Fatty Acids Activate the Transcriptional Coactivator YAP1 to Promote Liver Fibrosis via p38 Mitogen-Activated Protein Kinase.
Fatty Acids Activate the Transcriptional Coactivator YAP1 to Promote Liver Fibrosis via p38 Mitogen-Activated Protein Kinase.
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DOI：
10.1016/j.jcmgh.2021.06.003
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发表时间：
2021
影响因子：
7.2
通讯作者：
Chung RT
中科院分区：
文献类型：
--
作者：
Salloum S;Jeyarajan AJ;Kruger AJ;Holmes JA;Shao T;Sojoodi M;Kim MH;Zhuo Z;Shroff SG;Kassa A;Corey KE;Khan SK;Lin W;Alatrakchi N;Schaefer EAK;Chung RT
单纯性脂肪变性（SS）和非酒精性脂肪性肝炎患者可发生进行性肝纤维化，与肝脏相关死亡率相关。然而，对SS肝纤维化发展的机制知之甚少。SS的特征是肝细胞游离脂肪酸（FFA）蓄积，无小叶炎症，见于非酒精性脂肪性肝炎。由于Hippo信号转录辅激活因子YAP 1（雅普）先前与非酒精性脂肪肝（NAFLD）相关的纤维化有关，我们试图探索肝细胞FFA如何激活YAP介导的促纤维化程序。我们分析了来自GEO数据集（登录号：GSE 162694）的RNA测序数据，该数据集由143名NAFLD患者组成。我们还对NAFLD受试者、鼠饮食NAFLD模型和FFA处理的肝球状体和肝细胞的肝脏标本进行了免疫组织化学、免疫荧光、免疫印迹和定量逆转录聚合酶链反应（qRT-PCR）分析。YAP靶基因表达与NAFLD患者纤维化阶段的增加相关，并且与喂食NAFLD诱导饮食的小鼠的纤维化相关。鼠NAFLD模型中肝细胞特异性雅普缺失减弱了饮食诱导的纤维化，表明雅普在NAFLD相关纤维化中的致病作用。同样，在由Huh 7肝癌细胞和原代人肝星状细胞组成的肝球状体中，Huh 7雅普沉默降低FFA诱导的纤维化基因表达。值得注意的是，抑制p38丝裂原活化蛋白激酶可以阻断FFA处理的Huh 7细胞中的雅普活化。这些研究为雅普在NAFLD相关纤维化中的病理作用提供了进一步的证据，并且NAFLD中的雅普活化可能由FFA诱导的p38 MAPK活化驱动。
Patients with simple steatosis (SS) and nonalcoholic steatohepatitis can develop progressive liver fibrosis, which is associated with liver-related mortality. The mechanisms contributing to liver fibrosis development in SS, however, are poorly understood. SS is characterized by hepatocellular free fatty acid (FFA) accumulation without lobular inflammation seen in nonalcoholic steatohepatitis. Because the Hippo signaling transcriptional coactivator YAP1 (YAP) has previously been linked with nonalcoholic fatty liver disease (NAFLD)–related fibrosis, we sought to explore how hepatocyte FFAs activate a YAP-mediated profibrogenic program. We analyzed RNA sequencing data from a GEO DataSet (accession: GSE162694) consisting of 143 patients with NAFLD. We also performed immunohistochemical, immunofluorescence, immunoblot, and quantitative reverse-transcription polymerase chain reaction analyses (qRT-PCR) in liver specimens from NAFLD subjects, from a murine dietary NAFLD model, and in FFA-treated hepatic spheroids and hepatocytes. YAP-target gene expression correlated with increasing fibrosis stage in NAFLD patients and was associated with fibrosis in mice fed a NAFLD-inducing diet. Hepatocyte-specific YAP deletion in the murine NAFLD model attenuated diet-induced fibrosis, suggesting a causative role of YAP in NAFLD-related fibrosis. Likewise, in hepatic spheroids composed of Huh7 hepatoma cells and primary human hepatic stellate cells, Huh7 YAP silencing reduced FFA-induced fibrogenic gene expression. Notably, inhibition of p38 mitogen-activated protein kinase could block YAP activation in FFA-treated Huh7 cells. These studies provide further evidence for the pathological role of YAP in NAFLD-associated fibrosis and that YAP activation in NAFLD may be driven by FFA-induced p38 MAPK activation.
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影响因子：
2.2
作者：
Almpanis Z;Demonakou M;Tiniakos D
通讯作者：
Tiniakos D
p38 信号传导对 Hippo 信号传导的调节
影响因子：
5.5
作者：
Huang D;Li X;Sun L;Huang P;Ying H;Wang H;Wu J;Song H
通讯作者：
Song H
影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
5.1
作者：
Nasr P;Ignatova S;Kechagias S;Ekstedt M
通讯作者：
Ekstedt M
影响因子：
4.6
作者：
Oh, Hyangyee;Irvine, Kenneth D.
通讯作者：
Irvine, Kenneth D.