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1.
Gastroenterology ; 160(6): 2119-2132.e9, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33524400

RESUMEN

BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.


Asunto(s)
Carcinoma Ductal Pancreático/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Genes BRCA1 , Genes BRCA2 , Neoplasias Pancreáticas/genética , Reparación del ADN por Recombinación , Anciano , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/terapia , Cisplatino/administración & dosificación , Proteínas de Unión al ADN/genética , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/genética , Femenino , Fluorouracilo/uso terapéutico , Inestabilidad Genómica , Mutación de Línea Germinal , Recombinación Homóloga , Humanos , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Oxaliplatino/uso terapéutico , Pancreatectomía , Neoplasias Pancreáticas/terapia , Pronóstico , Sensibilidad y Especificidad , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/genética , Secuenciación Completa del Genoma , Gemcitabina
2.
Int J Cancer ; 143(1): 179-183, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29396858

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA-mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA-mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in vivo in three BRCA-associated PDAC PDXs models: (1) HRD-genome naïve to treatments; (2) stable-genome naïve to treatment; (3) HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD-genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA-associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Compuestos de Platino/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Animales , Carcinoma Ductal Pancreático/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Inestabilidad Genómica , Recombinación Homóloga , Humanos , Ratones , Mutación , Metástasis de la Neoplasia , Trasplante de Neoplasias , Neoplasias Pancreáticas/genética , Compuestos de Platino/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Pronóstico , Secuenciación Completa del Genoma
3.
Nat Commun ; 15(1): 6162, 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39039076

RESUMEN

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.


Asunto(s)
Linfocitos T CD8-positivos , Fibroblastos Asociados al Cáncer , Carcinoma Ductal Pancreático , Senescencia Celular , Inmunoterapia , Neoplasias Pancreáticas , Sulfonamidas , Animales , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Linfocitos T CD8-positivos/inmunología , Ratones , Humanos , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/genética , Senescencia Celular/inmunología , Inmunoterapia/métodos , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Ratones Endogámicos C57BL , Línea Celular Tumoral , Activación de Linfocitos/inmunología , Femenino , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Adenocarcinoma/inmunología , Adenocarcinoma/terapia , Adenocarcinoma/genética , Adenocarcinoma/patología , Masculino , Compuestos Bicíclicos Heterocíclicos con Puentes
4.
Cancer Discov ; 13(8): 1826-1843, 2023 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-37449843

RESUMEN

Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified based on the spectrum of response to platinum/PARP inhibition: (i) refractory [overall survival (OS) <6 months], (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions. SIGNIFICANCE: glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Platino (Metal)/farmacología , Platino (Metal)/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Mutación , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas
5.
Adv Drug Deliv Rev ; 171: 257-265, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33617901

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease. The majority of patients diagnosed at an advanced, metastatic stage, and poor overall survival rates. The most clinically meaningful subtype obtained from PDAC genomic classification is represented by unstable genomes, and co-segregated with inactivation of DNA damage repair genes, e.g., Breast cancer 1/2 (BRCA1/2). The FDA and EMA has recently approved olaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor, as a maintenance strategy for platinum-sensitive advanced PDAC patients with BRCA mutations. However, susceptibility to treatment varies, and resistance may develop. Resistance can be defined as innate or acquired resistance to platinum/PARP-inhibition. Patient-derived xenograft (PDX) models have been utilized in cancer research for many years. We generated a unique PDX model, obtained from BRCA-associated PDAC patients at distinct time points of the disease recapitulating the different clinical scenario. In this review we discuss the relevant PDX-derived models for investigating BRCA-associated PDAC and drug development.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal Pancreático , Modelos Animales de Enfermedad , Neoplasias Pancreáticas , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Xenoinjertos , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Lab Invest ; 90(5): 674-84, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20231820

RESUMEN

We have previously shown that hyperthyroidism is detrimental for liver fibrosis and in this study we have investigated the mechanisms regulating triiodothyronine (T3) and L-thyroxine (T4) activation of hepatic stellate cells (HSC). Expression of alpha-smooth muscle actin (alphaSMA) and p75 neurotrophin receptor (p75NTR) was determined by western blot analyses and transient transfection of the promoters. Rho activation was assayed using a pull-down assay and by ELISA. Expression of thyroid hormone receptor alpha1 decreases, whereas T4 receptor integrin alphaVbeta3 increases, with transdifferentiation of HSC to myofibroblasts. T3 and T4 enhance HSC activation, without affecting proliferation or phosphorylation of mitogen-activated protein kinase, signal transducer and activator of transcription 3 or Akt. Addition of 10(-7) M T3 or T4 to thyroid hormone-depleted serum induces a twofold increase in activation marker alphaSMA, as well as upregulation of p75NTR protein levels. Both hormones enhance transcription of alphaSMA and p75NTR. We report a novel signaling pathway for thyroid hormones, activation of Rho. T4 induces activation of Rho acting through alphavbeta3 integrin, and the activation is abolished by the T4 antagonist, tetraiodothyroacetic acid, by peptide RGD and by a function-blocking antibody to integrin beta3. T3 and T4 increase phosphorylation of non-muscle myosin light chain II, a downstream signal to Rho/Rho-kinase activation. T3 also induces expression of tumor necrosis factor-alpha. In vivo, administration of T3 or T4 together with thioacetamide (TAA) enhances fibrosis after 3 weeks, compared with the TAA-treated group, accompanied by increased alphaSMA in T3- and T4-treated groups, and of p75NTR in T4-treated rats. Thyroid hormones enhance activation of HSC through increased p75NTR and alphaSMA expression and activation of Rho, therefore accelerating development of liver fibrosis.


Asunto(s)
Células Estrelladas Hepáticas/efectos de los fármacos , Receptor de Factor de Crecimiento Nervioso/metabolismo , Hormonas Tiroideas/farmacología , Quinasas Asociadas a rho/metabolismo , Actinas/genética , Actinas/metabolismo , Animales , Western Blotting , Transdiferenciación Celular/efectos de los fármacos , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Células Estrelladas Hepáticas/citología , Células Estrelladas Hepáticas/metabolismo , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Músculo Liso/química , Ratas , Ratas Wistar , Receptor de Factor de Crecimiento Nervioso/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptores alfa de Hormona Tiroidea/genética , Receptores alfa de Hormona Tiroidea/metabolismo , Hormonas Tiroideas/metabolismo , Tiroxina/metabolismo , Tiroxina/farmacología , Triyodotironina/metabolismo , Triyodotironina/farmacología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
7.
Oncotarget ; 11(5): 571-572, 2020 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-32082490

RESUMEN

[This corrects the article DOI: 10.18632/oncotarget.27268.].

8.
Oncotarget ; 11(14): 1290-1291, 2020 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-32292578

RESUMEN

[This corrects the article DOI: 10.18632/oncotarget.15343.].

9.
Oncotarget ; 10(58): 6269-6282, 2019 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-31692907

RESUMEN

Recent reports demonstrate an exclusive eradication of a variety of human cancer cells by the modified phenanthridine PJ34. Their eradication during mitosis is attributed to PJ34 preventing NuMA clustering in the mitotic spindle poles of human malignant cells, which is crucial for their normal mitosis. Here, the effect of PJ34 is tested in cell cultures and xenografts of human pancreas ductal adenocarcinoma. Evidence is presented for a substantial reduction (80-90%) of PANC1 cancer cells in xenografts, measured 30 days after the treatment with PJ34 has been terminated. Benign cells infiltrated into the PANC1 tumors (stroma) were not affected. Growth, weight gain and behavior of the treated nude mice were not impaired during, and 30 days after the treatment with PJ34. The efficient eradication of malignant cells in human pancreas cancer xenografts presents a new model of pancreas cancer treatment.

10.
Cancer Res ; 79(17): 4491-4502, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31273064

RESUMEN

Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have an average survival of less than 1 year, underscoring the importance of evaluating novel targets with matched targeted agents. We recently identified that poly (ADP) ribose glycohydrolase (PARG) is a strong candidate target due to its dependence on the pro-oncogenic mRNA stability factor HuR (ELAVL1). Here, we evaluated PARG as a target in PDAC models using both genetic silencing of PARG and established small-molecule PARG inhibitors (PARGi), PDDX-01/04. Homologous repair-deficient cells compared with homologous repair-proficient cells were more sensitive to PARGi in vitro. In vivo, silencing of PARG significantly decreased tumor growth. PARGi synergized with DNA-damaging agents (i.e., oxaliplatin and 5-fluorouracil), but not with PARPi therapy. Mechanistically, combined PARGi and oxaliplatin treatment led to persistence of detrimental PARylation, increased expression of cleaved caspase-3, and increased γH2AX foci. In summary, these data validate PARG as a relevant target in PDAC and establish current therapies that synergize with PARGi. SIGNIFICANCE: PARG is a potential target in pancreatic cancer as a single-agent anticancer therapy or in combination with current standard of care.


Asunto(s)
Carcinoma Ductal Pancreático/tratamiento farmacológico , Glicósido Hidrolasas/antagonistas & inhibidores , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Daño del ADN , Inhibidores Enzimáticos/farmacología , Femenino , Silenciador del Gen , Glicósido Hidrolasas/genética , Humanos , Ratones Desnudos , Terapia Molecular Dirigida , Oxaliplatino/farmacología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Reparación del ADN por Recombinación , Bibliotecas de Moléculas Pequeñas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Nat Commun ; 9(1): 2546, 2018 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-29959327

RESUMEN

While synthetic lethality (SL) holds promise in developing effective cancer therapies, SL candidates found via experimental screens often have limited translational value. Here we present a data-driven approach, ISLE (identification of clinically relevant synthetic lethality), that mines TCGA cohort to identify the most likely clinically relevant SL interactions (cSLi) from a given candidate set of lab-screened SLi. We first validate ISLE via a benchmark of large-scale drug response screens and by predicting drug efficacy in mouse xenograft models. We then experimentally test a select set of predicted cSLi via new screening experiments, validating their predicted context-specific sensitivity in hypoxic vs normoxic conditions and demonstrating cSLi's utility in predicting synergistic drug combinations. We show that cSLi can successfully predict patients' drug treatment response and provide patient stratification signatures. ISLE thus complements existing actionable mutation-based methods for precision cancer therapy, offering an opportunity to expand its scope to the whole genome.


Asunto(s)
Antineoplásicos/uso terapéutico , Ensayos Analíticos de Alto Rendimiento , Neoplasias/tratamiento farmacológico , Medicina de Precisión/métodos , Mutaciones Letales Sintéticas/efectos de los fármacos , Animales , Biomarcadores Farmacológicos , Hipoxia de la Célula , Línea Celular Tumoral , Combinación de Medicamentos , Sinergismo Farmacológico , Humanos , Ratones , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/mortalidad , Selección de Paciente , Medicina de Precisión/estadística & datos numéricos , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Oncotarget ; 8(13): 20813-20824, 2017 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-28209915

RESUMEN

We identified target proteins modified by phenanthrenes that cause exclusive eradication of human cancer cells. The cytotoxic activity of the phenanthrenes in a variety of human cancer cells is attributed by these findings to post translational modifications of NuMA and kinesins HSET/kifC1 and kif18A. Their activity prevented the binding of NuMA to α-tubulin and kinesins in human cancer cells, and caused aberrant spindles. The most efficient cytotoxic activity of the phenanthridine PJ34, caused significantly smaller aberrant spindles with disrupted spindle poles and scattered extra-centrosomes and chromosomes. Concomitantly, PJ34 induced tumor growth arrest of human malignant tumors developed in athymic nude mice, indicating the relevance of its activity for cancer therapy.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Mitosis/fisiología , Neoplasias/patología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Huso Acromático/patología , Animales , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/genética , Proteínas de Ciclo Celular , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Cinesinas/genética , Cinesinas/metabolismo , Ratones , Mitosis/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Asociadas a Matriz Nuclear/genética , Proteínas Asociadas a Matriz Nuclear/metabolismo , Fenantrenos/farmacología , Huso Acromático/efectos de los fármacos , Huso Acromático/genética , Huso Acromático/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Oncotarget ; 8(25): 40778-40790, 2017 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-28489577

RESUMEN

Pancreatic ductal adenocarcinoma has limited treatment options. There is an urgent need for developing appropriate pre-clinical models recapitulating metastatic disease, the most common clinical scenario at presentation. Ascites accumulation occurs in up to 20-30% of patients with pancreatic cancer; this milieu represents a highly cellular research resource of metastatic peritoneal spread. In this study, we utilized pancreatic ascites/pleural effusion cancer cells to establish patient derived xenografts.Ascites/pleural effusion-patient derived xenografts were established from twelve independent cases. Xenografts were serially passed in nude mice and tissue bio-specimen banking has been established. Histopathology of emergent tumors demonstrates poorly to moderately differentiated, glandular and mucin producing tumors, mirroring morphology of primary pancreatic cancer tumors. Whole genome sequencing of six patient derived xenografts samples demonstrates common mutations and structural variations similar to those reported in primary pancreatic cancer. Xenograft tumors were dissociated to single-cells and in-vitro drug sensitivity screen assays demonstrated chemo-resistance, correlating with patient clinical scenarios, thus serving as a platform for clinically relevant translational research.Therefore, establishment of this novel ascites/pleural effusion patient derived xenograft model, with extensive histopathology and genomic characterization, opens an opportunity for the study of advanced aggressive pancreatic cancer. Characterization of metastatic disease and mechanisms of resistance to therapeutics may lead to the development of novel drug combinations.


Asunto(s)
Ascitis/patología , Carcinoma Ductal Pancreático/patología , Animales , Ascitis/etiología , Ascitis/genética , Carcinoma Ductal Pancreático/genética , Modelos Animales de Enfermedad , Femenino , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Desnudos , Transfección , Secuenciación Completa del Genoma/métodos
14.
Obesity (Silver Spring) ; 20(1): 151-6, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21818154

RESUMEN

The present study examined whether the perinephric and epididymal visceral fat (PEVF) depot under short-term excess nutrient protected the liver by trapping nutrient-derived nonesterified free fatty acids (NEFAs) or had deleterious effects on hepatic triglycerides (TGs) accumulation and insulin resistance due to adipokine secretion. Young rats pre-emptively underwent surgical PEVF removal or sham operations and were fed with either high-fat diet (HFD) (PEVF-HFD) or regular chow (RC) (PEVF-RC) for 3 days. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Liver TG, serum NEFA, and fat-derived adipokines were assessed. Insulin and lipogenesis signaling were assessed by western blots. Pre-emptive PEVF removal significantly decreases insulin-induced suppression of hepatic glucose production (HGP) both in RC and in HFD-fed rats. In accordance with the clamp results, hepatic TG accumulation is also significantly reduced by PEVF excision both in RC and HFD-fed rats. These results are further validated by insulin signaling results, which show that pre-emptive PEVF removal increases phosphorylation of hepatic Akt, irrespective of diet. Notably, high levels of serum leptin induced by HFD are significantly reduced by pre-emptive PEVF excision. Additionally, expression of lipogenic enzyme p-acetyl-CoA-carboxylase, denoting reduced lipogenesis, is increased in the PEVF-HFD rats. In conclusion, PEVF has a deleterious effect on the liver as a source of insulin resistance-inducing adipokines irrespective of diet, and does not serve as a buffer for excess nutrients.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Hígado Graso/metabolismo , Grasa Intraabdominal/metabolismo , Hígado/metabolismo , Obesidad/metabolismo , Triglicéridos/metabolismo , Análisis de Varianza , Animales , Western Blotting , Epidídimo , Ácidos Grasos no Esterificados/metabolismo , Hígado Graso/etiología , Resistencia a la Insulina , Riñón , Masculino , Enfermedad del Hígado Graso no Alcohólico , Obesidad/complicaciones , Fosforilación , Ratas , Ratas Sprague-Dawley , Transducción de Señal
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