic steatohepatitis (NASH). Effective strategies to counteract this progression are essential, especially considering that at the moment, there is a lack of approved pharmacological therapies. Our previous study showed that the daily consumption of Navelina oranges significantly reduced hepatic steatosis in patients with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). Starting with our previous study, here, we have investigated the molecular targets through which Hesperidin (HE), a citrus flavanone, is able to prevent the progression of NAFLD to NASH using an in vitro model. In Hepa-RG cells exposed to NAFLD Promoting Agents, HE reduced lipid droplet accumulation (~35%) and suppressed de novo lipogenesis, with decreased expression of FASN (0.62 ± 0.06 vs. 0.39 ± 0.03 at 100 µg/mL) and SCD1 (0.05 ± 0.001 vs. 0.03 ± 0.004 at 50 µg/mL). HE also enhanced fatty acid oxidation by increasing SIRT1 (0.73 ± 0.16 vs. 2.36 ± 0.10 at 50 µg/mL) and PGC1α (0.71 ± 0.03 vs. 0.89 ± 0.003 at 50 µg/mL). In LX-2 cells, HE downregulated COL1A1 (1.48 ± 0.10 vs. 0.90 ± 0.11 at 100 µg/mL) and α-SMA (1.21 ± 0.16 vs. 0.76 ± 0.07 at 75 µg/mL) and upregulated MMP3 (0.64 ± 0.05 vs. 0.98 ± 0.07) and MMP9 (0.99 ± 0.005 vs. 2.61 ± 0.16 at 100 µg/mL). In conclusion, HE may offer a promising approach for NAFLD/NASH prevention and treatment, demonstrating in vitro its potential to reduce hepatic steatosis and fibrosis. Full article

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is closely associated with type 2 diabetes mellitus (T2DM), where T2DM serves as a crucial driving factor for MAFLD progression. While vitamin D (VD) demonstrates protective effects against MAFLD, the underlying mechanisms through which it influences MAFLD-related liver sinusoidal endothelial cell (LSEC) capillarization remain to be elucidated. This study aimed to explore how vitamin D ameliorates LSEC capillarization in T2DM-associated MAFLD. Methods: Culture human liver sinusoidal endothelial cells (HLSECs) according to the established protocol. After 1,25(OH)₂D₃ intervention in high glucose (HG)-induced HLSECs, determine the changes in liver sinusoidal capillarization-related proteins (LN, PLVAP), autophagy and pyroptosis levels. Observe the changes in cell lipid accumulation and fenestration structures. After adding Bafilomycin A1, MCC950, compound C and rapamycin to HLSECs, explore the therapeutic mechanism of 1,25(OH)₂D₃. After supplementing VD to MAFLD model mice, further verify the therapeutic mechanism of VD on MAFLD. Results: HG can induce the capillarization and lipid accumulation of HLSEC, increase the level of pyroptosis, and simultaneously reduce the autophagy level. Vitamin D alleviated high-glucose-induced pyroptosis (by suppressing GSDMD/NLRP3) and autophagic inhibition by activating the AMPK-mTOR axis (upregulating p-AMPK and downregulating mTOR), and improved lipid accumulation and hepatic sinusoidal capillarization. In the mouse model of MAFLD, VD supplementation can induce autophagy, inhibit pyroptosis and capillarization, and improve MAFLD. Conclusions: These results demonstrate, for the first time, that VD mitigates LSEC dysfunction through dual mechanisms: activating AMPK-dependent autophagy and inhibiting pyroptosis, providing a therapeutic rationale for VD in treating MAFLD-related sinusoidal pathology. Full article

Background/Objectives: Fatty liver disease (FLD) is currently the most common liver disorder, affecting 25–30% of the global population. Its occurrence is strongly associated with overweight, obesity, and type 2 diabetes. In 2020, the disease definition was revised from NAFLD (non-alcoholic fatty liver disease) to MAFLD (metabolic-associated fatty liver disease), emphasizing its link to metabolic dysfunction and marking a major shift in clinical evaluation and risk stratification. We assessed the association between MAFLD and cardiovascular risk factors in a geriatric population by comparing patients with and without fatty liver disease and evaluating the influence of selected metabolic and echocardiographic parameters on MAFLD prevalence. Methods: This retrospective study was conducted using data from patients treated at the Department of Geriatrics, the University Clinical Hospital, in Wrocław. The study included 237 patients diagnosed with fatty liver disease and 148 controls without liver pathology. The groups were compared in terms of comorbidities, laboratory abnormalities, body mass index (BMI), and left ventricular hypertrophy. Statistical analysis was performed to assess the association between the severity of selected variables and the risk of MAFLD. Results: Patients with MAFLD had significantly higher body weight and BMI compared to controls. Diabetes mellitus and hypertriglyceridemia were more frequent in the MAFLD group, whereas HDL and vitamin D3 levels were lower. Echocardiographic indicators of left ventricular hypertrophy [IVSd, LVPWd, (IVSd + LVPWd)/2] were significantly elevated in MAFLD patients. Conclusions: This study confirms a strong association between MAFLD and cardiovascular risk factors in elderly patients. The inclusion of a control group allowed for more precise evaluation, supporting the role of MAFLD as an independent cardiometabolic risk indicator in geriatric care. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a global health burden, however, therapeutic advancements remain hindered by incomplete insights on mechanisms and suboptimal clinical interventions. This review focused on the transcription factors (TFs) associated with the gut–liver axis, emphasizing their roles as molecular interpreters of systemic crosstalk in MAFLD. We delineate how TF networks integrate metabolic, immune, and gut microbial signals to manage hepatic steatosis, inflammation, and fibrosis. For instance, metabolic TFs such as peroxisome proliferator-activated receptor α (PPARα) and farnesoid X receptor (FXR) are responsible for regulating lipid oxidation and bile acid homeostasis, while immune-related TFs like signal transducer and activator of transcription 3 (STAT3) modulate inflammatory cascades involving immune cells. Emerging evidence highlights microbiota-responsive TFs, like hypoxia-inducible factor 2α (HIF2α) and aryl hydrocarbon receptor (AHR), linking microbial metabolite signaling to hepatic metabolic reprogramming. Critically, TF-centric therapeutic strategies, including selective TF-agonists, small molecules targeted to degrade TF, and microbiota modulation, hold considerable promise for treating MAFLD. By synthesizing these insights, this review underscores the necessity to dissect TF-mediated interorgan communication and proposes a roadmap for translating mechanism discoveries into precision therapies. Future research should prioritize the use of multi-omics approaches to map TF interactions and validate their clinical relevance to MAFLD. Full article

Background: Accumulating evidence indicates a link between folate and metabolic dysfunction-associated fatty liver disease (MAFLD). Objectives: The aim of this study was to ascertain whether different serum folate forms are associated with newly defined MAFLD as well as liver fibrosis in the US general population. Methods: This cross-sectional study used data from the 2017–2020 (March) cycle and 2017–2018 cycle of the National Health and Nutrition Examination Survey (NHANES) in the US. Hepatic steatosis and fibrosis were evaluated by transient elastography, which employed controlled attenuation parameters and liver stiffness measurements as assessment indicators. Results: 7447 eligible individuals were included. The estimated prevalence of MAFLD and liver fibrosis was 51.6% (95% confidence interval [CI]: 50.4–52.7%) and 10.0% (95% CI: 9.3–10.7%). After adjusting for confounding factors, for every 1 nmol/L increase in serum 5-methyltetrahydrofolate (5-mTHF), the risk of developing liver fibrosis decreased by 1% (95% CI: 1–2%, p < 0.001), and the risk of developing MAFLD decreased by 1% (95% CI: 0–2%, p = 0.005). There were also significant differences in indicators such as alanine aminotransferase (ALT), gamma-glutamyl transaminase (GGT), and C-reactive protein (CRP) between the MAFLD group and the non-MAFLD group (all p values < 0.001). Conclusions: This study suggests the prevalence of MAFLD and liver fibrosis decreased significantly with the increase in serum 5-mTHF concentration. Full article

Recent studies have demonstrated that dietary plant extracts can inhibit the development of lipid droplets (LDs) and oxidized LDs (oxLDs) in hepatic cells. These findings suggest that such extracts may be beneficial in combating metabolic dysfunction-associated fatty liver disease (MAFLD) and its more advanced stage, metabolic dysfunction-associated steatohepatitis (MASH). We examined nine Allium extracts (ALs: AL1–9) to assess their capacity to decrease lipid droplet accumulation (LDA) and oxidative stress by suppressing lipid formation and oxidation in liver cells. Among the Allium extracts tested, AL6 exhibited significant inhibitory effects against LDA. Furthermore, we employed our lipidomic method to assess the accumulation and suppression of intracellular triacylglycerol (TAG) and oxidized TAG hydroperoxide [TG (OOH) n = 3] by AL6 in liver cells under oleic acid (OA) and linoleic acid (LA) loading conditions. These findings indicate that foods derived from Allium species prevent the formation of lipid droplets by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. Analysis of the metabolome of bioactive lipid droplet accumulation inhibition (LDAI) AL6 using LC-MS/MS and 1D-NMR [¹H, ¹³C, DEPT 90, and 135] techniques revealed that AL6 is primarily composed of carbohydrates, glucosidic metabolites, and organosulfur compounds, with small amounts of polyols, fatty acyls, small peptides, and amino acids. This implies that AL6 could be a valuable resource for developing functional foods and drug discovery targeting metabolic dysfunction-associated fatty liver disease (MAFLD)/metabolic dysfunction-associated steatohepatitis (MASH) and related disorders. Full article

Both metabolic dysfunction-associated fatty liver disease (MAFLD) and gestational diabetes mellitus (GDM) during pregnancy are emerging as an adverse synergistic relationship of growing concern. This narrative review focuses on the maternal and fetal consequences associated with women who have MAFLD and/or GDM during pregnancy, including an exploration of long-term cardiometabolic risks for postpartum maternal and childhood health. We conclude that implementation of a life course approach to management of these high-risk women remains paramount. Full article