RESUMEN
BACKGROUND AND AIMS: Epidemiological evidence on the associations between female reproductive features and nonalcoholic fatty liver disease (NAFLD) is conflicting. To explore their causalities, we conducted a Mendelian randomization (MR) study. METHODS: Summary-level data were obtained, and univariable MR was performed to explore the causalities between female reproductive features and NAFLD. And we performed multivariable MR and MR mediation analysis to explore the mediation effects of educational attainment (EA) and body mass index (BMI) for these associations. Sensitivity analyses were performed to evaluate pleiotropy and heterogeneity. RESULTS: There were causal effects of age at menarche (AAMA) (odds ratio [OR]: 0.817, 95% confidence interval [CI]: 0.736-0.907, per year-increase), age at first birth (AFB) (OR: 0.851, 95%CI: 0.791-0.926, per year-increase) and age at first sexual intercourse (AFS) (OR: 0.676, 95%CI: 0.511-0.896, per standard deviation-increase) on NAFLD risk. Besides, the causal effects were also observed on NAFLD phenotypes including liver fat content (LFC) and alanine aminotransferase (ALT). Further mediation analysis showed that BMI mediated partial proportion of effects of AAMA and AFS on NAFLD/ALT, AFB on NAFLD/LFC/ALT, while EA mediated partial proportion of effects of AFB on NAFLD/LFC/ALT, and AFS on NAFLD/ALT. CONCLUSIONS: This study provided convincing evidence that early AAMA, AFB, and AFS were risk factors for NAFLD. Reproductive health education, obesity management, and education spread might be the beneficial strategies for NAFLD prevention.
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Índice de Masa Corporal , Análisis de la Aleatorización Mendeliana , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Femenino , Factores de Riesgo , Menarquia , Reproducción/genética , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Oportunidad RelativaRESUMEN
Non-alcoholic fatty liver disease (NAFLD) and myocardial infarction (MI) are two major health burdens with significant prevalence and mortality. This study aimed to explore the co-expressed genes to understand the relationship between NAFLD and MI and identify potential crucial biomarkers of NAFLD-related MI using bioinformatics and machine learning. Functional enrichment analysis was conducted, a co-protein-protein interaction (PPI) network diagram was constructed, and support vector machine-recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) techniques were employed to identify one differentially expressed gene (DEG), Thrombospondin 1 (THBS1). THBS1 demonstrated strong performance in distinguishing NAFLD patients (AUC = 0.981) and MI patients (AUC = 0.900). Immuno-infiltration analysis revealed significantly lower CD8+ T cells and higher neutrophil levels in patients with NAFLD and MI. CD8+ T cells and neutrophils were effective in distinguishing NAFLD/MI from healthy controls. Correlation analysis showed that THBS1 was positively correlated with CCR (chemokine receptor), MHC class (major histocompatibility complex class), neutrophils, parainflammation, and Tfh (follicular helper T cells), and negatively correlated with CD8+ T cells, cytolytic activity, and TIL (tumor-infiltrating lymphocytes) in NAFLD and MI patients. THBS1 emerged as a novel biomarker for diagnosing NAFLD/MI in comparison to healthy controls. The results indicate that CD8+ T cells and neutrophils could serve as inflammatory immune features for differentiating patients with NAFLD/MI from healthy individuals.
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Enfermedad del Hígado Graso no Alcohólico , Trombospondina 1 , Humanos , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , Infarto del Miocardio/inmunología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/genética , Máquina de Vectores de Soporte , Biomarcadores/metabolismo , Biomarcadores/análisisRESUMEN
Abnormal SUMOylation is implicated in non-alcoholic fatty liver disease (NAFLD) progression. Forkhead box protein A1 (FoxA1) has been shown to protect liver from steatosis, which was down-regulated in NAFLD. This study elucidated the role of FoxA1 deSUMOylation in NAFLD. NAFLD models were established in high-fat diet (HFD)-induced mice and palmitate acid (PAL)-treated hepatocytes. Hepatic steatosis was evaluated by biochemical and histological methods. Lipid droplet formation was determined by BODIPY and Oil red O staining. Target molecule levels were analyzed by RT-qPCR, Western blotting, and immunohistochemistry staining. SUMOylation of FoxA1 was determined by Ni-NTA pull-down assay and SUMOylation assay Ultra Kit. Protein interaction and ubiquitination were detected by Co-IP. Gene transcription was assessed by ChIP and dual luciferase reporter assays. Liver FoxA1 knockout mice developed severe liver steatosis, which could be ameliorated by sirtuin 6 (Sirt6) overexpression. Nutritional stresses reduced Sumo2/3-mediated FoxA1 SUMOylation at lysine residue K6, which promoted lipid droplet formation by repressing fatty acid ß-oxidation. Moreover, Sirt6 was a target gene of FoxA1, and Sirt6 transcription activity was restrained by deSUMOylation of FoxA1 at site K6. Furthermore, nutritional stresses-induced deSUMOylation of FoxA1 promoted the ubiquitination and degradation of FoxA1 with assistance of murine double minute 2 (Mdm2). Finally, activating FoxA1 SUMOylation delayed the progression of NAFLD in mice. DeSUMOylation of FoxA1 at K6 promotes FoxA1 degradation and then inhibits Sirt6 transcription, thereby suppressing fatty acid ß-oxidation and facilitating NAFLD development. Our findings suggest that FoxA1 SUMOylation activation might be a promising therapeutic strategy for NAFLD.
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Regulación hacia Abajo , Factor Nuclear 3-alfa del Hepatocito , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico , Sirtuinas , Sumoilación , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Factor Nuclear 3-alfa del Hepatocito/genética , Ratones , Humanos , Sirtuinas/metabolismo , Sirtuinas/genética , Masculino , Ratones Endogámicos C57BL , Dieta Alta en Grasa , Modelos Animales de EnfermedadRESUMEN
Background: Observational data posits a correlation between reproductive traits and nonalcoholic fatty liver disease (NAFLD), but their causal inference is still unclear. This investigation seeks to elucidate the causal influence of reproductive traits on NAFLD and determine the intervening role of health condition and socioeconomic status in these connections. Methods: Utilizing a Mendelian Randomization (MR) approach, this research leveraged a comprehensive dataset from the Genome-wide Association Study (GWAS) database. The study incorporated body mass index, major depression, educational level, household income and Townsend deprivation index as intermediary variables. Initially, a bidirectional two-sample MR study was conducted to explore the genetic associations between reproductive traits and NAFLD. Then, two-step MR analyses were implemented to quantify the extent of mediation by these indicators. The weighted inverse variance method was the primary analytical approach, complemented by several sensitivity analyses to affirm the robustness of the MR assumptions. Finally, these findings were validated in the FinnGen research. Results: The bidirectional MR analysis indicated that earlier reproductive traits (age at menarche, age at first sexual intercourse, and age at first birth) were associated with an elevated risk of NAFLD, absent any evidence of the reverse relationship. Body mass index accounted for 35.64% of the association between premature menarche and NAFLD. Additionally, body mass index, major depression, educational level and household income mediated 41.65%, 14.35%, 37.88%, and 18.59% of the connection between early sexual intercourse and NAFLD, respectively. Similarly, these same variables elucidated 36.36%, 15.58%, 41.56%, and 22.73% of the correlation between younger age at first birth and NAFLD. Conclusion: Our study elucidated the causal relationships between reproductive traits and NAFLD. Potential underlying mechanisms may involve factors such as body mass index, major depression, educational attainment and household income.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Enfermedad del Hígado Graso no Alcohólico , Clase Social , Humanos , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/genética , Femenino , Índice de Masa Corporal , Estado de Salud , Masculino , Adulto , Reproducción/genética , Polimorfismo de Nucleótido Simple , Persona de Mediana Edad , Menarquia/genética , Factores de RiesgoRESUMEN
BACKGROUND: Increasing evidences suggest that nonalcoholic fatty liver disease (NAFLD) is associated with neuropsychiatric disorders. Nevertheless, whether there were causal associations between them remained vague. A causal association between neuropsychiatric disorders and NAFLD was investigated in this study. METHODS: We assessed the published genome-wide association study summary statistics for NAFLD, seven mental disorder-related diseases and six central nervous system dysfunction-related diseases. The causal relationships were first assessed using two-sample and multivariable Mendelian randomization (MR). Then, sensitivity analyses were performed, followed by a reverse MR analysis to determine whether reverse causality is possible. Finally, we performed replication analyses and combined the findings from the above studies. RESULTS: Our meta-analysis results showed NAFLD significantly increased the risk of anxiety disorders (OR = 1.016, 95% CI = 1.010-1.021, P value < 0.0001). In addition, major depressive disorder was the potential risk factor for NAFLD (OR = 1.233, 95% CI = 1.063-1.430, P value = 0.006). Multivariable MR analysis showed that the causal effect of major depressive disorder on NAFLD remained significant after considering body mass index, but the association disappeared after adjusting for the effect of waist circumference. Furthermore, other neuropsychiatric disorders and NAFLD were not found to be causally related. CONCLUSIONS: These results implied causal relationships of NAFLD with anxiety disorders and Major Depressive Disorder. This study highlighted the need to recognize and understand the connection between neuropsychiatric disorders and NAFLD to prevent the development of related diseases.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Trastornos Mentales , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Trastornos Mentales/genética , Trastornos Mentales/epidemiología , Factores de Riesgo , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/epidemiología , Causalidad , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/genéticaRESUMEN
NAFLD has emerged as a significant public health concern, with its prevalence increasing globally. Emphasizing the complex relationship between dietary patterns and epigenetic modifications such as DNA methylation or miRNA expression can exert a positive impact on preventing and managing metabolic disorders, including NAFLD, within the 2030 Sustainable Development Goals. This review aims to evaluate the influence of dietary patterns on hepatic epigenetic gene modulation and provide dietary recommendations for the prevention and management of NAFLD in the general population. METHODS: Comprehensive screening and eligibility criteria identified eleven articles focusing on epigenetic changes in NAFLD patients through dietary modifications or nutrient supplementation. RESULTS AND DISCUSSION: Data were organized based on study types, categorizing them into evaluations of epigenetic changes in NAFLD patients through dietary pattern modifications or specific nutrient intake. CONCLUSIONS: The study highlights the importance of dietary interventions in managing and preventing NAFLD, emphasizing the potential of dietary patterns to influence hepatic epigenetic gene modulation. This study provides valuable insights and recommendations to mitigate the risk of developing NAFLD: (i) eat a primarily plant-based diet; (ii) increase consumption of high-fiber foods; (iii) consume more polyunsaturated and monounsaturated fatty acids; (iv) limit processed foods, soft drinks, added sugars, and salt; and (v) avoid alcohol.
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Epigénesis Genética , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/genética , Hígado/metabolismo , Dieta , Metilación de ADN , Conducta Alimentaria , Patrones DietéticosRESUMEN
Background: The minor G-allele of FOXO3 rs2802292 is associated with human longevity. The aim of this study was to test the protective effect of the variant against the association with type 2 Diabetes and NAFLD. Methods: rs2802292 was genotyped in a large population of middle-aged subjects (n = 650) from a small city in Southern Italy. All participants were interviewed to collect information about lifestyle and dietary habits; clinical characteristics were recorded, and blood samples were collected from all subjects. The association between rs2802292 and NAFLD or diabetes was tested using a logistic model and mediation analysis adjusted for covariates. Results: Overall, the results indicated a statistical association between diabetes and rs2802292, especially for the TT genotype (OR = 2.14, 1.01 to 4.53 95% C.I., p = 0.05) or in any case for those who possess the G-allele (OR = 0.45, 0.25 to 0.81 95% C.I., p = 0.008). Furthermore, we found a mediation effect of rs2802292 on diabetes (as mediator) and NAFLD. There is no direct relationship between rs2802292 and NAFLD, but the effect is direct (ß = 0.10, -0.003 to 0.12 95% C.I., p = 0.04) on diabetes, but only in TT genotypes. Conclusions: The data on our cohort indicate that the longevity-associated FOXO3 variant may have protective effects against diabetes and NAFLD.
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Diabetes Mellitus Tipo 2 , Proteína Forkhead Box O3 , Predisposición Genética a la Enfermedad , Enfermedad del Hígado Graso no Alcohólico , Polimorfismo de Nucleótido Simple , Humanos , Masculino , Femenino , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Italia/epidemiología , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiología , Proteína Forkhead Box O3/genética , Estudios de Cohortes , Genotipo , Alelos , AdultoRESUMEN
Fatty acid-binding protein 1 (FABP1) plays an important role in regulating fatty acid metabolism in liver, which is a potential therapeutic target for diseases such as non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are not well defined. Using complementary experimental models, we discovered FABP1 induction in hepatocytes as a primary mediator of lipogenesis when exposed to fatty acids, especially saturated fatty acids (SFAs). In the feeding trial, palm oil led to excess lipid accumulation in the liver of large yellow croaker (Larimichthys crocea), accompanied by significant induction of FABP1. In cultured cells, palmitic acid (PA), a kind of SFA, triggered the fabp1 expression and increased triglyceride (TG) contents. Knockdown of FABP1 dampened PA-induced TG accumulation through mitigated lipogenesis. The overexpression of FABP1 showed the opposite result. Furthermore, the inactivation of FABP1 led to induction in insulin-induced gene 1 (INSIG1) expression, which attenuated the processing of sterol regulatory element-binding protein 1 (SREBP1) by down-regulating the nuclear-localized SREBP1. These results revealed a previously unrecognized function of FABP1 in response to PA, providing additional evidence for targeting FABP1 in the treatment of NAFLD caused by SFA.
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Proteínas de Unión a Ácidos Grasos , Hepatocitos , Lipogénesis , Perciformes , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Animales , Hepatocitos/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Perciformes/metabolismo , Perciformes/genética , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Triglicéridos/metabolismo , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Ácido Palmítico/farmacología , Células CultivadasRESUMEN
Non-alcoholic Fatty Liver Disease (NAFLD), noted for its widespread prevalence among adults, has become the leading chronic liver condition globally. Simultaneously, the annual disease burden, particularly liver cirrhosis caused by NAFLD, has increased significantly. Neutrophil Extracellular Traps (NETs) play a crucial role in the progression of this disease and are key to the pathogenesis of NAFLD. However, research into the specific roles of NETs-related genes in NAFLD is still a field requiring thorough investigation. Utilizing techniques like AddModuleScore, ssGSEA, and WGCNA, our team conducted gene screening to identify the genes linked to NETs in both single-cell and bulk transcriptomics. Using algorithms including Random Forest, Support Vector Machine, Least Absolute Shrinkage, and Selection Operator, we identified ZFP36L2 and PHLDA1 as key hub genes. The pivotal role of these genes in NAFLD diagnosis was confirmed using the training dataset GSE164760. This study identified 116 genes linked to NETs across single-cell and bulk transcriptomic analyses. These genes demonstrated enrichment in immune and metabolic pathways. Additionally, two NETs-related hub genes, PHLDA1 and ZFP36L2, were selected through machine learning for integration into a prognostic model. These hub genes play roles in inflammatory and metabolic processes. scRNA-seq results showed variations in cellular communication among cells with different expression patterns of these key genes. In conclusion, this study explored the molecular characteristics of NETs-associated genes in NAFLD. It identified two potential biomarkers and analyzed their roles in the hepatic microenvironment. These discoveries could aid in NAFLD diagnosis and management, with the ultimate goal of enhancing patient outcomes.
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Biomarcadores , Trampas Extracelulares , Aprendizaje Automático , Enfermedad del Hígado Graso no Alcohólico , Análisis de la Célula Individual , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Humanos , Análisis de la Célula Individual/métodos , Trampas Extracelulares/metabolismo , Biomarcadores/metabolismo , Neutrófilos/metabolismo , Transcriptoma , Perfilación de la Expresión GénicaRESUMEN
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition worldwide, demanding further investigation into its pathogenesis. Circular RNAs (circRNAs) are emerging as pivotal regulators in MASLD processes, yet their pathological implications in MASLD remain poorly understood. This study focused on elucidating the role of circular RNA ribonucleotide reductase subunit M2 (circRRM2) in MASLD progression. In this study, we used both in vitro and in vivo MASLD models using long-chain-free fatty acid (FFA)-treated hepatocytes and high-fat diet (HFD)-induced MASLD in mice, respectively. We determined the expression patterns of circRRM2, microRNA-142-5p (miR-142-5p), and neuregulin 1 (NRG1) in livers of MASLD-afflicted mice and MASLD hepatocytes by RT-qPCR. Dual-luciferase reporter assays verified the binding relationships among circRRM2, miR-142-5p, and NRG1. We conducted further analyses of their roles in MASLD hepatocytes and modulated circRRM2, miR-142-5p, and NRG1 expression in vitro by transfection. Our findings were validated in vivo. The results demonstrated reduced levels of circRRM2 and NRG1, along with elevated miR-142-5p expression in MASLD livers and hepatocytes. Overexpression of circRRM2 downregulated lipogenesis-related genes and decreased triglycerides accumulation in livers of MASLD mice. MiR-142-5p, which interacts with circRRM2, effectively counteracted the effects of circRRM2 in MASLD hepatocytes. Furthermore, NRG1 was identified as a miR-142-5p target, and its overexpression mitigated the regulatory impact of miR-142-5p on MASLD hepatocytes. In conclusion, circRRM2, via its role as a miR-142-5p sponge, upregulating NRG1, possibly influenced triglycerides accumulation in both in vitro and in vivo MASLD models.NEW & NOTEWORTHY CircRRM2 expression was downregulated in free fatty acid (FFA)-challenged hepatocytes and high-fat diet (HFD) fed mice. Overexpressed circular RNA ribonucleotide reductase subunit M2 (circRRM2) attenuated metabolic dysfunction-associated steatotic liver disease (MASLD) development by suppressing FFA-induced triglycerides accumulation. CircRRM2 targeted microRNA-142-5p (miR-142-5p), which served as an upstream inhibitor of neuregulin 1 (NRG1) and collaboratively regulated MASLD progression.
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Dieta Alta en Grasa , Hepatocitos , MicroARNs , Neurregulina-1 , ARN Circular , Animales , MicroARNs/metabolismo , MicroARNs/genética , Ratones , Hepatocitos/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Masculino , Neurregulina-1/genética , Neurregulina-1/metabolismo , Ratones Endogámicos C57BL , Hígado Graso/metabolismo , Hígado Graso/genética , Humanos , Hígado/metabolismo , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Ribonucleósido Difosfato ReductasaRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by the accumulation of fat in the liver in the absence of excessive alcohol consumption or a secondary cause of hepatic steatosis. The prevalence of NAFLD is increasing worldwide and its management has become a public health concern. Animal models are traditionally used to elucidate disease mechanisms and identify potential drug targets; however, their translational aspects in human diseases have not been fully established. This study aimed to clarify the utility of animal models for translational research by assessing their relevance to human diseases using gene expression analysis. Weighted gene co-expression network analysis of liver tissues from Western diet (WD)-induced NAFLD mice was performed to identify the modules associated with disease progression. Moreover, the similarity of the gene co-expression network across species was evaluated using module preservation analysis. Nineteen disease-associated modules were identified. The brown module was positively associated with disease severity, and functional analyses indicated that it may be involved in inflammatory responses in immune cells. Moreover, the gene co-expression network of the brown module was highly preserved in human NAFLD liver gene expression datasets. These results indicate that WD-induced NAFLD mice have similar gene co-expression networks (especially genes associated with inflammatory responses) to humans and are thought to be a useful experimental tool for preclinical research on NAFLD. Keywords: Nonalcoholic fatty liver disease (NAFLD), Weighted gene co-expression network analysis (WGCNA), Western diet (WD).
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Dieta Occidental , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Transcriptoma , Animales , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Dieta Occidental/efectos adversos , Ratones , Humanos , Masculino , Hígado/metabolismo , Hígado/patología , Perfilación de la Expresión Génica/métodosRESUMEN
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common liver disease associated with obesity and is caused by the accumulation of ectopic fat without alcohol consumption. Coxsackievirus and adenovirus receptor (CAR) are vital for cardiac myocyte-intercalated discs and endothelial cell-to-cell tight junctions. CAR has also been reported to be associated with obesity and high blood pressure. However, its function in the liver is still not well understood. The liver of obese mice exhibit elevated CAR mRNA and protein levels. Furthermore, in the liver of patients with non-alcoholic steatohepatitis, CAR is reduced in hepatocyte cell-cell junctions compared to normal levels. We generated liver-specific CAR knockout (KO) mice to investigate the role of CAR in the liver. Body and liver weights were not different between wild-type (WT) and KO mice fed a paired or high-fat diet (HFD). However, HFD induced significant liver damage and lipid accumulation in CAR KO mice compared with WT mice. Additionally, inflammatory cytokines transcription, hepatic permeability, and macrophage recruitment considerably increased in CAR KO mice. We identified a new interaction partner of CAR using a protein pull-down assay and mass spectrometry. Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3C (APOBEC3C) demonstrated a complex relationship with CAR, and hepatic CAR expression tightly regulated its level. Moreover, Apolipoprotein B (ApoB) and Low-density lipoprotein receptor (LDLR) levels correlated with APOBEC3C expression in the liver of CAR KO mice, suggesting that CAR may regulate lipid accumulation by controlling APOBEC3C activity. In this study, we showed that hepatic CAR deficiency increased cell-to-cell permeability. In addition, CAR deletion significantly increased hepatic lipid accumulation by inducing ApoB and LDLR expression. Although the underlying mechanism is unclear, CARs may be a target for the development of novel therapies for MAFLD.
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Proteína de la Membrana Similar al Receptor de Coxsackie y Adenovirus , Hígado , Ratones Noqueados , Animales , Proteína de la Membrana Similar al Receptor de Coxsackie y Adenovirus/metabolismo , Proteína de la Membrana Similar al Receptor de Coxsackie y Adenovirus/genética , Hígado/metabolismo , Hígado/patología , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Dieta Alta en Grasa/efectos adversos , Humanos , Hepatocitos/metabolismo , Masculino , Ratones Endogámicos C57BLRESUMEN
This study examines the complex interplay of genetic and environmental interactions that shape chronic illness risk. Evidence is mounting for the role of genetic expression and the immune response in the pathogenesis of chronic disease. In the Rio Grande Valley of south Texas, where 90% of the population is Mexican American, chronic illnesses (including obesity, diabetes, nonalcoholic liver disease, and depression) are reaching epidemic proportions. This study leverages an ongoing family study of the genetic determinants of risk for obesity, diabetes, hypertension, hyperlipidemia, and depression in a Mexican American population. Data collected included blood pressure, BMI, hepatic transaminases, HbA1c, depression (BDI-II), acculturation/marginalization (ARSMA-II), and liver health as assessed by elastography. Heritability and genotype-by-environment (G×E) interactions were analyzed, focusing on the marginalization/separation measure of the ARSMA-II. Significant heritabilities were found for traits such as HbA1c (h2 = 0.52), marginalization (h2 = 0.30), AST (h2 = 0.25), ALT (h2 = 0.41), and BMI (h2 = 0.55). Genotype-by-environment interactions were significant for HbA1c, AST/ALT ratio, BDI-II, and CAP, indicating that genetic factors interact with marginalization to influence these traits. This study found that acculturation stress exacerbates the genetic response to chronic illness. These findings underscore the importance of considering G×E interactions in understanding disease susceptibility and may inform targeted interventions for at-risk populations. Further research is warranted to elucidate the underlying molecular pathways and replicate these findings in diverse populations.
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Aculturación , Interacción Gen-Ambiente , Americanos Mexicanos , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/etnología , Masculino , Femenino , Americanos Mexicanos/genética , Adulto , Persona de Mediana Edad , Enfermedad Crónica , Genotipo , Estrés Psicológico/genética , Predisposición Genética a la Enfermedad , Obesidad/genética , Texas/epidemiologíaRESUMEN
PURPOSE: Nonalcoholic steatohepatitis (NASH) has been an increasingly significant contributor to hepatocellular carcinoma (HCC). Understanding the progression from NASH to HCC is critical to early diagnosis and elucidating the underlying mechanisms. RESULTS: 5 significant prognostic genes related to NASH-HCC transformation were identified through algorithm selection, which were ME1, TP53I3, SOCS2, GADD45G and CYP7A1. A diagnostic model for NASH prediction was established (AUC=0.988). TP53I3 and SOCS2 were selected as potential critical genes in the progression of NASH-HCC by external dataset validation and in vitro experiments on NASH and HCC cell lines. Immune infiltration analysis illustrated the correlation between 5 significant prognostic genes and immune cells. Single-cell analysis identified hepatocytes related to NASH-HCC transformation markers, revealing their promoting role in the transformation from NASH to HCC. CONCLUSION: With bulk-seq analysis and single-cell analysis, 5 significant prognostic genes related to NASH-HCC transformation were identified and validated at both dataset and in vitro experiment level. Among them, TP53I3 and SOCS2 might be potential critical genes in NASH-HCC progression. Single-cell analysis identified and revealed the critical role that NASH-HCC related hepatocytes play in NASH-HCC tansformation. Our research may introduce a new perspective to the diagnosis, treatment of NASH-related HCC.
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Carcinoma Hepatocelular , Biología Computacional , Neoplasias Hepáticas , Aprendizaje Automático , Enfermedad del Hígado Graso no Alcohólico , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Biología Computacional/métodos , Pronóstico , Transformación Celular Neoplásica/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Proteínas Supresoras de la Señalización de Citocinas/genética , Línea Celular Tumoral , Análisis de la Célula Individual/métodosRESUMEN
BACKGROUND: Nonalcoholic Steatohepatitis (NASH) results from complex liver conditions involving metabolic, inflammatory, and fibrogenic processes. Despite its burden, there has been a lack of any approved food-and-drug administration therapy up till now. PURPOSE: Utilizing machine learning (ML) algorithms, the study aims to identify reliable potential genes to accurately predict the treatment response in the NASH animal model using biochemical and molecular markers retrieved using bioinformatics techniques. METHODS: The NASH-induced rat models were administered various microbiome-targeted therapies and herbal drugs for 12 weeks, these drugs resulted in reducing hepatic lipid accumulation, liver inflammation, and histopathological changes. The ML model was trained and tested based on the Histopathological NASH score (HPS); while (0-4) HPS considered Improved NASH and (5-8) considered non-improved, confirmed through rats' liver histopathological examination, incorporates 34 features comprising 20 molecular markers (mRNAs-microRNAs-Long non-coding-RNAs) and 14 biochemical markers that are highly enriched in NASH pathogenesis. Six different ML models were used in the proposed model for the prediction of NASH improvement, with Gradient Boosting demonstrating the highest accuracy of 98% in predicting NASH drug response. FINDINGS: Following a gradual reduction in features, the outcomes demonstrated superior performance when employing the Random Forest classifier, yielding an accuracy of 98.4%. The principal selected molecular features included YAP1, LATS1, NF2, SRD5A3-AS1, FOXA2, TEAD2, miR-650, MMP14, ITGB1, and miR-6881-5P, while the biochemical markers comprised triglycerides (TG), ALT, ALP, total bilirubin (T. Bilirubin), alpha-fetoprotein (AFP), and low-density lipoprotein cholesterol (LDL-C). CONCLUSION: This study introduced an ML model incorporating 16 noninvasive features, including molecular and biochemical signatures, which achieved high performance and accuracy in detecting NASH improvement. This model could potentially be used as diagnostic tools and to identify target therapies.
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Modelos Animales de Enfermedad , Aprendizaje Automático , Enfermedad del Hígado Graso no Alcohólico , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Ratas , Hígado/patología , Hígado/metabolismo , Hígado/efectos de los fármacos , Masculino , Proteínas Señalizadoras YAP/genética , Biomarcadores/sangre , MicroARNs/genéticaRESUMEN
BACKGROUND: Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are prevalent metabolic disorders with overlapping pathophysiological mechanisms. A comprehensive understanding of the shared molecular pathways involved in these conditions can advance the development of effective therapeutic interventions. METHODS: We used two datasets sourced from the Gene Expression Omnibus (GEO) database to identify common differentially expressed genes (DEGs) between T2D and NAFLD. Subsequently, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to identify the enriched biological processes and signaling pathways. In addition, we performed a protein-protein interaction (PPI) network analysis to identify hub genes with pivotal roles. To validate our findings, we established a type 2 diabetic mouse model with NAFLD. RESULTS: Our analysis identified 53 DEGs shared between T2D and NAFLD. Enrichment analysis revealed their involvement in signal transduction, transcriptional regulation, and cell proliferation as well as in the ferroptosis signaling pathways. PPI network analysis identified ten hub genes, namely CD44, CASP3, FYN, KLF4, HNRNPM, HNRNPU, FUBP1, RUNX1, NOTCH3, and ANXA2. We validated the differential expression of FYN, HNRNPU, and FUBP1 in liver tissues of a type 2 diabetic mouse model with NAFLD. CONCLUSIONS: Our study offers valuable insights into the shared molecular mechanisms underlying T2D and NAFLD. The identified hub genes and pathways present promising prospects as therapeutic targets to address these prevalent metabolic disorders.
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Biología Computacional , Diabetes Mellitus Tipo 2 , Modelos Animales de Enfermedad , Enfermedad del Hígado Graso no Alcohólico , Mapas de Interacción de Proteínas , Animales , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Ratones , Biología Computacional/métodos , Factor 4 Similar a Kruppel , Masculino , Ratones Endogámicos C57BL , Redes Reguladoras de Genes , Transducción de Señal , Perfilación de la Expresión Génica , HumanosRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and represents the main cause of liver cirrhosis and hepatocellular carcinoma. Cav3.2 is a T-type calcium channel that is widely present in tissues throughout the body and plays a vital role in energy and metabolic balance. However, the effects of Cav3.2 on the NFALD remain unclear. Here, we investigated the role of Cav3.2 channel in the development and progression of NAFLD. After 16 weeks on a high-fat diets (HFD), Cav3.2 knockout (Cav3.2 KO) improved hepatic steatosis, liver injury and metabolic syndrome in an NAFLD mouse model. We provided evidence that Cav3.2 KO inhibited HFD-induced hepatic oxidative stress, inflammation and hepatocyte apoptosis. In addition, Cav3.2 KO also attenuated hepatic lipid accumulation, oxidative stress, inflammation and hepatocyte apoptosis in palmitic acid/oleic acid (PAOA)-treated primary hepatocytes. These results suggest that therapeutic approaches targeting Cav3.2 provide effective approaches for treating NAFLD.
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Apoptosis , Canales de Calcio Tipo T , Dieta Alta en Grasa , Hepatocitos , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico , Estrés Oxidativo , Animales , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Canales de Calcio Tipo T/genética , Canales de Calcio Tipo T/metabolismo , Ratones , Dieta Alta en Grasa/efectos adversos , Hepatocitos/metabolismo , Hepatocitos/patología , Masculino , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Hígado/metabolismo , Hígado/patología , Inflamación/genética , Inflamación/metabolismoRESUMEN
Obesity, cardiovascular diseases (CVD), and nonalcoholic fatty liver disease (NAFLD) pose significant worldwide health challenges, characterized by complex interplay among inflammatory pathways that underlie their development. In this review, we examine the contribution of inflammation and associated signaling molecules to the pathogenesis of these conditions, while also emphasizing the significant participation of non-coding RNAs (ncRNAs) in modulating inflammatory pathways. In the context of obesity, aberrant expression patterns of inflammatory-associated miRNAs play a contributory role in adipose tissue inflammation and insulin resistance, thereby exacerbating disturbances in metabolic homeostasis. Similarly, in CVD, dysregulated miRNA expression alters inflammatory reactions, disrupts endothelial function, and induces cardiac remodeling, thereby impacting the advancement of the disease. Moreover, in the context of NAFLD, inflammatory-associated miRNAs are implicated in mediating hepatic inflammation, lipid deposition, and fibrosis, underscoring their candidacy as promising therapeutic targets. Additionally, the competing endogenous RNA (ceRNA) network has emerged as a novel regulatory mechanism in the etiology of CVD, obesity, and NAFLD, wherein ncRNAs assume pivotal roles in facilitating communication across diverse molecular pathways. Moreover, in the concluding section, we underscored the potential efficacy of directing interventions towards inflammatory-related miRNAs utilizing herbal remedies and therapies based on exosome delivery systems as a promising strategy for ameliorating pathologies associated with inflammation in obesity, CVD, and NAFLD.
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Enfermedades Cardiovasculares , Inflamación , MicroARNs , Enfermedad del Hígado Graso no Alcohólico , Obesidad , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Inflamación/genética , Inflamación/metabolismo , Obesidad/genética , Obesidad/metabolismo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , AnimalesRESUMEN
OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) has significant genetic susceptibility. Adipocytokines play a crucial role in NAFLD development by participating in insulin resistance and hepatic steatosis. However, the association between adipocytokine pathway genes and NAFLD remains unclear. This study aims to explore the association of gene polymorphisms in the adipocytokine pathway and their interactions with NAFLD in obese children. METHODS: A case-control study was conducted, dividing obese children into NAFLD and control groups. Peripheral venous blood (2 mL) was collected from each participant for DNA extraction. A total of 14 single nucleotide polymorphisms (SNP) in the adipocytokine pathway were genotyped using multiplex PCR and high-throughput sequencing. Univariate and multivariate Logistic regression analyses were used to assess the association between SNP and NAFLD in obese children. Dominant models were used to analyze additive and multiplicative interactions via crossover analysis and Logistic regression. Generalized multifactor dimensionality reduction (GMDR) was used to detect gene-gene interactions among the 14 SNPs and their association with NAFLD in obese children. RESULTS: A total of 1 022 children were included, with 511 in the NAFLD group and 511 in the control group. After adjusting for age, gender, and BMI, multivariate Logistic regression showed that PPARG rs1801282 was associated with NAFLD in the obese children in 3 genetic models: heterozygote model (CG vs CC, OR=0.58, 95% CI 0.36 to 0.95, P=0.029), dominant model (GG+CG vs CC, OR=0.62, 95% CI 0.38 to 1.00, P=0.049), and overdominant model (CC+GG vs CG, OR=1.72, 95% CI 1.06 to 2.80, P=0.028). PRKAG2 rs12703159 was associated with NAFLD in 4 genetic models: heterozygous model (CT vs CC, OR=1.51, 95% CI 1.10 to 2.07, P=0.011), dominant model (CT+TT vs CC, OR=1.50, 95% CI 1.10 to 2.03, P=0.010), overdominant model (CC+TT vs CT, OR=0.67, 95% CI 0.49 to 0.92, P=0.012), and additive model (CC vs CT vs TT, OR=1.40, 95% CI 1.07 to 1.83, P=0.015). No significant multiplicative or additive interaction between PPARG rs1801282 and PRKAG2 rs12703159 was found in association with NAFLD. GMDR analysis, adjusted for age, gender, and BMI, revealed no statistically significant interactions among the 14 SNPs (all P>0.05). CONCLUSIONS: Mutations in PPARG rs1801282 and PRKAG2 rs12703159 are associated with NAFLD in obese children. However, no gene-gene interactions among the SNP are found to be associated with NAFLD in obese children.
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Adipoquinas , Predisposición Genética a la Enfermedad , Enfermedad del Hígado Graso no Alcohólico , Polimorfismo de Nucleótido Simple , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Niño , Estudios de Casos y Controles , Masculino , Femenino , Adipoquinas/genética , Adipoquinas/sangre , Obesidad/genética , Obesidad/complicaciones , PPAR gamma/genética , Adolescente , Obesidad Infantil/genética , Obesidad Infantil/complicacionesRESUMEN
BACKGROUND: Previous studies have suggested that psychiatric factors may be pathogenic for NAFLD. However, the association between depression and NAFLD is not been consistent, and whether depression plays a causal role in the development of NAFLD remains unclear. METHODS: We extracted data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 to assess the correlation between depression and NAFLD risk. Based on previous genome-wide association studies (GWAS) meta-analyses on NAFLD and depression, we performed a Mendelian randomization (MR) analysis to explore the causal effect of depression on NAFLD. The primary analysis method used in the MR analysis was inverse variance weighted. RESULTS: We ultimately extracted the data from 3878 individuals in the NHANES database to perform the cross-sectional study. Multivariable-adjusted logistic regression showed that depressed individuals had a higher risk of NAFLD than controls (odds ratio [OR] 1.33, 95 % CI 1.03-1.72, p = 0.027) among women. Based on GWAS data, we included 36 genetic variants as instrumental variables to estimate the causal effect of depression on NAFLD risk. The MR analysis revealed a causal association between genetically predicted depression and an increased risk of NAFLD (OR = 1.504, 95 % CI 1.13-2.00, p = 0.005). LIMITATIONS: The consistency of these findings in Eastern populations requires further longitudinal studies. CONCLUSIONS: This cross-sectional study suggested that depression might increase the risk of NAFLD in women. The MR analysis demonstrated that there exists a causal association between genetically predicated depression and NAFLD risk.