Metformin prevents liver tumourigenesis by attenuating fibrosis in a transgenic mouse model of hepatocellular carcinoma

Metforminis a hypoglycaemic agent used to treat type 2 diabetes mellitus (DM2) patients, with a broad safety profile. Since previous epidemiological studies had shown that the incidence of hepatocellular carcinoma (HCC) decreased significantly in metformintreated DM2 patients, we hypothesised that intervention with metformincould reduce the risk of neoplastic transformation of hepatocytes. HCC is the most common primary liver malignancy and it generally originates in a background of liver fibrosis and cirrhosis. In the present study, we took advantage of a transgenic mouse (TG221) characterized by microRNA-221 overexpression, with cirrhotic liver background induced by chronic administration of carbon tetrachloride ( CCl4). This mouse model develops fibrosis, cirrhosis and liver tumours that become visible in 100% of mice at 5–6 months of age. Our results demonstrated that metforminintervention improves liver function, inhibits hepatic stellate cell(HSC) activation, reduces liver fibrosis, depletes lipid accumulation in hepatocytes, halts progression to decompensated cirrhosis and abrogates development HCC in CCl4challenged transgenic mouse model. The study establishes the rationale for investigating metforminin cirrhotic patients regardless of concomitant DM2 status.