Genetic Ablation of Fas-Activated Serine/Threonine Kinase Ameliorates Alcoholic Liver Disease Through Modulating HuR-SIRT1 mRNA Complex Stability.
Genetic Ablation of Fas-Activated Serine/Threonine Kinase Ameliorates Alcoholic Liver Disease Through Modulating HuR-SIRT1 mRNA Complex Stability.
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Fas 激活的丝氨酸/苏氨酸激酶的基因消除通过调节 HuR-SIRT1 mRNA 复合物的稳定性来改善酒精性肝病。
DOI：
10.1016/j.freeradbiomed.2021.02.002
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发表时间：
2021-02
影响因子：
7.4
通讯作者：
Jianming Pei
中科院分区：
文献类型：
--
作者：
Fuyang Zhang;Kai Wang;Guangyu Hu;Feng Fu;Rong Fan;Jun Li;Lu Yang;Yali Liu;Na Feng;Xiaoming Gu;Ming Jia;Xiyao Chen;Jianming Pei
慢性酒精中毒常引起以肝脂肪变性、炎症和氧化应激为特征的肝损伤，最终导致晚期肝硬化和肝癌。Fas激活的丝氨酸/苏氨酸激酶（FASTK）及其同源物作为多功能蛋白参与多种生物学过程，但其在酒精性肝病（ALD）中的作用尚不清楚。在这里，我们发现，在FASTK家族成员中，FASTK的表达在接受慢性乙醇摄入的小鼠的肝脏和乙醇刺激的肝细胞中都被特异性诱导。动物研究表明，FASTK基因缺失可减轻慢性乙醇摄入引起的肝损伤、脂肪变性和炎症。此外，FASTK缺陷与慢性乙醇刺激后肝脏中氧化/抗氧化系统稳态的改善和活性氧（ROS）生成的减少有关。重要的是，FASTK消融在慢性乙醇摄入后保留了肝脏sirtuin-1（SIRT 1）的表达/活性，而通过腺病毒介导的小干扰RNA转移的SIRT 1沉默减少了FASTK缺失对酒精相关性肝脂肪变性、炎症和氧化应激的有益作用。从机制上讲，乙醇增加了人抗原R（HuR，一种稳定SIRT 1 mRNA的RNA结合蛋白）的磷酸化，并引发HuR-SIRT 1 mRNA复合物的解离，进而促进SIRT 1 mRNA的衰变。FASTK的基因缺失减少了乙醇诱导的HuR磷酸化和HuR-SIRT 1 mRNA复合物的解离，从而增强了SIRT 1 mRNA的稳定性。总的来说，这些发现首次强调了FASTK在ALD发病机制中的关键作用，并暗示HuR-SIRT 1 mRNA复合物参与了这一过程。
Chronic alcoholism often causes liver injuries characterized by hepatic steatosis, inflammation as well as oxidative stress and finally leads to advanced cirrhosis and liver cancer. Fas-activated serine/threonine kinase (FASTK) and its homologs are gradually known as multifunctional proteins involved in various biological processes; however, the role of FASTK and its family members in alcoholic liver disease (ALD) is still unexplored. Here we found that, among FASTK family members, the expression of FASTK was specifically induced both in livers of mice received chronic ethanol ingestion and in ethanol-stimulated hepatocytes. Animal studies showed that genetic deletion of FASTK attenuated chronic ethanol ingestion-induced liver damage, steatosis, and inflammation. Moreover, FASTK deficiency was associated with improved oxidative/anti-oxidative system homeostasis and reduced reactive oxygen species (ROS) generation in livers upon chronic ethanol stimulation. Importantly, FASTK ablation preserved hepatic sirtuin-1 (SIRT1) expression/activity upon chronic ethanol ingestion and SIRT1 silencing via adenovirus-mediated small interfering RNA transfer diminished FASTK deletion-elicited beneficial effects on alcohol-associated hepatic steatosis, inflammation, and oxidative stress. Mechanistically, ethanol increased the phosphorylation of human antigen R (HuR, a RNA binding protein that stabilizes SIRT1 mRNA) and triggered the dissociation of HuR-SIRT1 mRNA complex, in turn promoting SIRT1 mRNA decay. Genetic deletion of FASTK diminished ethanol-induced HuR phosphorylation and HuR-SIRT1 mRNA complex dissociation, thereby enhancing SIRT1 mRNA stability. Collectively, these findings for the first time highlight a critical role of FASTK in the pathogenesis of ALD and implicate HuR-SIRT1 mRNA complex involves in this process.
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影响因子：
7.4
作者：
Zhang H;Davies KJA;Forman HJ
通讯作者：
Forman HJ
DOI：
10.4049/jimmunol.1000104
发表时间：
2010-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Simarro M;Giannattasio G;De la Fuente MA;Benarafa C;Subramanian KK;Ishizawar R;Balestrieri B;Andersson EM;Luo HR;Orduña A;Boyce J;Anderson P
通讯作者：
Anderson P
影响因子：
11.4
作者：
Wang S;Wan T;Ye M;Qiu Y;Pei L;Jiang R;Pang N;Huang Y;Liang B;Ling W;Lin X;Zhang Z;Yang L
通讯作者：
Yang L
影响因子：
25.7
作者：
Asrani, Sumeet K.;Devarbhavi, Harshad;Kamath, Patrick S.
通讯作者：
Kamath, Patrick S.
DOI：
10.1073/pnas.0704964104
发表时间：
2007-07-03
影响因子：
11.1
作者：
Simarro, Maria;Mauger, David;Anderson, Paul
通讯作者：
Anderson, Paul