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.
Highlights
Metformin is a biguanide drug that has been used to treat type 2 diabetes mellitus and to help control blood glucose levels for more than 60 years [1, 2]
A clinical study suggested that metformin has beneficial effects in patients with chronic hepatitis C [53], raising the possibility that metformin can be a therapeutic option for viral hepatitis
We demonstrated that metformin treatment ameliorated liver injury in mice with viral hepatitis as evidenced by decreased serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, and alleviated liver pathological changes (Figure 1)
Summary
Metformin is a biguanide drug that has been used to treat type 2 diabetes mellitus and to help control blood glucose levels for more than 60 years [1, 2]. No significant safety issues from longterm use of metformin have been identified for diabetes prevention [3], indicating that, as an affordable medicine, metformin is safe and effective. Signaling through mTOR regulates metabolism and is an important molecular connection between nutrient signals and the metabolic processes that are indispensable for cell growth and function [13]. Accumulating evidence has showed that metformin may have therapeutic potential in liver diseases [1], as metformin can improve the survival of diabetic liver cancer patients [17]. Results from human and animal studies showed that the administration of metformin improves liver function in non-alcoholic fatty liver disease (NAFLD) subjects [19, 20]. It remains unclear as to whether and how metformin directly modulates T cell responses in viral hepatitis
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