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BACKGROUND AND AIM: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed as an alternative for the validated definition of metabolic dysfunction-associated fatty liver disease (MAFLD). We compared the abilities of MAFLD and MASLD to predict the risk of atherosclerotic cardiovascular disease (ASCVD). METHODS: Six thousand and ninety six participants from the 2017 to 2020 National Health and Nutrition Examination Survey cohort who received a thorough medical health check-up were chosen for the study. The associations between fatty liver status and coronary risk surrogates, such as 10-year ASCVD risk and self-reported cardiovascular events, were analysed. RESULTS: MAFLD and MASLD were identified in 2911 (47.7%) and 2758 (45.2%) patients, respectively. MAFLD (odds ratio [OR]: 2.14, 95% confidence interval [CI], 1.78-2.57, p < .001) was more strongly independently associated with high ASCVD risk than MASLD (OR: 1.82, 95% CI, 1.52-2.18, p < .001) was in comparison with the absence of each condition. However, compared with MAFLD, MASLD alone was not associated with increased ASCVD risk. Multiple logistic regression revealed that MAFLD alone was significantly more strongly associated with a high risk of ASCVD (OR: 2.82; 95% CI: 1.13-7.01; p < .03) than MASLD alone. CONCLUSIONS: Although both MAFLD and MASLD were associated with different ASCVD risks, MAFLD predicted the ASCVD risk better than MASLD. The higher predictive ability of MAFLD compared to MASLD was attributed to metabolic dysfunction rather than moderate alcohol use.
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Doenças Cardiovasculares , Inquéritos Nutricionais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Doenças Cardiovasculares/epidemiologia , Medição de Risco , Adulto , Fatores de Risco , Estados Unidos/epidemiologia , Idoso , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Modelos Logísticos , Fatores de Risco de Doenças CardíacasRESUMO
INTRODUCTION AND OBJECTIVES: Fatty liver disease is a multisystem disease. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a more accurate indicator of chronic kidney disease (CKD) than nonalcoholic fatty liver disease (NAFLD). However, the relationship between recently defined metabolic dysfunction-associated steatotic liver disease (MASLD) and CKD is currently unclear. The objective of this cross-sectional study was to investigate the prevalence of CKD and albuminuria among individuals diagnosed with either MAFLD or MASLD. PATIENTS AND METHODS: This study involved 5,492 participants who provided biochemical marker and liver ultrasound data from the U.S. National Health and Nutrition Examination Survey (2017-2020). Multiple logistic regression analyses were conducted to assess the independent associations of nonoverlapping MAFLD and MASLD with the presence of CKD or albuminuria (urinary albumin-to-creatinine ratio ≥ 3 mg/mmol). RESULTS: MAFLD and MASLD were identified in 47% and 44.5% of the participants, respectively. Individuals with MAFLD-only had a greater prevalence of CKD (24.7% vs. 8.3 %, P < 0.006) and albuminuria (18.6% vs. 5%, P < 0.01) than did those with MASLD-only. Importantly, after adjusting for factors such as sex, age, ethnicity, and alcohol use, it was demonstrated that individuals in the MAFLD-only group had a 4.73-fold greater likelihood of having prevalent CKD than those in the MASLD-only group (P < 0.03). CONCLUSIONS: The MAFLD criteria better identify patients with CKD than do the MASLD criteria. Therefore, it is suggested that the MASLD criteria be reconsidered, as currently, the justification for changing from MAFLD to MASLD criteria may not be appropriate.
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COVID-19 , Saúde Mental , Humanos , Exercício Físico , Meio Social , Meio Ambiente , População Rural , ChinaRESUMO
Organ fibrosis is a devastating medical challenge that is collectively responsible for an estimated 45% of all deaths in developed countries and poses a substantial health and economic burden. The process of fibrosis has common characteristics that can occur in various organs, such as the liver, kidney, lung, and skin. Currently, there is a paucity of effective treatments available for fibrosis. Therefore, it is crucial to identify new approaches to find potential therapeutic targets. Genetic studies have shown great promise in advancing the drug development process. Mer tyrosine kinase (MERTK) was recently identified as a crucial regulator of fibrosis that specifically controls the activity of transforming growth factor beta (TGFß). In this brief review, we provide an overview of the potential role of MERTK as a targeted and valuable approach for treating organ fibrosis.
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Fibrose , c-Mer Tirosina Quinase , Humanos , c-Mer Tirosina Quinase/metabolismo , c-Mer Tirosina Quinase/genética , Animais , Fator de Crescimento Transformador beta/metabolismo , Terapia de Alvo MolecularRESUMO
BACKGROUND: Disease risk variants are likely to affect gene expression in a context- and cell-type specific manner. The membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs8736 metabolic-dysfunction-associated fatty liver disease (MAFLD)-risk variant was recently reported to be a negative regulator of toll-like receptors (TLRs) signalling in macrophages. Whether this effect is generic or cell-type specific in immune cells is unknown. METHODS: We investigated the impact of modulating TLR signaling on MBOAT7 expression in peripheral blood mononuclear cells (PBMCs). We also examined whether the rs8736 polymorphism in MBOAT7 regulates this effect. Furthermore, we measured the allele-specific expression of MBOAT7 in various immune cell populations under both unstimulated and stimulated conditions. RESULTS: We show that MBOAT7 is down-regulated by TLRs in PBMCs. This effect is modulated by the MBOAT7 rs8736 polymorphism. Additionally, we provide evidence that MBOAT7 acts primarily as a modulator of TLR signalling in mononuclear phagocytes. CONCLUSION: Our results highlight the importance of studying Genome-Wide Association Studies (GWAS) signals in the specific cell types in which alterations of gene expression are found.
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Aciltransferases , Leucócitos Mononucleares , Proteínas de Membrana , Humanos , Aciltransferases/genética , Predisposição Genética para Doença/genética , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/imunologia , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMO
BACKGROUND AND AIMS: Healthy weight (lean) patients with metabolic dysfunction-associated fatty liver disease (MAFLD) have a more favorable metabolic and histological profile in cross-sectional studies compared with their non-lean counterparts. Paradoxically, they also have higher overall mortality. The underpinning pathophysiology of this paradox is not understood. Telomere attrition is associated with increased mortality in various diseases. METHODS: We investigated the role of telomere length in the pathogenesis of lean MAFLD in cohorts with biopsy-proven MAFLD (n = 303). We measured serum malondialdehyde (MDA) levels and hepatic 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) expression (reactive oxygen species (ROS) markers), growth/differentiation factor-15 (GDF-15) and tested the effect of H2O2 on telomere length and activity in hepatocyte cell lines. The association between leukocyte telomere length and mortality was examined. RESULTS: Telomere length was significantly lower in patients with lean MAFLD (p < 0.001). They also demonstrated an increase in ROS levels and decreases in GDF-15. H2O2 induced telomere shortening and reducing telomere activity in hepatocyte cell lines. We subsequently confirmed that telomere length shortening at baseline is associated with increased hazards of all-cause mortality; the deleterious effect was more profound in lean people. CONCLUSION: Differences in telomere length in part explain the increased mortality of lean compared to non-lean patients with MAFLD. The effect is in part mediated through ROS activation and provide opportunities for therapy.
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A role for exportin 4 (XPO4) in the pathogenesis of liver fibrosis was recently identified. We sought to determine changes in hepatic XPO4 promoter methylation levels during liver fibrosis. The quantitative real-time RT-PCR technique was used to quantify the mRNA level of XPO4. Additionally, pyrosequencing was utilized to assess the promoter methylation status of XPO4. The methylation rate of the XPO4 promoter was significantly increased with fibrosis in human and mouse models, while XPO4 mRNA expression negatively correlated with methylation of its promoter. DNA methyltransferases (DNMTs) levels (enzymes that drive DNA methylation) were upregulated in patients with liver fibrosis compared to healthy controls and in hepatic stellate cells upon transforming growth factor beta (TGFß) stimulation. The DNA methylation inhibitor 5-Aza or specific siRNAs for these DNMTs led to restoration of XPO4 expression. The process of DNA methylation plays a crucial role in the repression of XPO4 transcription in the context of liver fibrosis development.
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Metilação de DNA , Carioferinas , Cirrose Hepática , Regiões Promotoras Genéticas , Animais , Humanos , Masculino , Camundongos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Carioferinas/genética , Carioferinas/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genéticaRESUMO
BACKGROUND AND AIMS: Diagnostic criteria for metabolic dysfunction-associated steatotic liver disease (MASLD) have been proposed but not yet validated. This study aimed to compare the diagnostic accuracy of the MASLD definition with the existing criteria for metabolic dysfunction-associated fatty liver disease (MAFLD) in identifying patients with significant fibrosis. METHODS: The analysis included a total of 8317 individuals who had complete biochemical and liver ultrasonography data from the National Health and Nutrition Examination Survey (2017-2020). In this study, significant fibrosis (≥ F2) was determined by a median liver stiffness of ≥ 8.0 kPa. To identify independent factors associated with significant fibrosis, multivariable logistic regression analyses were applied. RESULTS: MAFLD (OR 3.44; 95% CI 2.88-4.12; P < 0.0001) has a trend for stronger and independent association with significant fibrosis compared to MASLD (OR 2.63; 95% CI 2.22-3.11; P < 0.0001). Non-MASLD MAFLD is independently associated with a 14.28-fold higher odds of significant fibrosis compared to non-MAFLD MASLD. The sensitivity for detecting significant fibrosis for MAFLD and MASLD was 76.23% vs 69.94%, respectively. The performance of MAFLD remains consistent in a sub-analysis of patients with no or mild alcohol intake. CONCLUSIONS: The definition of MAFLD provides a more precise identification of individuals who have both fatty liver and significant fibrosis, assessed by non-invasive tests.
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Cirrose Hepática , Humanos , Masculino , Cirrose Hepática/diagnóstico , Cirrose Hepática/diagnóstico por imagem , Feminino , Pessoa de Meia-Idade , Adulto , Ultrassonografia/métodos , Inquéritos Nutricionais , Técnicas de Imagem por Elasticidade/métodos , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/diagnóstico por imagem , Fígado/patologia , Fígado/diagnóstico por imagem , Sensibilidade e EspecificidadeRESUMO
The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is significant, impacting almost one-third of the global population. MAFLD constitutes a primary cause of end-stage liver disease, liver cancer and the need for liver transplantation. Moreover, it has a strong association with increased mortality rates due to various extrahepatic complications, notably cardiometabolic diseases. While MAFLD is typically correlated with obesity, not all individuals with obesity develop the disease and a significant percentage of MAFLD occurs in patients without obesity, termed lean MAFLD. The clinical features, progression and underlying physiological mechanisms of patients with lean MAFLD remain inadequately characterized. The present review aims to provide a comprehensive summary of current knowledge on lean MAFLD and offer a perspective on defining MAFLD in individuals with normal weight. Key to this process is the concept of metabolic health and flexibility, which links states of dysmetabolism to the development of lean MAFLD. This perspective offers a more nuanced understanding of MAFLD and its underlying mechanisms and highlights the importance of considering the broader metabolic context in which the disease occurs. It also bridges the knowledge gap and offers insights that can inform clinical practice.
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Transforming growth factor-ß (TGFß) drives fibrosis and disease progression in a number of chronic disorders, but targeting this ubiquitously expressed cytokine may not yield a viable and safe antifibrotic therapy. Here, we sought to identify alternative ways to inhibit TGFß signaling using human hepatic stellate cells and macrophages from humans and mice in vitro, as well as mouse models of liver, kidney, and lung fibrosis. We identified Mer tyrosine kinase (MERTK) as a TGFß-inducible effector of fibrosis that was up-regulated during fibrosis in multiple organs in three mouse models. We confirmed these findings in liver biopsy samples from patients with metabolic dysfunction-associated fatty liver disease (MAFLD). MERTK also induced TGFß expression and drove TGFß signaling resulting in a positive feedback loop that promoted fibrosis in cultured cells. MERTK regulated both canonical and noncanonical TGFß signaling in both mouse and human cells in vitro. MERTK increased transcription of genes regulating fibrosis by modulating chromatin accessibility and RNA polymerase II activity. In each of the three mouse models, disrupting the fibrosis-promoting signaling loop by reducing MERTK expression reduced organ fibrosis. Pharmacological inhibition of MERTK reduced fibrosis in these mouse models either when initiated immediately after injury or when initiated after fibrosis was established. Together, these data suggest that MERTK plays a role in modulating organ fibrosis and may be a potential target for treating fibrotic diseases.
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Fígado , Proteínas Tirosina Quinases , Animais , Humanos , Camundongos , c-Mer Tirosina Quinase/metabolismo , Modelos Animais de Doenças , Fibrose , Fígado/metabolismo , Proteínas Tirosina Quinases/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Lean patients with MAFLD have an initial adaptive metabolic response characterised by increased serum bile acids and Farnesoid X Receptor (FXR) activity. How this adaptive response wanes resulting in an equal or perhaps worse long-term adverse outcome compared to patients with obese MAFLD is not known. We show that patients with lean MAFLD have endotoxemia while their macrophages demonstrate excess production of inflammatory cytokines in response to activation by Toll-like receptor (TLR) ligands when compared to healthy subjects. Alterations of the lean MAFLD macrophage epigenome drives this response and suppresses bile acids signalling to drive inflammation. Our data suggests that selectively restoring bile acids signalling might restore adaptive metabolic responses in patients with MAFLD who are lean.
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Endotoxemia , Hepatopatia Gordurosa não Alcoólica , Humanos , Receptores Citoplasmáticos e Nucleares/genética , Endotoxemia/genética , Inflamação/genética , Ácidos e Sais Biliares , Epigênese GenéticaRESUMO
In this work, we convert a plastic waste, i.e., polystyrene (PS), into a sorbent by a simple sulfonation process. The sulfonation time was optimized and the structures of the resulting sulfonated polystyrene (SPS) was characterized by field emission scanning electron microscopy, energy-dispersive X-ray and contact angle tests. The results showed that the sulfonation time of 7 h can introduce abundant sulfonic groups and preserve the self-standing structure. Additionally, the SPS has a three-dimensional porous structure and hydrophilic surface because of the presence of numerous sulfonic groups, which could serve as effective binding sites for immobilizing varying pollutants. Furthermore, as a proof-of-concept, the adsorption performance of the SPS foams was evaluated using three pollutants, namely Pb2+, lysozyme and methylene blue. The adsorption isotherms were fitted by the Langmuir and Freundlich models, while the kinetics of the adsorption processes were analyzed using the pseudo-first-order, pseudo-second-order and intraparticle diffusion equations. It was found that the adsorption isotherms of Pb2+ and lysozyme can be better described by the Langmuir model, leading to maximum equilibrium adsorption uptakes of 10.5 and 15.7 mg g-1 for the adsorption of Pb2+ and lysozyme, respectively. Importantly, the pollutant-saturated SPS is readily regenerated by acid washing, and the recovered sorbents exhibit outstanding cyclic performance. The abundant availability of feedstock, facile preparation and regeneration processes render the SPS foams a promising sorbent for practical applications.
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The breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.
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COVID-19 , Hepatopatias , Humanos , Receptores Toll-Like , Aciltransferases , Proteínas de MembranaRESUMO
Despite the rising health burden of metabolic (dysfunction) associated fatty liver disease (MAFLD), there are no approved pharmacotherapies for MAFLD currently. This situation led to a significant escalation in drug development and randomized controlled trials for MAFLD, particularly as novel information about its molecular pathogenesis unfolds. Currently, there are numerous investigational candidate drugs for MAFLD in various stages of clinical development that act on different pathophysiological processes, such as metabolism/steatosis, inflammation or fibrosis. Here, we provide an update on drug development for the treatment of MAFLD and discuss the prospects and challenges for improving and accelerating the nonalcoholic fatty liver disease drug discovery pipeline.
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Hepatopatia Gordurosa não Alcoólica , Desenvolvimento de Medicamentos , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológicoRESUMO
Uniform positively charged polystyrene microspheres were synthesized and further examined as a new sorbent for water remediation. The structures of the resulting sorbent were characterized by field-emission scanning electron microscopy, Fourier transform infrared spectroscopy, and 1H nuclear magnetic resonance spectroscopy. The adsorption performance of the sorbent was evaluated using three typical pollutants, namely, Congo red, phosphate, and Cr(VI). The adsorption isotherms were fitted by the Langmuir and Freundlich models, while the adsorption kinetics was analyzed by the pseudo-first-order, pseudo-second-order, and intraparticle diffusion equations. The thermodynamic parameters of the adsorption process including changes of enthalpy, entropy and Gibbs free energy, and binding constant were obtained by isothermal titration calorimetry measurements. The effects of solution pH and competitive ions on the adsorption process were investigated. The adsorption isotherms could be better fitted by the Langmuir model, yielding maximum adsorption capacities of 18, 6.2, and 1.1 mg g-1 for the adsorption of Congo red, Cr(VI), and phosphate, respectively. The adsorption kinetics could be best described by the pseudo-second-order equation. The spent sorbent was regenerated by washing with 1 M KOH and showed outstanding long-term cyclic performance. The findings suggested that the positive charges at the surface of polystyrene microspheres could serve as effective sites for the immobilization of anionic pollutants in solutions owing to the electrostatic attraction.
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This work reports the feasibility of utilizing sulfonated polystyrene nanospheres (SPS NSs) to extract heavy metals from collagen solutions. We have endeavored to present a detailed study on the adsorption characteristics and mechanism of heavy metals including Pb2+, Mn2+, Cr3+ and Cd2+. The adsorption isotherms were fitted by the Langmuir and Freundlich models while the adsorption kinetics data were described by the pseudo-first-order, pseudo-second-order and intraparticle diffusion equations. The adsorption isotherms were better fitted by the Langmuir model, leading to theoretical maximum capacities of 50.7, 15.0, 8.7 and 39.0â¯mgâ¯g-1 for the adsorption of Pb2+, Mn2+, Cr3+ and Cd2+, respectively. Isothermal titration calorimetry (ITC) measurements were conducted to detect the heat exchange of the adsorption processes. As a proof of concept, SPS NSs were practically applied in sequestrating heavy metals from Talapia-fish-scale derived collagen. The effects of pH of the collagen solutions in the removal of metals were investigated. By a single treatment, the concentrations of the metal ions were decreased to the regulatory standards whilst the concentration of collagen proteins was well maintained.
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Colágeno/química , Metais Pesados/isolamento & purificação , Nanosferas/química , Poluentes Químicos da Água/isolamento & purificação , Adsorção , Calorimetria/métodos , Difusão , Concentração de Íons de Hidrogênio , Cinética , Poliestirenos/químicaRESUMO
Developing low-cost bifunctional electrocatalysts with superior activity for both the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) is of great importance for the widespread application of the water splitting technique. In this work, using earth-abundant transition metals (i.e., nickel, iron, and copper), 3D hierarchical nanoarchitectures, consisting of ultrathin Ni-Fe layered-double-hydroxide (Ni-Fe LDH) nanosheets or porous Ni-Fe oxides (NiFeOx ) assembled to a metallic NiCu alloy, are delicately constructed. In alkaline solution, the as-prepared Ni-Fe LDH@NiCu possesses outstanding OER activity, achieving a current density of 10 mA cm-2 at an overpotential of 218 mV, which is smaller than that of RuO2 catalyst (249 mV). In contrast, the resulting NiFeOx @NiCu exhibits better HER activity, yielding a current density of 10 mA cm-2 at an overpotential of 66 mV, which is slightly higher than that of Pt catalyst (53 mV) but superior to all other transition metal (hydr)oxide-based electrocatalysts. The remarkable activity of the Ni-Fe LDH@NiCu and NiFeOx @NiCu is further demonstrated by a 1.5 V solar-panel-powered electrolyzer, resulting in current densities of 10 and 50 mA cm-2 at overpotentials of 293 and 506 mV, respectively. Such performance renders the as-prepared materials as the best bifunctional electrocatalysts so far.