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Colorectal cancer and Crohn's disease patients develop pyogenic liver abscesses due to failures of immune cells to fight off bacterial infections. Here, we show that mice lacking iron regulatory protein 2 (Irp2), globally (Irp2-/-) or myeloid cell lineage (Lysozyme 2 promoter-driven, LysM)-specifically (Irp2ΔLysM), are highly susceptible to liver abscesses when the intestinal tissue was injured with dextran sodium sulfate treatment. Further studies demonstrated that Irp2 is required for lysosomal acidification and biogenesis, both of which are crucial for bacterial clearance. In Irp2-deficient liver tissue or macrophages, the nuclear location of transcription factor EB (Tfeb) was remarkably reduced, leading to the downregulation of Tfeb target genes that encode critical components for lysosomal biogenesis. Tfeb mislocalization was reversed by hypoxia-inducible factor 2 inhibitor PT2385 and, independently, through inhibition of lactic acid production. These experimental findings were confirmed clinically in patients with Crohn's disease and through bioinformatic searches in databases from Crohn's disease or ulcerative colitis biopsies showing loss of IRP2 and transcription factor EB (TFEB)-dependent lysosomal gene expression. Overall, our study highlights a mechanism whereby Irp2 supports nuclear translocation of Tfeb and lysosomal function, preserving macrophage antimicrobial activity and protecting the liver against invading bacteria during intestinal inflammation.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Enfermedad de Crohn , Proteína 2 Reguladora de Hierro , Lisosomas , Macrófagos , Animales , Lisosomas/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Ratones , Humanos , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Proteína 2 Reguladora de Hierro/metabolismo , Proteína 2 Reguladora de Hierro/genética , Ratones Noqueados , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/inmunología , Hígado/patologíaRESUMEN
Ovarian cancer (OC) is a gynecological malignancy that results in a global threat to women's lives. Lactic acid, a key metabolite produced from the glycolytic metabolism of glucose molecules, is correlated with tumor immune infiltration and platinum resistance. In our previous study, we found that endothelial cell-specific molecule 1 (ESM1) plays a key role in OC progression. This study revealed that lactate could upregulate ESM1, which enhances SCD1 to attenuate the antitumor CD8+ T-cell response. ESM1 and SCD1 expression levels were significantly greater in OC patients with high lactic acid levels than in those with low lactic acid levels. Further mechanistic studies suggested that the Wnt/ß-catenin pathway was inactivated after ESM1 knockdown and rescued by SCD1 overexpression. IC50 analysis indicated that the ESM1-SCD1 axis induces the resistance of OC cells to platinum agents, including cisplatin, carboplatin, and oxaliplatin, by upregulating P-gp. In conclusion, our study indicated that the induction of SCD1 by lactic acid-induced ESM1 can impede the CD8+ T-cell response against tumors and promote resistance to cisplatin by activating the Wnt/ß-catenin pathway in ovarian cancer. Consequently, targeting ESM1 may have considerable therapeutic potential for modulating the tumor immune microenvironment and enhancing drug sensitivity in OC patients.
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Antineoplásicos , Linfocitos T CD8-positivos , Cisplatino , Resistencia a Antineoplásicos , Ácido Láctico , Proteínas de Neoplasias , Neoplasias Ováricas , Proteoglicanos , Vía de Señalización Wnt , Femenino , Humanos , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Cisplatino/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Ácido Láctico/metabolismo , Proteoglicanos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/inmunología , Animales , Ratones , Estearoil-CoA DesaturasaRESUMEN
BACKGROUND AND AIMS: The global rise of chronic hepatitis B (CHB) superimposed on hepatic steatosis (HS) warrants noninvasive, precise tools for assessing fibrosis progression. This study leveraged machine learning (ML) to develop diagnostic models for advanced fibrosis and cirrhosis in this patient population. METHODS: Treatment-naive CHB patients with concurrent HS who underwent liver biopsy in 10 medical centers were enrolled as a training cohort and an independent external validation cohort (NCT05766449). Six ML models were implemented to predict advanced fibrosis and cirrhosis. The final models, derived from SHAP (Shapley Additive exPlanations), were compared with Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index using the area under receiver-operating characteristic curve (AUROC) and decision curve analysis (DCA). RESULTS: Of 1,198 eligible patients, the random forest model achieved AUROCs of 0.778 (95% confidence interval [CI], 0.749-0.807) for diagnosing advanced fibrosis (random forest advanced fibrosis model) and 0.777 (95% CI, 0.748-0.806) for diagnosing cirrhosis (random forest cirrhosis model) in the training cohort, and maintained high AUROCs in the validation cohort. In the training cohort, the random forest advanced fibrosis model obtained an AUROC of 0.825 (95% CI, 0.787-0.862) in patients with hepatitis B virus DNA ≥105 IU/mL, and the random forest cirrhosis model had an AUROC of 0.828 (95% CI, 0.774-0.883) in female patients. The 2 models outperformed Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index in the training cohort, and also performed well in the validation cohort. CONCLUSIONS: The random forest models provide reliable, noninvasive tools for identifying advanced fibrosis and cirrhosis in CHB patients with concurrent HS, offering a significant advancement in the comanagement of the 2 diseases. CLINICALTRIALS: gov, Number: NCT05766449.
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BACKGROUND AND AIMS: Data on the effects of liver fibrosis and hepatic steatosis on outcomes in individuals living with diabetes are limited. Therefore, we investigated the predictive value of the fibrosis and the severity of hepatic steatosis for all-cause mortality in individuals living with diabetes. METHODS: A total of 1903 patients with diabetes from the Third National Health and Nutrition Examination Survey (NHANES III) dataset were enrolled. Presumed hepatic fibrosis was evaluated with Fibrosis-4 index (FIB-4). The mortality risk and corresponding hazard ratio (HR) were analyzed with the Kaplan-Meier method and multivariable Cox proportional hazard models. RESULTS: Over a median follow-up of 19.4 years, all-cause deaths occurred in 69.6%. FIB-4 ≥ 1.3 was an independent predictor of mortality in individuals living with diabetes (HR 1.219, 95% confidence interval [CI]: 1.067-1.392, p = 0.004). Overall, FIB-4 ≥ 1.3 without moderate-severe steatosis increased the mortality risk (HR 1.365; 95%CI 1.147-1.623, p < 0.001). The similar results were found in individuals living with diabetes with metabolic dysfunction-associated fatty liver disease (MAFLD) (HR 1.499; 95%CI 1.065-2.110, p = 0.020), metabolic syndrome (MetS) (HR 1.397; 95%CI 1.086-1.796, p = 0.009) or abdominal obesity (HR 1.370; 95%CI 1.077-1.742, p = 0.010). CONCLUSIONS: Liver fibrosis, as estimated by FIB-4, may serve as a more reliable prognostic indicator for individuals living with diabetes than hepatic steatosis. Individuals living with diabetes with FIB-4 ≥ 1.3 without moderate-severe steatosis had a significantly increased all-cause mortality risk. These findings highlight the importance of identifying and monitoring those individuals, as they may benefit from further evaluation and risk stratification.
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Cirrosis Hepática , Encuestas Nutricionales , Índice de Severidad de la Enfermedad , Humanos , Masculino , Femenino , Persona de Mediana Edad , Cirrosis Hepática/mortalidad , Cirrosis Hepática/complicaciones , Hígado Graso/mortalidad , Hígado Graso/complicaciones , Hígado Graso/patología , Anciano , Adulto , Diabetes Mellitus/mortalidad , Factores de Riesgo , Modelos de Riesgos ProporcionalesRESUMEN
OBJECTIVE: Liver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis. DESIGN: HSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat-Cre mice or the Postn-CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation. RESULTS: We report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme. CONCLUSIONS: Our data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.
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Células Estrelladas Hepáticas , Cirrosis Hepática , Humanos , Ratones , Animales , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/patología , Hígado/metabolismo , MiofibroblastosRESUMEN
Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function. In the present study we investigated the contribution of megakaryocytic leukemia 1 (MKL1), a transcriptional modulator, to liver regeneration. We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients. Mice with MKL1 deletion exhibited defective regenerative response in the liver. Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription. MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1. Of interest, phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid (PA). PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure. Finally, PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients. In conclusion, our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration. Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.
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BACKGROUND AND AIMS: The relationship between moderate alcohol intake and health outcomes among individuals with metabolic dysfunction-associated fatty liver disease (MAFLD) is complex. Our aim was to investigate the association of minimal alcohol consumption with all-cause and cause-specific mortality among MAFLD individuals of different genders. METHODS: Our study included 2630 MAFLD individuals from the Third National Health and Nutrition Examination Survey. Cox regression analysis was performed to assess the association between alcohol use measures and all-cause and cause-specific mortality. Restricted cubic spline curves were used to evaluate the relationship between alcohol consumption per week and all-cause mortality. RESULTS: In the entire MAFLD cohort, we observed significant disparities in clinical characteristics between male and female individuals with MAFLD. Higher weekly alcohol consumption was significantly associated with all-cause and cause-specific mortality (male, hazard ratios [HRs]: 1.009, 95% CIs: 1.004-1.014; female, HRs: 1.032, 95% CIs: 1.022-1.042). In males with MAFLD, a linear association with all-cause mortality was observed for weekly alcohol consumption (p for non-linearity = .21). Conversely, in females with MAFLD, the risk of all-cause mortality remained relatively stable until 2 drinks per week, after which it rapidly increased with each additional drink consumed, and the increase in mortality risk was higher than that observed in males (p for non-linearity < .05). CONCLUSIONS: Our findings indicate that any increase in weekly alcohol consumption was associated with increased all-cause mortality in men with MAFLD. Conversely, consuming less than 2 drinks per week had minimal impact on the risk of mortality among female.
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Consumo de Bebidas Alcohólicas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Femenino , Masculino , Encuestas Nutricionales , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Conductas Relacionadas con la SaludRESUMEN
Background: With increasingly prevalent coexistence of chronic hepatitis B (CHB) and hepatic steatosis (HS), simple, non-invasive diagnostic methods to accurately assess the severity of hepatic inflammation are needed. We aimed to build a machine learning (ML) based model to detect hepatic inflammation in patients with CHB and concurrent HS. Methods: We conducted a multicenter, retrospective cohort study in China. Treatment-naive CHB patients with biopsy-proven HS between April 2004 and September 2022 were included. The optimal features for model development were selected by SHapley Additive explanations, and an ML algorithm with the best accuracy to diagnose moderate to severe hepatic inflammation (Scheuer's system ≥ G3) was determined and assessed by decision curve analysis (DCA) and calibration curve. This study is registered with ClinicalTrials.gov (NCT05766449). Findings: From a pool of 1,787 treatment-naive patients with CHB and HS across eleven hospitals, 689 patients from nine of these hospitals were chosen for the development of the diagnostic model. The remaining two hospitals contributed to two independent external validation cohorts, comprising 509 patients in validation cohort 1 and 589 in validation cohort 2. Eleven features regarding inflammation, hepatic and metabolic functions were identified. The gradient boosting classifier (GBC) model showed the best performance in predicting moderate to severe hepatic inflammation, with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% CI 0.83-0.88) in the training cohort, and 0.89 (95% CI 0.86-0.92), 0.76 (95% CI 0.73-0.80) in the first and second external validation cohorts, respectively. A publicly accessible web tool was generated for the model. Interpretation: Using simple parameters, the GBC model predicted hepatic inflammation in CHB patients with concurrent HS. It holds promise for guiding clinical management and improving patient outcomes. Funding: This research was supported by the National Natural Science Foundation of China (No. 82170609, 81970545), Natural Science Foundation of Shandong Province (Major Project) (No. ZR2020KH006), Natural Science Foundation of Jiangsu Province (No.BK20231118), Tianjin Key Medical Discipline (Specialty), Construction Project, TJYXZDXK-059B, Tianjin Health Science and Technology Project key discipline special, TJWJ2022XK034, and Research project of Chinese traditional medicine and Chinese traditional medicine combined with Western medicine of Tianjin municipal health and Family Planning Commission (2021022).
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The intrinsic fragility and insoluble nature of covalent organic frameworks (COFs) have strongly impeded their processability for practical applications. Herein, an aqueous-based sol-gel synthetic strategy is reported for the synthesis and shaping of COFs with task-specific applications that satisfy the principles of green chemistry for gram-scale production of crystalline materials. Our successful approach involves three pivotal aspects: the "prodrug mimic" design of water-soluble monomers, the utilization of hydrolyzable bonds, and the manipulation of reaction kinetics. The generality of the method is demonstrated by the successful preparation of representative high-surface area two-dimensional (2D) COFs with several commonly used amines. By virtue of this strategy, a COF colloidal dispersion is achieved and can be formulated into processable fluids, structured films, and COF monoliths. Remarkably, the obtained lightweight (â¼0.020 g cm-3) and robust aerogels displayed outstanding adsorption capacity (exceeding 57 times its own weight) toward a variety of organic solvents and exhibited superior thermal insulating properties compared to the widely used sponge and cotton. This work demonstrates a versatile strategy for the synthesis and shaping of processable COF materials in water that will contribute to the development of COF monoliths for advanced applications.
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AIMS: Hepatic ischemia-reperfusion injury (IRI) is a common complication secondary to liver transplantation. Extensive death of hepatocytes, typically in the form of apoptosis, is observed in and contributes to IRI. In the present study we investigated the role of BRG1 (encoded by Smarca4), a chromatin remodeling protein, in the pathogenesis of liver IRI focusing on the transcriptional mechanism and translational potential. METHODS: Smarca4f/f mice were crossed to Alb-Cre mice to generate hepatocytes-specific BRG1 knockout mice (CKO). Alterations in cellular transcriptome were evaluated by RNA-seq. RESULTS: BRG1 expression was up-regulated in liver tissues of mice subjected to I/R and in hepatocytes exposed to hypoxia-reoxygenation (H/R). Compared to wild type (WT) littermates, the BRG1 CKO mice displayed significant amelioration of liver injury following ischemia-reperfusion as evidenced by decreased ALT/AST levels and cell apoptosis. Primary hepatocytes isolated from the CKO mice were protected from H/R-induced apoptosis compared to those from the WT mice. RNA-seq analysis revealed phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, also known as NOXA) as a novel target for BRG1. Consistently, NOXA knockdown attenuated liver IRI in mice. More importantly, administration of a small-molecule BRG1 inhibitor (PFI-3) protected the mice from liver IRI. CONCLUSIONS: Our data uncover a pivotal role for BRG1 in liver IRI and suggest that targeting BRG1 with small-molecule inhibitors can be considered as a reasonable therapeutic strategy.
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Ensamble y Desensamble de Cromatina , Daño por Reperfusión , Animales , Ratones , Apoptosis , Proteínas Reguladoras de la Apoptosis/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Daño por Reperfusión/metabolismoRESUMEN
Lithium-sulfur (Li-S) battery features a high theoretical energy density, but the shuttle of soluble polysulfides between the two electrodes often results in a rapid capacity decay. Herein, a straightforward electrostatic adsorption strategy based on a cross-linked polyimidazolium separator as a snaring shield of polysulfides is reported, which suppresses the undesirable migration of polysulfides to the anode. The porous ionic network (PIN)-modified carbon nanotubes (CNTs) are successfully prepared and coated onto a commercial porous polypropylene membrane in a vacuum-filtration step. The favorable affinity of the imidazolium ring toward polysulfide via the polar interaction and the electrostatic effect of ions mitigates the undesirable shuttle of polysulfides in the electrolyte, improving the LiâS battery in terms of rate performance and cycling life. Compared to the reference PIN-free CNT-coated separator, the PIN/CNT-coated one has an increased initial capacity of 1.3 folds (up to 1394.8 mAh g-1 for PIN/CNT/PP-3) at 0.1 C.
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Litio , Nanotubos de Carbono , Porosidad , Iones , AzufreRESUMEN
Elaborately designed multifunctional electrocatalysts capable of promoting Li+ and CO2 transport are essential for upgrading the cycling stability and rate capability of Li-CO2 batteries. Hydrogen-bonded organic frameworks (HOFs) with open channels and easily functionalized surfaces hold great potential for applications in efficient cathodes of Li-CO2 batteries. Herein, a robust HOFS (HOF-FJU-1) is introduced for the first time as a co-catalyst in the cathode material of Li-CO2 batteries. HOF-FJU-1 with cyano groups located periodically in the pore can induce homogeneous deposition of discharge products and accommodate volumetric expansion of discharge products during cycling. Besides, HOF-FJU-1 enables effective interaction between Ru0 nanoparticles and cyano groups, thus forming efficient and uniform catalytic sites for CRR/CER. Moreover, HOF-FJU-1 with regularly arranged open channels are beneficial for CO2 and Li+ transport, enabling rapid redox kinetic conversion of CO2 . Therefore, the HOF-based Li-CO2 batteries are capable of stable operation at 400â mA g-1 for 1800â h and maintain a low overpotential of 1.96â V even at high current densities up to 5â A g-1 . This work provides valuable guidance for developing multifunctional HOF-based catalysts to upgrade the longevity and rate capability of Li-CO2 batteries.
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Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by accelerated lipid deposition, aberrant inflammation, and excessive extracellular matrix production in the liver. Short of effective intervention, NAFLD can progress to cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of the C-C motif ligand 11 (CCL11) in NAFLD pathogenesis. Methods: NAFLD was induced by feeding mice with a high-fat high-carbohydrate diet. CCL11 targeting was achieved by genetic deletion or pharmaceutical inhibition. The transcriptome was analysed using RNA-seq. Results: We report that CCL11 expression was activated at the transcription level by free fatty acids (palmitate) in hepatocytes. CCL11 knockdown attenuated whereas CCL11 treatment directly promoted production of pro-inflammatory/pro-lipogenic mediators in hepatocytes. Compared with wild-type littermates, CCL11 knockout mice displayed an ameliorated phenotype of NAFLD when fed a high-fat high-carbohydrate diet as evidenced by decelerated body weight gain, improved insulin sensitivity, dampened lipid accumulation, reduced immune cell infiltration, and weakened liver fibrosis. RNA-seq revealed that interferon regulatory factor 1 as a mediator of CCL11 induced changes in hepatocytes. Importantly, CCL11 neutralisation or antagonism mitigated NAFLD pathogenesis in mice. Finally, a positive correlation between CCL11 expression and NAFLD parameters was identified in human patients. Conclusions: Our data suggest that CCL11 is a novel regulator of NAFLD and can be effectively targeted for NAFLD intervention. Impact and implications: Non-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper we describe the regulatory role of CCL11, a C-C motif ligand chemokine, in NAFLD pathogenesis. Our data provide novel insights and translational potential for NAFLD intervention.
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BACKGROUND: Liver fibrosis is the strongest histological risk factor for liver-related complications and mortality in metabolic dysfunction-associated fatty liver disease (MAFLD). Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) is a powerful tool for label-free two-dimensional and three-dimensional tissue visualisation that shows promise in liver fibrosis assessment. AIM: To investigate combining multi-photon microscopy (MPM) and deep learning techniques to develop and validate a new automated quantitative histological classification tool, named AutoFibroNet (Automated Liver Fibrosis Grading Network), for accurately staging liver fibrosis in MAFLD. METHODS: AutoFibroNet was developed in a training cohort that consisted of 203 Chinese adults with biopsy-confirmed MAFLD. Three deep learning models (VGG16, ResNet34, and MobileNet V3) were used to train pre-processed images and test data sets. Multi-layer perceptrons were used to fuse data (deep learning features, clinical features, and manual features) to build a joint model. This model was then validated in two further independent cohorts. RESULTS: AutoFibroNet showed good discrimination in the training set. For F0, F1, F2 and F3-4 fibrosis stages, the area under the receiver operating characteristic curves (AUROC) of AutoFibroNet were 1.00, 0.99, 0.98 and 0.98. The AUROCs of F0, F1, F2 and F3-4 fibrosis stages for AutoFibroNet in the two validation cohorts were 0.99, 0.83, 0.80 and 0.90 and 1.00, 0.83, 0.80 and 0.94, respectively, showing a good discriminatory ability in different cohorts. CONCLUSION: AutoFibroNet is an automated quantitative tool that accurately identifies histological stages of liver fibrosis in Chinese individuals with MAFLD.
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Aprendizaje Profundo , Enfermedad del Hígado Graso no Alcohólico , Adulto , Humanos , Microscopía , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/patología , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/patología , BiopsiaRESUMEN
AIMS: Hepatocytes resume proliferation following liver injuries to compensate for the loss of liver mass. Robust liver regeneration is an intrinsic and pivotal process that facilitates restoration of liver anatomy and function. In the present study we investigated the role of ubiquitin-specific peptidase 47 (USP47) in liver regeneration. METHODS AND MATERIALS: Proliferation of hepatocytes was evaluated by Ki67 staining in vivo and EdU incorporation in vitro. DNA-protein interaction was evaluated by chromatin immunoprecipitation (ChIP). RESULTS: USP47 expression was up-regulated in hepatocytes isolated from mice subjected to partial hepatectomy (PHx) or exposed to HGF treatment. Ingenuity pathway analysis revealed E2F1 as a primary regulator of USP47 transcription. Reporter assay and ChIP assay confirmed that E2F1 directly bound to the USP47 promoter and activated USP47 transcription. Consistently, E2F1 knockdown abrogated USP47 induction by HGF. Compared to the wild type littermates, USP47 knockout mice displayed compromised liver regeneration following PHx. In addition, USP47 inhibition by a small-molecule compound impaired liver regeneration in mice. On the contrary, USP47 over-expression enhanced proliferation of hepatocytes in vitro and promoted liver regeneration in mice. Importantly, a positive correlation between USP47 expression and hepatocyte proliferation was identified in patients with acute liver failure (ALF). SIGNIFICANCE: Our data suggest that USP47, transcriptionally activated by E2F1, plays an essential role in liver regeneration.
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Hepatocitos , Regeneración Hepática , Proteasas Ubiquitina-Específicas , Masculino , Animales , Ratones , Proteasas Ubiquitina-Específicas/metabolismo , Hepatocitos/citología , Proliferación Celular , Ratones Noqueados , Factor de Transcripción E2F1/metabolismo , HumanosRESUMEN
Robust regenerative response post liver injuries facilitates the architectural and functional recovery of the liver. Intrahepatic redox homeostasis plays a key role in liver regeneration. In the present study, we investigated the contributory role of Tribbles homolog 1 (Trib1), a pseudokinase, in liver regeneration and the underlying mechanism. We report that Trib1 expression was transiently down-regulated in animal and cell models of liver regeneration. Further analysis revealed that hepatocyte growth factor (HGF) repressed Trib1 transcription by evicting liver X receptor (LXRα) from the Trib1 promoter. Knockdown of Trib1 enhanced whereas over-expression of Trib1 suppressed liver regeneration after partial hepatectomy in mice. Of interest, regulation of liver regenerative response by Trib1 coincided with alterations of intracellular ROS levels, GSH levels, and antioxidant genes. Transcriptional assays suggested that Trib1 influenced cellular redox status by attenuating nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Mechanistically, Trib1 interacted with the C-terminus of Nrf2 thus masking a potential nuclear localization signal (NLS) and blocking nuclear accumulation of Nrf2. Finally, correlation between Trib1 expression, Nrf2 nuclear localization, and cell proliferation was identified in liver specimens taken from patients with acute liver failure. In conclusion, our data unveil a novel pathway that depicts Trib1 as a critical link between intracellular redox homeostasis and cell proliferation in liver regeneration.
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Antioxidantes , Regeneración Hepática , Ratones , Animales , Regeneración Hepática/genética , Antioxidantes/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Hígado/metabolismo , Hepatectomía , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismoRESUMEN
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) contributes to the global epidemic of metabolic syndrome and is considered a prelude to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. During NAFLD pathogenesis, hepatic parenchymal cells (hepatocytes) undergo both morphological and functional changes owing to a rewired transcriptome. The underlying mechanism is not entirely clear. In the present study, we investigated the involvement of early growth response 1 (Egr1) in NAFLD. Methods: Quantitative PCR, Western blotting, and histochemical staining were used to assess gene expression levels. Chromatin immunoprecipitation was used to evaluate protein binding to DNA. NAFLD was evaluated in leptin receptor-deficient (db/db) mice. Results: We report here that Egr1 was upregulated by pro-NAFLD stimuli in vitro and in vivo. Further analysis revealed that serum response factor (SRF) was recruited to the Egr1 promoter and mediated Egr1 transactivation. Importantly, Egr1 depletion markedly mitigated NAFLD in db/db mice. RNA sequencing revealed that Egr1 knockdown in hepatocytes, on the one hand, boosted fatty acid oxidation (FAO) and, on the other hand, suppressed the synthesis of chemoattractants. Mechanistically, Egr1 interacted with peroxisome proliferator-activated receptor α (PPARα) to repress PPARα-dependent transcription of FAO genes by recruiting its co-repressor NGFI-A binding protein 1 (Nab1), which potentially led to promoter deacetylation of FAO genes. Conclusions: Our data identify Egr1 as a novel modulator of NAFLD and a potential target for NAFLD intervention. Impact and Implications: Non-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper, we describe a novel mechanism whereby early growth response 1 (Egr1), a transcription factor, contributes to NAFLD pathogenesis by regulating fatty acid oxidation. Our data provide novel insights and translational potential for NAFLD intervention.
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BACKGROUND: Due to the low incidence and histological heterogeneity, the molecular features and underlying carcinogenic mechanisms of thymic epithelial tumors (TETs) are yet to be fully elucidated, especially for different subtypes of TETs. METHODS: Tumor tissue samples of 43 TETs with distinct histological subtypes were collected. We analyzed the molecular characteristics in different subtypes based on whole exome sequencing data. RESULTS: The mutational profiles of the different subtypes of TETs varied. Compared with thymomas, thymic carcinomas (TCs) had a higher mutation frequency of MYO16 (33% vs. 3%, p = 0.024) and a lower frequency of ZNF729 mutations (0% vs. 35%, p = 0.044). No significant difference was observed in the median tumor mutation burden across different subtypes. The value of copy number variation burden, weighted genome instability index, and the number of amplified segments were all higher in TCs than thymomas, and they also tended to be higher in B3 thymoma than in non-B3 thymomas, while they had no significant differences between B3 thymoma and TCs. Clustering analyses revealed that Wnt, MAPK, Hedgehog, AMPK, and cell junction assembly signaling pathways were exclusively enriched in non-B3 thymomas, lysine degradation pathway in B3 thymoma, and extracellular matrix-receptor (ECM-receptor) interaction, positive regulation of cell cycle process, and activation of innate immune response pathways in TCs. CONCLUSIONS: This study revealed distinct molecular landscapes of different subtypes of TETs, suggesting diverse pathogenesis of non-B3 thymomas, B3 thymomas, and TCs. Our findings warrant further validation in future large-scale studies and may provide a theoretical basis for potential personalized therapeutic strategies.
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Neoplasias Glandulares y Epiteliales , Timoma , Neoplasias del Timo , Humanos , Timoma/genética , Timoma/patología , Variaciones en el Número de Copia de ADN , Neoplasias del Timo/genética , Neoplasias del Timo/patología , Neoplasias Glandulares y Epiteliales/genética , Biología MolecularRESUMEN
The WD-repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1-6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune-competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A-DDB1-ROC1 E3 ubiquitin ligase complex through a unique WDxR motif and promotes its degradation. This upregulates chromatin accessibility at the TNFα locus by blocking autophagic degradation of p65, elevates intratumoral myeloid-derived suppressor cell (MDSC) number, and reduces CD8+ T cell infiltration, thereby promoting HCC progression. These immunosuppressive effects are reversed by TNFα blockade. TNFα recruits NF-κB to activate the transcription of WDR6, establishing a WDR6-TNFα loop. Clinically, the WDR6/UVRAG/NF-κB pathway is hyperactivated in HCC, predicting a poor prognosis. Importantly, a WDxR-like peptide disrupts the WDR6/UVRAG complex and enhances the efficiency of anti-PD-L1 against HCC with WDR6 dysregulation.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Ratones , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Factor de Necrosis Tumoral alfa , FN-kappa B , Ratones Endogámicos C57BL , Ratones Endogámicos , Microambiente Tumoral , Línea Celular TumoralRESUMEN
BACKGROUND: Diabetes mellitus (DM) is a comorbidity commonly presenting with metabolic-dysfunction-associated fatty liver disease (MAFLD); however, few tests for interaction have been reported. Our target was to evaluate the prognostic implications of DM in patients with different forms of MAFLD. METHODS: Using data from the Third National Health and Nutrition Examination Survey (NHANES III) in the United States, we screened 14,797 participants aged 20-74 who received ultrasound examinations from 1988-1994. Among them, 4599 patients met the diagnosis of MAFLD, and we defined mortality as the outcome event. Survival analysis of competitive risk events was performed using Cox regression and sub-distributed risk ratio (SHR). RESULTS: During 21.1 years of follow-up, cardiovascular diseases seemed to be the most common cause of death among MAFLD patients. Of them, DM was present in 25.48% and was independently associated with increased risk of all-cause mortality (HRs: 1.427, 95% CIs: 1.256-1.621, p < 0.001) and cause-specific mortality (cardiovascular-related mortality (HRs: 1.458, 95% CIs: 1.117-1.902, p = 0.005), non-cardiovascular-related mortality (HRs: 1.423, 95% CIs: 1.229-1.647, p < 0.001), and non-cancer-related mortality (HRs: 1.584, 95% CIs: 1.368-1.835, p < 0.001), respectively). Surprisingly, this association was more significant for young patients (p-value for interaction <0.001). Moreover, DM had a greater risk of all-cause and cause-specific mortality among overweight and obese MAFLD patients (p-value for interaction <0.001). CONCLUSIONS: DM increased the risk of all-cause and cause-specific mortality (cardiovascular-related, non-cardiovascular-related, and non-cancer-related) in MAFLD patients, especially in younger patients with excess obesity.