Lipotoxicity-induced STING1 activation stimulates MTORC1 and restricts hepatic lipophagy
Lipotoxicity-induced STING1 activation stimulates MTORC1 and restricts hepatic lipophagy
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脂毒性诱导的 STING1 激活刺激 MTORC1 并限制肝脏自噬
DOI：
10.1080/15548627.2021.1961072
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发表时间：
2021-08-12
期刊：
影响因子：
13.3
通讯作者：
Zhang, Qi
中科院分区：
文献类型：
--
作者：
Liu, Kunpeng;Qiu, Dongbo;Zhang, Qi
脂质积累常导致肝细胞脂毒性损伤，可引起非酒精性脂肪性肝炎。炎症与肝组织脂质积累的关系已经研究了几十年;然而，关键机制直到最近才被确定。特别是，肝脏炎症如何调节肝细胞脂质代谢尚不清楚。本研究中，我们发现PA处理或直接刺激STING1可以促进MTORC1的激活，而缺乏STING1则会损害MTORC1的激活，这表明STING1参与了PA诱导的MTORC1激活。机制研究表明，在PA处理下，STING1与MTORC1复合物的几个组分相互作用，并在MTORC1复合物的形成中发挥重要作用。STING1参与MTORC1激活依赖于SQSTM1， SQSTM1是MTORC1通路的关键调节因子。在sqstm1缺失的细胞中，STING1与MTORC1组分的相互作用较弱。此外，通过雷帕霉素处理或STING1缺失导致MTORC1活性受损，减少了细胞中ld的数量。PA处理抑制了脂噬，而在sting1缺陷细胞和雷帕霉素处理的细胞中没有观察到这种现象。通过氨基酸处理恢复MTORC1活性，阻断脂噬和ld降解。最后，在非酒精性脂肪性肝病患者肝组织中观察到MTORC1激活增加同时伴有STING1激活，这为STING1参与MTORC1激活提供了临床证据。总之，我们发现了一个新的STING1-MTORC1调节环，并解释了肝脏炎症如何调节脂质积累。我们的发现可能促进肝脂肪变性临床治疗新策略的发展。
Lipid accumulation often leads to lipotoxic injuries to hepatocytes, which can cause nonalcoholic steatohepatitis. The association of inflammation with lipid accumulation in liver tissue has been studied for decades; however, key mechanisms have been identified only recently. In particular, it is still unknown how hepatic inflammation regulates lipid metabolism in hepatocytes. Herein, we found that PA treatment or direct stimulation of STING1 promoted, whereas STING1 deficiency impaired, MTORC1 activation, suggesting that STING1 is involved in PA-induced MTORC1 activation. Mechanistic studies revealed that STING1 interacted with several components of the MTORC1 complex and played an important role in the complex formation of MTORC1 under PA treatment. The involvement of STING1 in MTORC1 activation was dependent on SQSTM1, a key regulator of the MTORC1 pathway. In SQSTM1-deficient cells, the interaction of STING1 with the components of MTORC1 was weak. Furthermore, the impaired activity of MTORC1 via rapamycin treatment or STING1 deficiency decreased the numbers of LDs in cells. PA treatment inhibited lipophagy, which was not observed in STING1-deficient cells or rapamycin-treated cells. Restoration of MTORC1 activity via treatment with amino acids blocked lipophagy and LDs degradation. Finally, increased MTORC1 activation concomitant with STING1 activation was observed in liver tissues of nonalcoholic fatty liver disease patients, which provided clinical evidence for the involvement of STING1 in MTORC1 activation. In summary, we identified a novel regulatory loop of STING1-MTORC1 and explain how hepatic inflammation regulates lipid accumulation. Our findings may facilitate the development of new strategies for clinical treatment of hepatic steatosis.