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1.
Nat Immunol ; 24(11): 1921-1932, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37813964

RESUMEN

The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.


Asunto(s)
Ácidos Cetoglutáricos , NAD , Humanos , Oxidación-Reducción , NAD/metabolismo , Ácidos Cetoglutáricos/metabolismo , Amoníaco , Malatos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Infección Persistente , Antivirales
2.
Immunity ; 50(5): 1218-1231.e5, 2019 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-30952607

RESUMEN

Patients with the neurological disorder HSAN-I suffer frequent infections, attributed to a lack of pain sensation and failure to seek care for minor injuries. Whether protective CD8+ T cells are affected in HSAN-I patients remains unknown. Here, we report that HSAN-I-associated mutations in serine palmitoyltransferase subunit SPTLC2 dampened human T cell responses. Antigen stimulation and inflammation induced SPTLC2 expression, and murine T-cell-specific ablation of Sptlc2 impaired antiviral-T-cell expansion and effector function. Sptlc2 deficiency reduced sphingolipid biosynthetic flux and led to prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1), endoplasmic reticulum (ER) stress, and CD8+ T cell death. Protective CD8+ T cell responses in HSAN-I patient PBMCs and Sptlc2-deficient mice were restored by supplementing with sphingolipids and pharmacologically inhibiting ER stress-induced cell death. Therefore, SPTLC2 underpins protective immunity by translating extracellular stimuli into intracellular anabolic signals and antagonizes ER stress to promote T cell metabolic fitness.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Serina C-Palmitoiltransferasa/genética , Animales , Proliferación Celular , Células Cultivadas , Citocinas/biosíntesis , Estrés del Retículo Endoplásmico/genética , Estrés del Retículo Endoplásmico/inmunología , Femenino , Humanos , Coriomeningitis Linfocítica/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Transducción de Señal/inmunología , Esfingolípidos/biosíntesis
3.
Eur J Immunol ; 53(1): e2149400, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36263815

RESUMEN

While the immunosuppressive function of regulatory T (Treg) cells has been extensively studied, their immune-supportive roles have been less well investigated. Using a lymphocytic choriomeningitis virus (LCMV) Armstrong infection mouse model, we found that Treg cell-derived interleukin (IL)-15 is required for long-term maintenance of the KLRG1+ IL-7Rα- CD62L- terminal effector memory CD8+ T (tTEM) cell subset, but dispensable for the suppressive function of Treg cells themselves. In contrast, deletion of Il15 from other sources, including myeloid cells and muscles, did not affect the composition of the memory CD8+ T cell pool. Our findings identify Treg cells as an essential IL-15 source maintaining tTEM cells and suggest that Treg cells promote the diversity of immunological memory.


Asunto(s)
Coriomeningitis Linfocítica , Linfocitos T Reguladores , Ratones , Animales , Virus de la Coriomeningitis Linfocítica , Memoria Inmunológica , Interleucina-15 , Linfocitos T CD8-positivos , Ratones Endogámicos C57BL , Interleucina-2
4.
Int J Cancer ; 151(5): 797-808, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35499751

RESUMEN

Memory CD8+ T cells mature after antigen clearance and ultimately express CD8 protein at levels higher than those detected in effector CD8+ T cells. However, it is not clear whether engagement of CD8 in the absence of antigenic stimulation will result in the functional activation of T cells. Here, we found that CD8 antibody-mediated activation of memory CD8+ T cells triggered T cell receptor (TCR) downstream signaling, enhanced T cell-mediated cytotoxicity and promoted effector cytokine production in a glucose- and glutamine-dependent manner. Furthermore, pretreatment of memory CD8+ T cells with an agonistic anti-CD8 antibody enhanced their tumoricidal activity in vitro and in vivo. From these studies, we conclude that CD8 agonism activates glucose and glutamine metabolism in memory T cells and enhances the efficacy of memory T cell-based cancer immunotherapy.


Asunto(s)
Linfocitos T CD8-positivos , Glutamina , Glucosa/metabolismo , Glutamina/metabolismo , Humanos , Memoria Inmunológica , Activación de Linfocitos , Células T de Memoria , Receptores de Antígenos de Linfocitos T , Transducción de Señal
5.
Cell Mol Life Sci ; 76(1): 129-145, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30151693

RESUMEN

As an analgesic and antipyretic drug, acetaminophen (APAP) is commonly used and known to be safe at therapeutic doses. In many countries, the overuse of APAP provokes acute liver injury and even liver failure. APAP-induced liver injury (AILI) is the most used experimental model of drug-induced liver injury (DILI). Here, we have demonstrated elevated levels of growth arrest and DNA damage-inducible 45α (GADD45α) in the livers of patients with DILI/AILI, in APAP-injured mouse livers and in APAP-treated hepatocytes. GADD45α exhibited a protective effect against APAP-induced liver injury and alleviated the accumulation of small lipid droplets in vitro and in vivo. We found that GADD45α promoted the activation of AMP-activated protein kinase α and induced fatty acid beta-oxidation, tricarboxylic acid cycle (TCA) and glycogenolysis-related gene expression after APAP exposure. Liquid chromatography-mass spectrometry (LC-MS) analysis showed that GADD45α increased the levels of TCA cycle metabolites. Co-immunoprecipitation analysis showed that Ppp2cb, a catalytic subunit of protein phosphatase 2A, could interact directly with GADD45α. Our results indicate that hepatocyte GADD45α might represent a therapeutic target to prevent and rescue liver injury caused by APAP.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Acetaminofén/efectos adversos , Antipiréticos/efectos adversos , Proteínas de Ciclo Celular/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Hígado/efectos de los fármacos , Proteínas Nucleares/metabolismo , Proteínas Quinasas Activadas por AMP/análisis , Analgésicos no Narcóticos/efectos adversos , Animales , Proteínas de Ciclo Celular/análisis , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Ciclo del Ácido Cítrico/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Ácidos Grasos/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/análisis , Transducción de Señal/efectos de los fármacos
6.
Lipids Health Dis ; 16(1): 153, 2017 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-28807032

RESUMEN

BACKGROUND: Acetaminophen (APAP) overdose is one of the most common causes of acute liver failure in many countries. The aim of the study was to describe the profiling of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in the plasma and liver of Acetaminophen -induced liver injured mice. METHODS: A time course study was carried out using C57BL/6 mice after intraperitoneal administration of 300 mg/kg Acetaminophen 1 h, 3 h, 6 h, 12 h and 24 h. A high-throughput liquid chromatography mass spectrometry (LC-MS) lipidomic method was utilized to detect phosphatidylcholine and phosphatidylethanolamine species in the plasma and liver. The expressions of phosphatidylcholine and phosphatidylethanolamine metabolism related genes in liver were detected by quantitative Reverse transcription polymerase chain reaction (qRT-PCR) and Western-blot. RESULTS: Following Acetaminophen treatment, the content of many PC and PE species in plasma increased from 1 h time point, peaked at 3 h or 6 h, and tended to return to baseline at 24 h time point. The relative contents of almost all PC species in liver decreased from 1 h, appeared to be lowest at 6 h, and then return to normality at 24 h, which might be partly explained by the suppression of phospholipases mRNA expressions and the induction of choline kinase (Chka) expression. Inconsistent with PC profile, the relative contents of many PE species in liver increased upon Acetaminophen treatment, which might be caused by the down-regulation of phosphatidylethanolamine N-methyltransferase (Pemt). CONCLUSIONS: Acetaminophen overdose induced dramatic change of many PC and PE species in plasma and liver, which might be caused by damaging hepatocytes and interfering the phospholipid metabolism in Acetaminophen -injured liver.


Asunto(s)
Acetaminofén/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Hígado/efectos de los fármacos , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Colina Quinasa/genética , Colina Quinasa/metabolismo , Cromatografía Liquida , Regulación de la Expresión Génica , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Inyecciones Intraperitoneales , Hígado/metabolismo , Hígado/patología , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Fosfatidiletanolamina N-Metiltransferasa/genética , Fosfatidiletanolamina N-Metiltransferasa/metabolismo , Fosfolipasas/genética , Fosfolipasas/metabolismo
7.
Scand J Gastroenterol ; 50(9): 1152-9, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25877002

RESUMEN

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a mitochondrial disease associated with the metabolic syndrome, but few data are available on the mitochondrial dysfunction of NAFLD after the development of type 2 diabetes mellitus (T2DM). We aimed to identify the changes of mitochondrial function in rat livers when T2DM develops after NAFLD. MATERIAL AND METHODS: Rat models of nonalcoholic fatty liver (NAFL) and T2DM were established using high-fat diet and streptozocin. Mitochondria were isolated from the livers. The levels of reactive oxygen species (ROS) and mRNA and protein levels of mitochondrial complex IV (COX IV) and carnitine palmitoyltransferase-1 (CPT-1) were assessed in rat livers. The mitochondrial membrane potential (MP), and the enzyme activities of COX IV and CPT-1 were measured in isolated mitochondria. RESULTS: There were increased ROS, decreased mitochondrial MP, and reduced COX IV and CPT-1 activity in the NAFL and T2DM groups compared with controls (p < 0.05). Compared with NAFL, the T2DM group had higher ROS levels and lower enzyme activity (p < 0.05), but showed no difference in mitochondrial MP. Although COX IV and CPT-1 expression levels in liver decreased in NAFL and T2DM, there was no significant difference between two groups. CONCLUSION: This study first identified progressively impaired mitochondrial respiratory chain and ß-oxidation in NAFLD when T2DM develops, inducing overproduction of ROS, and finally triggering a vicious circle that leads to the aggravation of mitochondrial dysfunction in NAFLD after development of T2DM.


Asunto(s)
Carnitina O-Palmitoiltransferasa/genética , Diabetes Mellitus Tipo 2/complicaciones , Hígado/patología , Mitocondrias Hepáticas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Animales , Glucemia , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Sprague-Dawley
8.
Cell Mol Immunol ; 21(5): 419-435, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38565887

RESUMEN

T cells are an important component of adaptive immunity and protect the host from infectious diseases and cancers. However, uncontrolled T cell immunity may cause autoimmune disorders. In both situations, antigen-specific T cells undergo clonal expansion upon the engagement and activation of antigens. Cellular metabolism is reprogrammed to meet the increase in bioenergetic and biosynthetic demands associated with effector T cell expansion. Metabolites not only serve as building blocks or energy sources to fuel cell growth and expansion but also regulate a broad spectrum of cellular signals that instruct the differentiation of multiple T cell subsets. The realm of immunometabolism research is undergoing swift advancements. Encapsulating all the recent progress within this concise review in not possible. Instead, our objective is to provide a succinct introduction to this swiftly progressing research, concentrating on the metabolic intricacies of three pivotal nutrient classes-lipids, glucose, and amino acids-in T cells. We shed light on recent investigations elucidating the roles of these three groups of metabolites in mediating the metabolic and immune functions of T cells. Moreover, we delve into the prospect of "editing" metabolic pathways within T cells using pharmacological or genetic approaches, with the aim of synergizing this approach with existing immunotherapies and enhancing the efficacy of antitumor and antiinfection immune responses.


Asunto(s)
Diferenciación Celular , Subgrupos de Linfocitos T , Humanos , Animales , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Metabolismo Energético , Glucosa/metabolismo , Aminoácidos/metabolismo
9.
Sci Immunol ; 9(94): eadg8817, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38640251

RESUMEN

CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences Treg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1-dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits antitumor immunity.


Asunto(s)
Neoplasias , Esfingosina , Linfocitos T Reguladores , Receptor de Muerte Celular Programada 1/metabolismo , Serina/metabolismo , Esfingolípidos/metabolismo , Esfingosina/análogos & derivados , Microambiente Tumoral
10.
Int J Biol Sci ; 18(9): 3800-3817, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35813467

RESUMEN

Background : Acetaminophen (APAP)-induced liver injury (AILI) is a common cause of drug-induced liver injury (DILI). The mechanism underlying protection in AILI or DILI remains to be elucidated, and the role of early growth response 1 (Egr1) in AILI and potential mechanisms remain to be known. Methods : The role of Egr1 was studied both in vivo and in vitro. Liver-specific Egr1-knockout (Egr1LKO) mice and those overexpressing Egr1 via tail vein injection of Egr1-expressing adenovirus (Ad-Egr1) were utilized with AILI. Chromatin immunoprecipitation-sequencing, RNA-sequencing, seahorse XF analysis, and targeted fatty acid analysis were performed. EGR1 levels were also studied in liver tissues and serum samples from AILI/DILI patients. Results: In this study, we have demonstrated that Egr1 was upregulated in AILI models in vivo and in vitro. liver-specific Egr1 knockout aggravated AILI; however, Ad-Egr1 treatment ameliorated this. Mechanistically, Egr1 deficiency inhibited, whereas overexpression promoted, mitochondrial respiratory function and fatty acid ß-oxidation (FAO) activity in AILI. Egr1 transcriptionally upregulated FAO-related genes in hepatocytes. Notably, the knockdown of acetyl-coenzyme A acyltransferase 2 (Acaa2), a key gene involved in FAO, diminished this protective effect of Egr1. Clinically, EGR1 was markedly increased in liver tissues from AILI patients. Interestingly, EGR1 levels of liver tissues and serum samples were also obviously higher in idiosyncratic DILI patients. Conclusions: Egr1 confers adaptive protection in AILI, mediated via the transcriptional upregulation of Acaa2, which improves mitochondrial FAO, and might be a potential biomarker and novel therapeutic target for AILI.


Asunto(s)
Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Acetaminofén/toxicidad , Acetil-CoA C-Aciltransferasa , Aciltransferasas/farmacología , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/farmacología , Ácidos Grasos , Hígado , Ratones , Ratones Endogámicos C57BL
11.
Sci Immunol ; 7(71): eabh1873, 2022 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-35622904

RESUMEN

T cells become functionally exhausted in tumors, limiting T cell-based immunotherapies. Although several transcription factors regulating the exhausted T (Tex) cell differentiation are known, comparatively little is known about the regulators of Tex cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed Tex cell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16+CD8+ tumor-infiltrating lymphocytes (TILs) were terminally differentiated, expressed low levels of T cell factor 1 (Tcf1), and underwent apoptosis as early as 6 days after the onset of Rgs16 expression. Rgs16 deficiency inhibited CD8+ T cell apoptosis and promoted antitumor effector functions of CD8+ T cells. Furthermore, Rgs16 deficiency synergized with programmed cell death protein 1 (PD-1) blockade to enhance antitumor CD8+ T cell responses. Proteomics revealed that Rgs16 interacted with the scaffold protein IQGAP1, suppressed the recruitment of Ras and B-Raf, and inhibited Erk1 activation. Rgs16 deficiency enhanced antitumor CD8+ TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions of Rgs16-deficient CD8+ T cells. RGS16 mRNA expression levels in CD8+ TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such as SELL, TCF7, and IL7R, and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of Tex cell survival in tumors and has implications for improving T cell-based immunotherapies.


Asunto(s)
Linfocitos T CD8-positivos , Receptor de Muerte Celular Programada 1 , Proteínas RGS/inmunología , Animales , Diferenciación Celular , Humanos , Inmunoterapia , Linfocitos Infiltrantes de Tumor , Ratones
12.
Cells ; 8(8)2019 08 12.
Artículo en Inglés | MEDLINE | ID: mdl-31409057

RESUMEN

Background: Group VIA calcium-independent phospholipase A2 (iPla2ß) regulates homeostasis and remodeling of phospholipids (PL). We previously showed that iPla2ß-/- mice fed with a methionine-choline-deficient diet (MCD) exhibited exaggerated liver fibrosis. As iPla2ß is located in the endoplasmic reticulum (ER), we investigated the mechanisms for this by focusing on hepatic ER unfolded protein response (UPR), ER PL, and enterohepatic bile acids (BA). Methods: Female WT (wild-type) and iPla2ß-/- mice were fed with chow or MCD for 5 weeks. PL and BA profiles were measured by liquid chromatography-mass spectrometry. Gene expression analyses were performed. Results: MCD feeding of WT mice caused a decrease of ER PL subclasses, which were further decreased by iPla2ß deficiency. This deficiency alone or combined with MCD downregulated the expression of liver ER UPR proteins and farnesoid X-activated receptor. The downregulation under MCD was concomitant with an elevation of BA in the liver and peripheral blood and an increase of biliary epithelial cell proliferation measured by cytokeratin 19. Conclusion: iPla2ß deficiency combined with MCD severely disturbed ER PL composition and caused inactivation of UPR, leading to downregulated Fxr, exacerbated BA, and ductular proliferation. Our study provides insights into iPla2ß inactivation for injury susceptibility under normal conditions and liver fibrosis and cholangiopathies during MCD feeding.


Asunto(s)
Retículo Endoplásmico/metabolismo , Fibrosis/metabolismo , Fosfolipasas A2 Grupo VI/fisiología , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Ácidos y Sales Biliares/metabolismo , Proliferación Celular , Modelos Animales de Enfermedad , Retículo Endoplásmico/patología , Femenino , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Fosfolípidos/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Respuesta de Proteína Desplegada
13.
Toxicol Lett ; 283: 69-76, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29174983

RESUMEN

Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure in many countries. In the present study, we developed stable mouse models of acute drug-induced hepatic injury (DILI) and acute drug-induced hepatic failure (DILF) by sub-lethal and lethal APAP injection respectively. The differences in hepatic transcriptome profiling between these two models were compared by RNA sequencing, which were validated by qPCR, western-blot and ELISA. In results, serum IL-6, TNF-a and IL-10 levels are higher in DILF than in DILI. The upregulated genes in DILF compared with DILI were mostly enriched in the areas of "cellular development process", "cell division", "multicellular organism development," etc. The downregulated genes in DILF compared with DILI were mostly enriched in the areas of "cellular response to chemical stimulus", "cellular response to stress", "cell activation," etc. Sub-lethal doses of APAP increased Myc, Bag3 and Btc expression in mouse liver, but lethal doses of APAP did not, which suggested that these three genes might play important roles in adaptive protection reactions in DILI. The serum Btc level might be a potential biomarker of drug induced liver injury with good prognosis. Our data can help us better understand the mechanisms of hepatotoxicity that influence prognosis and seek novel prognostic indicators of DILI.


Asunto(s)
Acetaminofén/toxicidad , Analgésicos no Narcóticos/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Fallo Hepático Agudo/inducido químicamente , Fallo Hepático Agudo/genética , Transcriptoma/efectos de los fármacos , Animales , Biomarcadores , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-10/biosíntesis , Interleucina-10/genética , Interleucina-6/biosíntesis , Interleucina-6/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética
14.
Exp Mol Med ; 49(1): e283, 2017 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-28082742

RESUMEN

We sought to identify common key regulators and build a gene-metabolite network in different nonalcoholic fatty liver disease (NAFLD) phenotypes. We used a high-fat diet (HFD), a methionine-choline-deficient diet (MCDD) and streptozocin (STZ) to establish nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) and NAFL+type 2 diabetes mellitus (T2DM) in rat models, respectively. Transcriptomics and metabolomics analyses were performed in rat livers and serum. A functional network-based regulation model was constructed using Cytoscape with information derived from transcriptomics and metabolomics. The results revealed that 96 genes, 17 liver metabolites and 4 serum metabolites consistently changed in different NAFLD phenotypes (>2-fold, P<0.05). Gene-metabolite network analysis identified ccl2 and jun as hubs with the largest connections to other genes, which were mainly involved in tumor necrosis factor, P53, nuclear factor-kappa B, chemokine, peroxisome proliferator activated receptor and Toll-like receptor signaling pathways. The specifically regulated genes and metabolites in different NAFLD phenotypes constructed their own networks, which were mainly involved in the lipid and fatty acid metabolism in HFD models, the inflammatory and immune response in MCDD models, and the AMPK signaling pathway and response to insulin in HFD+STZ models. Our study identified networks showing the general and specific characteristics in different NAFLD phenotypes, complementing the genetic and metabolic features in NAFLD with hepatic and extra-hepatic manifestations.


Asunto(s)
Regulación de la Expresión Génica , Redes Reguladoras de Genes , Redes y Vías Metabólicas , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Fenotipo , Animales , Biomarcadores , Diabetes Mellitus Tipo 2 , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Hígado/metabolismo , Hígado/patología , Masculino , Metaboloma , Metabolómica/métodos , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Ratas , Reproducibilidad de los Resultados , Transducción de Señal , Transcriptoma
15.
J Cancer Res Clin Oncol ; 143(1): 131-142, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27650934

RESUMEN

OBJECTIVE: The aim of this study was to evaluate the clinical outcomes of ultrasound-guided percutaneous microwave ablation (US-guided PMWA) for the treatment of hepatocellular carcinoma (HCC) with the analysis of prognostic factors. MATERIALS AND METHODS: The treatment and survival parameters of 433 patients with HCC (≤10 cm), who met the inclusion criteria and had received US-guided PMWA in Renji Hospital from July 2010 to November 2014, were retrospectively analyzed. Imaging examination (contrast-enhanced CT or MR) and tumor markers (AFP and CA199) 1 month after MWA were used to evaluate the efficacy of US-guided PMWA. SPSS software was used to perform all statistical analyses. RESULTS: The initial complete ablation (CA) rate was 94.9 % (411/433). Twenty-two patients with incomplete ablation received repeat PMWA, and the total CA rate was up to 98.6 % (427/433). Multiple tumor number, tumor >5 cm in diameter, and higher serum AFP level (>20 ng/ml) were significant unfavorable prognosticators of progression-free survival (PFS). The cumulative 1-, 2-, and 3-year overall survival (OS) rates were 83.5, 66.1, and 58.7 %, respectively (median: 43 months). Tumor >5 cm in diameter and serum AFP >400 ng/ml were significant unfavorable prognosticators of OS. CONCLUSIONS: PMWA is well tolerated in HCC patients and capable of offering high CA rate. Tumor number, tumor size, and AFP level were significant prognosticators of patients' PFS, whereas tumor size and AFP level were significant prognosticators of OS.


Asunto(s)
Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia/prevención & control , Técnicas de Ablación , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Hígado/diagnóstico por imagen , Hígado/cirugía , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/mortalidad , Masculino , Microondas , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del Tratamiento , Ultrasonografía
16.
PLoS One ; 10(5): e0127352, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25993652

RESUMEN

UNLABELLED: Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. Additionally, there are no definite noninvasive methods for NASH diagnosis currently. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with non-alcoholic fatty liver disease (NAFLD) and its progression. Histologic features of rat livers were scored according to criteria established by the Nonalcoholic Steatohepatitis Clinical Research Network. Microarray was performed to assess gene expression changes in rat livers. We find that gene expression of s100a9 was higher in NAFL group compared with control, and was increased in NASH groups and decreased in NAFL + T2DM group compared with NAFL. In contrast, srebf1, tbx21, and gimap4 only showed limited discriminating abilities in different groups. There is a significant positive correlation between serum levels of S100A9 and NAFLD Activity Score (NAS), the severity of hepatic steatosis, and lobular inflammation (r = 0.80, 0.64 and 0.86, P < 0.001). These findings suggest that S100A9 may be extremely useful in the diagnosis of NASH (AUROC: 0.947, CI: 0.845-1.049). Additionally, serum S100A9 levels displayed a strong correlation with ALT, AST and TBil (r = 0.81, 0.89 and 0.91, P < 0.001) but a weak correlation with FBG, HOMA-IR, TG, and TC (r = -0.41, -0.40, 0.47 and 0.49, P < 0.05). CONCLUSIONS: The results we provide here suggest that S100A9 may be useful as a biomarker for the hepatic and metabolic progression of NAFLD and the non-invasive diagnosis of NASH.


Asunto(s)
Biomarcadores/metabolismo , Calgranulina B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Progresión de la Enfermedad , Ratas
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