...
首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Insights into molecular mechanisms contributing to individual susceptibility to steatohepatitis: Lessons learned from mouse models
【24h】

Insights into molecular mechanisms contributing to individual susceptibility to steatohepatitis: Lessons learned from mouse models

机译:深入了解导致个体对脂肪性肝炎易感性的分子机制:从小鼠模型中学到的经验教训

获取原文
获取原文并翻译 | 示例
           

摘要

Genetic factors impact liver injury susceptibility and disease progression. Prominent histological features of some chronic human liver diseases are hepatocyte ballooning and Mallory-Denk bodies. In mice, these features are induced by 3,5-dieth-oxycarbonyl-l,4-dihydrocollidine (DDC) in a strain-dependent manner, with the C57BL and C3H strains showing high and low susceptibility, respectively. To identify modifiers of DDC-induced liver injury, we compared C57BL and C3H mice using proteomic, biochemical, and cell biological tools. DDC elevated reactive oxygen species (ROS) and oxidative stress enzymes preferentially in C57BL livers and isolated hepato-cytes. C57BL livers and hepatocytes also manifested significant down-regulation, aggregation, and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). GAPDH knockdown depleted bioenergetic and antioxidant enzymes and elevated hepatocyte ROS, whereas GAPDH overexpression decreased hepatocyte ROS. On the other hand, C3H livers had higher expression and activity of the energy-generating nucleo-side-diphosphate kinase (NDPK), and knockdown of hepatocyte NDPK augmented DDC-induced ROS formation. Consistent with these findings, cirrhotic, but not normal, human livers contained GAPDH aggregates and NDPK complexes. We propose that GAPDH and NDPK are genetic modifiers of murine DDC-induced liver injury and potentially human liver disease.
机译:遗传因素影响肝损伤的易感性和疾病进展。一些慢性人类肝脏疾病的突出组织学特征是肝细胞膨胀和Mallory-Denk体。在小鼠中,这些特征是由3,5-二乙氧基羰基-1,4-二氢可力丁(DDC)以株依赖性方式诱导的,其中C57BL和C3H株分别显示出高敏感性和低敏感性。为了鉴定DDC诱导的肝损伤的调节剂,我们使用蛋白质组学,生化和细胞生物学工具比较了C57BL和C3H小鼠。 DDC在C57BL肝脏和分离的肝细胞中优先升高活性氧(ROS)和氧化应激酶。 C57BL肝脏和肝细胞还表现出甘油醛3-磷酸脱氢酶(GAPDH)的显着下调,聚集和核易位。 GAPDH组合式耗竭的生物能和抗氧化酶和肝细胞ROS升高,而GAPDH过表达降低肝细胞ROS。另一方面,C3H肝脏具有更高的能量生成核苷二磷酸激酶(NDPK)的表达和活性,而敲除肝细胞NDPK则增加了DDC诱导的ROS形成。与这些发现一致,肝硬化但非正常的人肝脏中含有GAPDH聚集体和NDPK复合物。我们建议GAPDH和NDPK是小鼠DDC诱导的肝损伤和潜在人类肝病的遗传修饰因子。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号