Dual organ beneficial effects of metformin in cirrhotic rats with hepatopulmonary syndrome.

Liver fibrosis causes portal hypertension which dilates collateral vasculature and enhances extra-hepatic angiogenesis including intrapulmonary shunts, which subsequently complicates with hepatopulmonary syndrome (HPS). Metformin is an anti-diabetic agent which has anti-inflammation and antiangiogenesis properties. HPS is a severe complication of liver cirrhosis which is characterized by deoxygenation in cirrhotic patients. In this issue of the Journal of the Chinese Medical Association, Chen and his colleagues comprehensively evaluated the hemodynamic and biochemistry parameters, and a blood-gas analysis of a 21-day regimen of metformin 150 mg/kg/day treatment on common bile duct ligated (CBDL)-cirrhotic rats. The study revealed that metformin treatment neither induced obvious hypoglycemic event nor altered hemodynamics in cirrhotic rats. The plasma levels of alanine aminotransferase, hepatic inflammation and fibrosis were significantly reduced by chronic metformin treatment. Metformin did not modify the cirrhotic-HPS-related hypoxia and intrapulmonary angiogenesis; however, it significantly reduced intrapulmonary shunts. Furthermore, metformin reduced the protein expressions of COX-2 and PI3K in the liver and COX-1 in the lung. In the Chan et al. study, the plasma level of ALT and hepatic inflammation and fibrosis were significantly attenuated by chronic metformin treatment in common bile duct-ligated (BDL)-cirrhotic rats. Consistent with the current study finding, metformin have been proven to enhance liver function in HCV-related cirrhotic patients. In an animal model, metformin protects galactosamin-induced liver injury by way of the AMPK-dependent pathway. In vitro studies with human hepatocytes also suggested that anti-inflammatory action of metformin comes from AMPK activation. Notably, the metformin-related amelioration of BDL-induced hepatic inflammation and fibrosis was independent of hepatic AMPK pathway, but through the PIK-3 pathway. Interestingly, plasminogen activator inhibitor-1 (PAI-1), an acute phase protein, has been known to correlate with hepatic fibrosis. Early liver injury and inflammation due to bile duct ligation was significantly blunted in PAI-1 ( / ) mice compared to wild-type mice. The hepatic protective effects of PAI-1 in cholestatic