Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis.
Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis.
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DOI：
10.3389/fimmu.2021.638575
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发表时间：
2021
影响因子：
7.3
通讯作者：
Sun J
中科院分区：
文献类型：
--
作者：
Xu L;Wang X;Chen Y;Soong L;Chen Y;Cai J;Liang Y;Sun J
二甲双胍不仅是治疗2型糖尿病的一线药物，而且作为一种抗炎、抗氧化和抗肿瘤药物也是有效的。然而，二甲双胍在病毒性肝炎中的作用仍不明确。利用腺病毒（Ad）诱导的病毒性肝炎小鼠模型，我们发现二甲双胍治疗显著减轻了肝损伤，血清天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平降低，肝脏组织学变化减轻，可能是通过降低效应T细胞反应实现的。然后我们证明二甲双胍降低了感染小鼠T细胞中的mTORC1活性，这可由核糖体蛋白S6（p - S6）磷酸化降低所证明。二甲双胍对mTORC1信号通路的抑制作用依赖于结节性硬化复合物1（TSC1）。从机制上讲，二甲双胍治疗调节了动力相关蛋白1（Drp - 1）和线粒体分裂1蛋白（FIS1）的磷酸化，导致效应T细胞的质量增加。此外，二甲双胍治疗促进了线粒体超氧化物的产生，这可以抑制病毒性肝炎中过度的T细胞活化。总之，我们的研究结果揭示了二甲双胍通过调节mTORC1通路和线粒体功能来调控效应T细胞活化，从而在急性病毒性肝炎中对肝损伤具有保护作用和治疗潜力。
Metformin is not only the first-line medication for the treatment of type 2 diabetes, but it is also effective as an anti-inflammatory, anti-oxidative and anti-tumor agent. However, the effect of metformin during viral hepatitis remains elusive. Using an adenovirus (Ad)-induced viral hepatitis mouse model, we found that metformin treatment significantly attenuated liver injury, with reduced serum aspartate transaminase (AST) and alanine transaminase (ALT) levels and liver histological changes, presumably via decreased effector T cell responses. We then demonstrated that metformin reduced mTORC1 activity in T cells from infected mice, as evidenced by decreased phosphorylation of ribosome protein S6 (p-S6). The inhibitory effects on the mTORC1 signaling by metformin was dependent on the tuberous sclerosis complex 1 (TSC1). Mechanistically, metformin treatment modulated the phosphorylation of dynamin-related protein 1 (Drp-1) and mitochondrial fission 1 protein (FIS1), resulting in increased mass in effector T cells. Moreover, metformin treatment promoted mitochondrial superoxide production, which can inhibit excessive T cell activation in viral hepatitis. Together, our results revealed a protective role and therapeutic potential of metformin against liver injury in acute viral hepatitis via modulating effector T cell activation via regulating the mTORC1 pathway and mitochondrial functions.
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影响因子：
29
作者：
Howell JJ;Hellberg K;Turner M;Talbott G;Kolar MJ;Ross DS;Hoxhaj G;Saghatelian A;Shaw RJ;Manning BD
通讯作者：
Manning BD
DOI：
10.3390/antiox7010013
发表时间：
2018-01-16
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Ježek J;Cooper KF;Strich R
通讯作者：
Strich R
影响因子：
30.5
作者：
Jackson, SH;Devadas, S;Williams, MS
通讯作者：
Williams, MS
影响因子：
9
作者：
通讯作者：
--
影响因子：
5.1
作者：
Chakraborty, Arpita;Chowdhury, Subhankar;Bhattacharyya, Maitree
通讯作者：
Bhattacharyya, Maitree