RESUMO
Diosgenin (Dio) is a steroid sapogenin found in plants such as Dioscorea species, and is recognized as a phytochemical against various disorders as well as a natural precursor of steroidal drugs. The present study used rats fed high-cholesterol (Chol) diets supplemented with or without 0.5% Dio for 6 wk to investigate the effects of dietary Dio on lipid metabolism. Dio supplementation significantly increased serum high-density lipoprotein Chol concentrations and fecal Chol content, and significantly decreased fecal bile acid content compared rats fed a high-Chol diet alone, showing that dietary Dio may facilitate excretion of Chol rather than bile acids. A reduction in the liver triglyceride content and intra-abdominal visceral fat was observed in Dio-supplemented rats. Interestingly, dietary Dio also significantly increased the skeletal muscle-fiber diameter and area in the thigh muscles of the rats. Mouse myoblast-derived C2C12 cells were used to examine whether Dio directly affected skeletal muscle. Dio promoted fusion of myoblasts into multinucleated cells or myotubes. Furthermore, in myotube C2C12 cells, protein levels of phosphorylated AMP-activated protein kinase (AMPK) increased with Dio treatment in a dose-dependent manner. These results indicate that Dio may not only induce myoblast fusion and enhance skeletal muscle as an energy expenditure organ, but may also activate the catabolic pathway via AMPK in skeletal muscle cells. Thus, these effects of Dio on skeletal muscles may contribute to inhibition of visceral fat accumulation.
Assuntos
Suplementos Nutricionais , Diosgenina/administração & dosagem , Hipercolesterolemia/terapia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ácidos e Sais Biliares/análise , Colesterol/análise , HDL-Colesterol/sangue , Dieta Hiperlipídica , Fezes/química , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Hipertrofia , Gordura Intra-Abdominal/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Ratos , Coxa da Perna/patologia , Triglicerídeos/análiseRESUMO
Exposure of cells to a wide variety of chemoprotective compounds confers resistance to a broad set of carcinogens. For a subset of the chemoprotective compounds, protection is generated by an increase in the abundance of phase 2 detoxification enzymes such as glutathione S-transferases (GSTs). Transcription factor Nrf2, which is sequestered in the cytoplasm by Keap1 (Kelch-like ECH-associated protein-1) under unstimulated conditions, regulates the induction of phase 2 enzymes. In this study, to explore the role of the proteasome in the detoxification response, we tested the effect of proteasome inhibitors such as MG132, clasto-lactacystin beta-lactone, and lactacystin on the induction of GST isozymes and found that these inhibitors selectively induced the class Pi GST isozyme (GST P1). Down-regulation of the proteasome by antisense oligonucleotides or RNA interference indeed resulted in significant up-regulation of GST P1, suggesting that a decline in the proteasome activity could be directly or indirectly linked to the induction of GST P1. From the functional analysis of various deletion constructs of the upstream regulatory region of the GST P1 promoter, GST P1 enhancer I was identified as the response element for proteasome inhibition. Overexpression of the wild-type and dominant-negative forms of Nrf2 and Keap1 had little effect on the induction of GST P1 not only by the proteasome inhibitor, but also by phase 2-inducing isothiocyanate, suggesting that there may be a process of GST P1 induction distinct from other phase 2 gene induction mechanisms. Because GST P1 is highly and specifically induced during early hepatocarcinogenesis as well as in hepatocellular carcinoma cells, these data may provide a potential critical role for the proteasome in the induction of a cellular defense program associated with carcinogenesis.