Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease.
Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease.
复制标题
DOI：
10.1016/j.jhep.2015.05.031
复制
发表时间：
2015-10
影响因子：
25.7
通讯作者：
Diehl AM
中科院分区：
文献类型：
--
作者：
Machado MV;Michelotti GA;Pereira TA;Xie G;Premont R;Cortez-Pinto H;Diehl AM
调节受损肝脏再生的机制是复杂的。雅普是一种干细胞相关因子，控制健康成年小鼠的肝脏生长。增加雅普的核定位触发具有肝祖细胞能力的反应性出现的小管细胞（雅普+RDC）的积累。雅普激活的意义和相关机制在患病肝脏中尚不清楚。我们评估了雅普在瘢痕形成的损伤肝脏中比在有效再生的肝脏中更活跃的假设。采用免疫组织化学和qRT-PCR分析对52例非酒精性脂肪性肝病（NAFLD）患者和两种饮食诱导的非酒精性脂肪性肝炎（NASH）小鼠模型中雅普和RDC的变化进行定位和定量。结果与肝脏疾病严重程度、代谢危险因素和被证明控制NAFLD进展的因素相关。雅普在NAFLD中增加，主要定位于表达祖细胞标志物的RDC细胞核。雅普+RDC的蓄积增加了肝细胞损伤的严重程度和Sonic hedgehog（Shh）的蓄积，但不增加脂肪变性或代谢危险因素。雅普+RDC表达骨桥蛋白，一种Shh调节的纤维化因子。肌成纤维细胞蓄积、纤维化和雅普+RDC的数量密切相关。在鼠NASH模型中，萎缩性纤维化肝脏比具有较不严重NASH的肝脏含有显著更多的雅普+RDC。在NASH期间，雅普+RDC促进瘢痕形成，而不是有效再生。
Mechanisms that regulate regeneration of injured livers are complex. YAP, a stem-cell associated factor, controls liver growth in healthy adult mice. Increasing nuclear localization of YAP triggers accumulation of reactive-appearing ductular cells (YAP+RDC) with liver progenitor capabilities. The significance of YAP activation, and mechanisms involved, are unknown in diseased livers. We evaluated the hypothesis that YAP is more activated in injured livers that are scarring than in those that are regenerating effectively. Immunohistochemistry and qRT-PCR analysis were used to localize and quantify changes in YAP and RDC in 52 patients with nonalcoholic fatty liver disease (NAFLD) and two mouse models of diet-induced nonalcoholic steatohepatitis (NASH). Results were correlated with liver disease severity, metabolic risk factors, and factors proven to control NAFLD progression. YAP increased in NAFLD where it mainly localized in nuclei of RDC that expressed progenitor markers. Accumulation of YAP+RDC paralleled the severity of hepatocyte injury and accumulation of Sonic hedgehog (Shh), but not steatosis or metabolic risk factors. YAP+RDC expressed osteopontin, a Shh-regulated fibrogenic factor. Myofibroblast accumulation, fibrosis, and numbers of YAP+RDC strongly correlated. In murine NASH models, atrophic fibrotic livers contained significantly more YAP+RDC than livers with less severe NASH. YAP+RDC promote scarring, rather than effective regeneration, during NASH.