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Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis

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...

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Detalles Bibliográficos
Autores principales: Xu, Lanman, Wang, Xiaofang, Chen, Yan, Soong, Lynn, Chen, Yongping, Cai, Jiyang, Liang, Yuejin, Sun, Jiaren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097169/
https://www.ncbi.nlm.nih.gov/pubmed/33968030
http://dx.doi.org/10.3389/fimmu.2021.638575
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author Xu, Lanman
Wang, Xiaofang
Chen, Yan
Soong, Lynn
Chen, Yongping
Cai, Jiyang
Liang, Yuejin
Sun, Jiaren
author_facet Xu, Lanman
Wang, Xiaofang
Chen, Yan
Soong, Lynn
Chen, Yongping
Cai, Jiyang
Liang, Yuejin
Sun, Jiaren
author_sort Xu, Lanman
collection PubMed
description 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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spelling pubmed-80971692021-05-06 Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis Xu, Lanman Wang, Xiaofang Chen, Yan Soong, Lynn Chen, Yongping Cai, Jiyang Liang, Yuejin Sun, Jiaren Front Immunol Immunology 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. Frontiers Media S.A. 2021-04-21 /pmc/articles/PMC8097169/ /pubmed/33968030 http://dx.doi.org/10.3389/fimmu.2021.638575 Text en Copyright © 2021 Xu, Wang, Chen, Soong, Chen, Cai, Liang and Sun https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Xu, Lanman
Wang, Xiaofang
Chen, Yan
Soong, Lynn
Chen, Yongping
Cai, Jiyang
Liang, Yuejin
Sun, Jiaren
Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis
title Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis
title_full Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis
title_fullStr Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis
title_full_unstemmed Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis
title_short Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis
title_sort metformin modulates t cell function and alleviates liver injury through bioenergetic regulation in viral hepatitis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097169/
https://www.ncbi.nlm.nih.gov/pubmed/33968030
http://dx.doi.org/10.3389/fimmu.2021.638575
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