Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana; Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China; The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
Cell Mol Gastroenterol Hepatol. 2021;12(3):921-942. doi: 10.1016/j.jcmgh.2021.04.015. Epub 2021 May 4.
BACKGROUND & AIMS: Sestrin 1/2/3 (Sesn1/2/3) belong to a small family of proteins that have been implicated in the regulation of metabolic homeostasis and oxidative stress. However, the underlying mechanisms remain incompletely understood. The aim of this work was to illustrate the collective function of Sesn1/2/3 in the protection against hepatic lipotoxicity.
We used Sesn1/2/3 triple knockout (TKO) mouse and cell models to characterize oxidative stress and signal transduction under lipotoxic conditions. Biochemical, histologic, and physiological approaches were applied to illustrate the related processes.
After feeding with a Western diet for 8 weeks, TKO mice developed remarkable metabolic associated fatty liver disease that was manifested by exacerbated hepatic steatosis, inflammation, and fibrosis compared with wild-type counterparts. Moreover, TKO mice exhibited higher levels of hepatic lipotoxicity and oxidative stress. Our biochemical data revealed a critical signaling node from sestrins to c-Jun N-terminal kinases (JNKs) in that sestrins interact with JNKs and mitogen-activated protein kinase kinase 7 and suppress the JNK phosphorylation and activity. In doing so, sestrins markedly reduced palmitate-induced lipotoxicity and oxidative stress in both mouse and human hepatocytes.
The data from this study suggest that Sesn1/2/3 play an important role in the protection against lipotoxicity-associated oxidative stress and related pathology in the liver.
Sesn1/2/3（Sesn1/2/3）属于一组蛋白质，它们被认为参与了代谢稳态和氧化应激的调节。然而，其潜在的机制仍不完全清楚。本研究旨在阐明 Sesn1/2/3 在抵抗肝脂肪毒性中的集体功能。
我们使用 Sesn1/2/3 三重敲除（TKO）小鼠和细胞模型来研究在脂肪毒性条件下的氧化应激和信号转导。应用生化、组织学和生理学方法来阐明相关过程。
用西方饮食喂养 8 周后，TKO 小鼠发生了明显的代谢相关脂肪性肝病，与野生型相比，肝脂肪变性、炎症和纤维化更为严重。此外，TKO 小鼠表现出更高的肝脂肪毒性和氧化应激水平。我们的生化数据揭示了 sestrins 到 c-Jun N 末端激酶（JNKs）的关键信号节点，即 sestrins 与 JNKs 和丝裂原活化蛋白激酶激酶 7 相互作用，并抑制 JNK 的磷酸化和活性。这样， sestrins 显著降低了棕榈酸诱导的小鼠和人肝细胞的脂肪毒性和氧化应激。
本研究的数据表明，Sesn1/2/3 在抵抗与脂肪毒性相关的氧化应激和肝脏相关病理方面发挥着重要作用。
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