Zhang Kun, Chang Yanan, Shi Zhemin, Han Xiaohui, Han Yawei, Yao Qingbin, Hu Zhimei, Cui Hongmei, Zheng Lina, Han Tao, Hong Wei
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
The Third Central Clinical College of Tianjin Medical University, Tianjin 300170, China.
Sci Rep. 2016 Jul 20;6:30029. doi: 10.1038/srep30029.
Elevated levels of the transcriptional regulators Yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, have been shown to play essential roles in controlling liver cell fate and the activation of hepatic stellate cells (HSCs). The dietary intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been positively associated with a number of health benefits including prevention and reduction of cardiovascular diseases, inflammation and cancers. However, little is known about the impact of ω-3 PUFAs on liver fibrosis. In this study, we used CCl4-induced liver fibrosis mouse model and found that YAP/TAZ is over-expressed in the fibrotic liver and activated HSCs. Fish oil administration to the model mouse attenuates CCl4-induced liver fibrosis. Further study revealed that ω-3 PUFAs down-regulate the expression of pro-fibrogenic genes in activated HSCs and fibrotic liver, and the down-regulation is mediated via YAP, thus identifying YAP as a target of ω-3 PUFAs. Moreover, ω-3 PUFAs promote YAP/TAZ degradation in a proteasome-dependent manner. Our data have identified a mechanism of ω-3 PUFAs in ameliorating liver fibrosis.
转录调节因子Yes相关蛋白（YAP）和具有PDZ结合基序的转录共激活因子（TAZ）是Hippo信号通路的关键效应因子，其水平升高已被证明在控制肝细胞命运和肝星状细胞（HSC）激活中起重要作用。饮食中摄入ω-3多不饱和脂肪酸（ω-3 PUFA）与许多健康益处呈正相关，包括预防和减少心血管疾病、炎症和癌症。然而，关于ω-3 PUFA对肝纤维化的影响知之甚少。在本研究中，我们使用CCl4诱导的肝纤维化小鼠模型，发现YAP/TAZ在纤维化肝脏和活化的HSC中过度表达。给模型小鼠喂食鱼油可减轻CCl4诱导的肝纤维化。进一步研究表明，ω-3 PUFA下调活化的HSC和纤维化肝脏中促纤维化基因的表达，且这种下调是通过YAP介导的，从而确定YAP是ω-3 PUFA的作用靶点。此外，ω-3 PUFA以蛋白酶体依赖的方式促进YAP/TAZ降解。我们的数据确定了ω-3 PUFA改善肝纤维化的机制。
