Mitigation of liver fibrosis via hepatic stellate cells mitochondrial apoptosis induced by metformin

Liver fibrosis, a disease characterized by the excessive accumulation of extracellular matrix originating from activated hepatic stellate cells (HSCs), is a common pathological response to chronic liver injury resulting from a variety of insults. However, drugs that effectively block the activation of HSCs have still not been adequately investigated. This study demonstrates that metformin decreased the number of activated-HSCs through induction of apoptosis, but did not impact numbers of hepatocytes. Metformin upregulated BAX activation with facilitation of BIM, BAD and PUMA; downregulated Bcl-2 and Bcl-xl, but did not affect Mcl-1. Additionally, metformin induced cytochrome c release from mitochondria into the cytoplasm, directly triggering caspase-9-mediated mitochondrial apoptosis. The decline in mitochondrial membrane potential (ΔΨm) and deposition of superoxide in mitochondria accelerated the destruction of the integrity of mitochondrial membrane. Moreover, we verified the therapeutic effect of metformin in our mouse model of liver fibrosis associated with nonalcoholic steatohepatitis (NASH) in which hepatic function, NASH lesions and fibrosis were improved by metformin. In conclusion, this study indicated that metformin has significant therapeutic value in NASH-derived liver fibrosis by inducing apoptosis in HSCs, but does not affect the proliferation of hepatocytes.