Metformin mitigates carbon tetrachloride-induced TGF-β1/Smad3 signaling and liver fibrosis in mice.

Increasing evidence suggests that the widely used antidiabetic drug metformin have an extensive therapeutic range beyond hypoglycemic therapy. We previously found that metformin significantly attenuated acute hepatitis. The present study investigated the potential effects of metformin on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. The results indicated that treatment with metformin suppressed CCl4-induced elevation of liver index, formation of fibrotic septa, accumulation of connective tissue and upregulation of collagen I. These effects were not associated with increase of the antioxidative transcription factor nuclear erythroid 2-related factor 2 (NRF2) or its downstream targets, heme oxygenase 1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). However, treatment with metformin suppressed CCl4-induced expression of transforming growth factor beta 1 (TGF-β1) and phosphorylation of Smad3, which was accompanied with decreased level of alpha smooth muscle actin (α-SMA), a marker for the activated hepatic stellate cells (HSCs). These data indicates that metformin could mitigate CCl4-induced liver fibrosis and these beneficial effects might result from suppressed TGF-β1/Smad3 signaling.