Metformin ameliorates bile duct ligation-induced acute hepatic injury via regulation of ER stress

Cholestasis is a condition in which the bile duct becomes narrowed or clogged by a variety of factors and bile acid is not released smoothly. Bile acid-induced liver injury is facilitated by necrotic cell death, neutrophil infiltration, and inflammation. Metformin, the first-line treatment for type 2 diabetes, is known to reduce not only blood glucose but also inflammatory responses. In this study, we investigated the effects of metformin on liver injury caused by cholestasis with bile acid-induced hepatocyte injury. Static bile acid-induced liver injury is thought to be related to endoplasmic reticulum (ER) stress, inflammatory response, and chemokine expression. Metformin treatment reduced liver injury caused by bile acid, and it suppressed ER stress, inflammation, chemokine expression, and neutrophil infiltration. Similar results were obtained in mouse primary hepatocytes exposed to bile acid. Hepatocytes treated with tauroursodeoxycholic acid, an ER stress inhibitor, showed inhibition of ER stress, as well as reduced levels of inflammation and cell death. These results suggest that metformin may protect against liver injury by suppressing ER stress and inflammation and reducing chemokine expression.