RESUMEN
Protein malnutrition promotes hepatic lipid accumulation in growing animals. In these animals, fibroblast growth factor 21 (FGF21) rapidly increases in the liver and circulation and plays a protective role in hepatic lipid accumulation. To investigate the mechanism by which FGF21 protects against liver lipid accumulation under protein malnutrition, we determined whether upregulated FGF21 promotes the thermogenesis or secretion of very-low-density lipoprotein (VLDL)-triacylglycerol (TAG). The results showed that protein malnutrition decreased VLDL-TAG secretion, but the upregulation of FGF21 did not oppose this effect. In addition, protein malnutrition increased expression of the thermogenic gene uncoupling protein 1 in inguinal white adipose and brown adipose tissue in an FGF21-dependent manner. However, surgically removing inguinal white adipose tissue did not affect liver triglyceride levels in protein-malnourished mice. These data suggest that FGF21 stimulates thermogenesis under protein malnutrition, but this is not the causative factor underlying the protective role of FGF21 against liver lipid accumulation.
Asunto(s)
Tejido Adiposo Blanco/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Metabolismo de los Lípidos/genética , Lipoproteínas VLDL/metabolismo , Desnutrición/genética , Termogénesis/genética , Triglicéridos/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/cirugía , Animales , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Colesterol/metabolismo , Dieta con Restricción de Proteínas/efectos adversos , Factores de Crecimiento de Fibroblastos/deficiencia , Regulación de la Expresión Génica , Glicerol-3-Fosfato O-Aciltransferasa/genética , Glicerol-3-Fosfato O-Aciltransferasa/metabolismo , Ingle , Hígado/metabolismo , Masculino , Desnutrición/metabolismo , Desnutrición/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neurregulinas/genética , Neurregulinas/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
An 83-year-old woman was hospitalized with abdominal discomfort. Abdominal computed tomography(CT)revealed a hugetumor (size, 15 cm)in thegastric body. Based on thefindings of endoscopic ultrasonography-guided fine-needle aspiration, she was diagnosed with gastrointestinal stromal tumor(GIST). Invasion of thesurrounding viscera and distant metastasis were not observed; however, owing to the tumor size(>10 cm), we initiated neoadjuvant chemotherapy with imatinib. CT performed a month after chemotherapy revealed tumor shrinkage, and CT repeated 6 months after the second CT revealed tumor shrinkage to 8 cm. The patient showed a partial response to chemotherapy. She was deemed suitable to undergo laparoscopic radical resection and subsequently underwent laparoscopic partial gastric resection. Histopathological examination of the resected specimen(measuring 10 cm)revealed hyaline degeneration in most tumor cells and positive ckit expression in only some proportion of tumor cells. Based on histopathological evaluation, the tumor was diagnosed as Grade 2b. The patient showed an uneventful postoperative course. After discharge, she received imatinib as adjuvant chemotherapy and is progressing well without recurrence. Taken together, we reported the case of a huge gastric GIST in a patient who showed significant tumor shrinkage following preoperative neoadjuvant chemotherapy and successfully underwent laparoscopic radical resection.
Asunto(s)
Antineoplásicos , Tumores del Estroma Gastrointestinal , Laparoscopía , Anciano de 80 o más Años , Femenino , Neoplasias Gastrointestinales/terapia , Tumores del Estroma Gastrointestinal/terapia , Humanos , Terapia Neoadyuvante , Recurrencia Local de NeoplasiaRESUMEN
Understanding the signaling pathways that regulate proliferation and differentiation of muscle progenitors is essential for successful cell transplantation for treatment of Duchenne muscular dystrophy. Here, we report that a γ-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine tertial butyl ester), which inhibits the release of NICD (Notch intercellular domain), promotes the fusion of human muscle progenitors in vitro and improves their engraftment in the tibialis anterior muscle of immune-deficient mice. Gene expression analysis revealed that DAPT severely down-regulates PTGER2, which encodes prostaglandin (PG) E2 receptor 2 (EP2), in human muscle progenitors in the differentiation condition. Functional analysis suggested that Notch signaling inhibits differentiation and promotes self-renewal of human muscle progenitors via PGE2/EP2 signaling in a cAMP/PKA-independent manner.