Switch-associated protein 70 protects against nonalcoholic fatty liver disease through suppression of TAK1.
Switch-associated protein 70 protects against nonalcoholic fatty liver disease through suppression of TAK1.
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开关相关蛋白70通过抑制TAK1预防非酒精性脂肪性肝病。
DOI：
10.1002/hep.32213
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发表时间：
2022-06
期刊：
影响因子：
13.5
通讯作者：
Liu, Jinping
中科院分区：
文献类型：
--
作者：
Qian, Qiaofeng;Li, Yang;Fu, Jiajun;Leng, Dewen;Dong, Zhe;Shi, Jiajun;Shi, Hongjie;Cao, Dengwei;Cheng, Xu;Hu, Yufeng;Luo, Qiujie;Hu, Manli;Ran, Yong;Tang, Hao;Liu, Hui;Liu, Jinping
NAFLD是一种进行性疾病，没有已知的有效药物治疗。开关相关蛋白70（SWAP 70）是一种鸟嘌呤核苷酸交换因子，参与许多细胞过程的调节。然而，SWAP 70在NAFLD中的作用仍不清楚。本研究旨在探讨SWAP 70在NAFLD中的作用及其机制。结果显示，代谢刺激后SWAP 70在小鼠和肝细胞中的表达显著增加。SWAP 70在肝细胞中的过表达抑制了脂质沉积和炎症，而SWAP 70敲低则产生了相反的效果。使用肝细胞特异性Swap 70敲除和过表达小鼠喂养高脂肪，高胆固醇饮食，我们证明SWAP 70通过抑制脂质积聚，炎症反应和纤维化抑制非酒精性脂肪性肝炎的进展。RNA测序分析和免疫沉淀分析显示，SWAP 70抑制转化生长因子β激活激酶1（TAK 1）结合蛋白1与TAK 1之间的相互作用，并随后抑制TAK 1的磷酸化和随后的c-Jun N-末端激酶/P38信号传导。抑制TAK 1活化可阻断SWAP 70敲低引起的肝细胞脂质沉积和炎症。SWAP 70是一种保护性分子，可以通过抑制肝脏脂肪变性和炎症来抑制NAFLD的进展。SWAP 70可能对减缓NAFLD的进展很重要。
NAFLD is a progressive disease without known effective drug treatments. Switch‐associated protein 70 (SWAP70) is a guanine nucleotide exchange factor that participates in the regulation of many cellular processes. However, the role of SWAP70 in NAFLD remains unclear. This study aimed to identify the function and mechanism of SWAP70 in NAFLD. The results showed that the expression of SWAP70 was significantly increased in mice and hepatocytes after metabolic stimulation. Overexpression of SWAP70 in hepatocytes suppressed lipid deposition and inflammation, and SWAP70 knockdown created the inverse effect. Using hepatocyte‐specific Swap70 knockout and overexpression mice fed a high‐fat, high‐cholesterol diet, we demonstrated that SWAP70 suppressed the progression of nonalcoholic steatohepatitis by inhibiting lipid accumulation, inflammatory response, and fibrosis. Mechanically, RNA sequencing analysis and immunoprecipitation assays revealed that SWAP70 inhibited the interaction between transforming growth factor β‐activated kinase 1 (TAK1) binding protein 1 and TAK1 and sequentially suppressed the phosphorylation of TAK1 and subsequent c‐Jun N‐terminal kinase/P38 signaling. Inhibition of TAK1 activation blocked hepatocyte lipid deposition and inflammation caused by SWAP70 knockdown. SWAP70 is a protective molecule that can suppress the progression of NAFLD by inhibiting hepatic steatosis and inflammation. SWAP70 may be important for mitigating the progression of NAFLD.
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