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Gastroenterology ; 157(5): 1413-1428.e11, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31352001


BACKGROUND & AIMS: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. METHODS: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. RESULTS: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival-only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. CONCLUSIONS: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.

Células Acinares/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Transformação Celular Neoplásica/metabolismo , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias Intraductais Pancreáticas/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células Acinares/patologia , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/prevenção & controle , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Regulação para Baixo , Fatores de Crescimento de Fibroblastos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Transgênicos , Mutação , PPAR gama/genética , PPAR gama/metabolismo , Cisto Pancreático/genética , Cisto Pancreático/metabolismo , Cisto Pancreático/patologia , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Intraductais Pancreáticas/prevenção & controle , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/prevenção & controle , Pancreatite/genética , Pancreatite/metabolismo , Pancreatite/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
Pol Arch Intern Med ; 128(10): 594-603, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30238932


Introduction Obese patients have a higher risk of gastroesophageal reflux disease (GERD), but obesity­related hormonal changes associated with GERD and the effects of bariatric therapy on reflux are unclear. Objectives The aim of the study was to assess reflux parameters in relation to bariatric therapy and hormonal changes in obese patients. Patients and methods This prospective observational study with a 1­year follow­up included 53 obese patients undergoing bariatric therapies. Esophageal pH and impedance monitoring tests were performed and circulating hormone levels were analyzed. Results Esophageal acid exposure time (%AET) and the number of refluxes correlated positively with body mass index. There were several significant, although weak, correlations of pH and impedance parameters with ghrelin and omentin levels. Patients with abnormal %AET had lower ghrelin levels and those with abnormal reflux number had lower omentin levels than patients with normal parameters. Although we observed certain changes including increased %AET and bolus clearance time (BCT) after laparoscopic sleeve gastrectomy, a reduced BCT and number of refluxes after gastric band, and nonsignificant changes after intragastric balloon, the overall bariatric therapy did not significantly impact on the final GERD diagnosis. GERD before and after therapy was present in 42% of patients. De novo GERD developed in 17.8% of patients, while a similar percentage of patients with initial GERD had normal pH and impedance after therapy. Patients with de novo or persistent GERD had a similar percentage of weight loss as patients without GERD. Conclusions Bariatric therapy and percentage of weight loss do not significantly affect GERD. The observed hormonal changes alone do not fully explain the high prevalence of GERD in obese patients.

Cirurgia Bariátrica/efeitos adversos , Refluxo Gastroesofágico/etiologia , Obesidade/cirurgia , Adulto , Idoso , Índice de Massa Corporal , Esôfago/química , Feminino , Seguimentos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Adulto Jovem