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

Abstract

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.

Symbiotic combination of Akkermansia muciniphila and inosine alleviates alcohol-induced liver injury by modulating gut dysbiosis and immune responses

“…IHLs were isolated using a previously established method ( Xu et al, 2021 ). Briefly, following anesthesia, the mouse liver was perfused with PBS.…”

The crosstalk within the breast tumor microenvironment in type II diabetes: Implications for cancer disparities

“…The first-line medication for treatment of T2D is metformin, a biguanide drug that lowers glucose production by the liver through inhibiting the mitochondrial respiratory chain, activating AMPK, lowering cAMP, and reducing the expression of gluconeogenic enzymes, thus enhancing insulin sensitivity ( 148 ). Even though metformin has been used for more than 60 years in the clinic, several studies have demonstrated new indications and mechanisms of action for the drug as an anti-tumor agent ( 149 ). Given that metformin activates AMPK, it thereby inhibits mTOR pathways and decreases circulating insulin levels, with hyperinsulinemia being tied to worse breast cancer prognosis.…”

“…Metformin has also been shown to have a beneficial effect in the regulation of T cell functions, providing a potential therapeutic for immune exhaustion via TSC1 /mTOR ( 149 ). Many previous studies have linked the anticancer effects of metformin to the differentiation of T cells ( 149 , 161 ).…”

“…Metformin has also been shown to have a beneficial effect in the regulation of T cell functions, providing a potential therapeutic for immune exhaustion via TSC1 /mTOR ( 149 ). Many previous studies have linked the anticancer effects of metformin to the differentiation of T cells ( 149 , 161 ). For instance, the use of metformin has been reported to increase the expression of CD8 and CD69 while decreasing PD-1 in TILs, thus increasing the number of CD8+ T cells while protecting them from apoptosis and exhaustion ( 161 ).…”

Low glucose availability potentiates the effects of metformin on model T cell activation and exhaustion markers in vitro

“…The inhibition of respiration by metformin could reduce this metabolic plasticity ( 25 ), and the combination of metformin and glycolysis inhibitor 2-deoxy-D-glucose (2DG) significantly suppressed T cell functions ( 53 ). However, metformin treatment can also lead to increased T cell mitochondrial mass ( 34 , 54 , 55 ), so it is necessary to investigate the effect of metformin on T cells at low as well as normal and elevated glucose levels.…”