Mice Lacking Liver‐Specific [beta]‐Catenin Develoop Steatohepatitis and Fibrosis After Iron Overload

Background & aims Iron overload disorders such as hereditary hemochromatosis and iron‐loading anemias are a common cause of morbidity from liver diseases and are risk factors for hepatic fibrosis and hepatocellular carcinoma (HCC). Once iron‐induced damage occurs, treatment options are limited, partly because of the lack of animal models recapitulating human disease, since mice do not exhibit fibrosis or HCC following chronic iron overload. Methods A high iron containing diet was fed to normal mice to assess any effect on Wnt signaling. Iron overload diet was also administered to liver‐specific β‐catenin knockout (KO) and control (CON) mice for three months. To ameliorate an oxidant‐mediated component of tissue injury, N‐Acetyl‐L‐(+)‐cysteine (NAC) was added to drinking water of mice on iron overload diet. Results KO on iron diet (KO+Fe) exhibited remarkable steatosis, inflammation, hepatic fibrosis, regenerating nodules, and sequelae associated with increased oxidative stress. We also noted increased activation of AKT and NFkB pathways in KO+Fe. Addition of NAC to drinking water protected KO+Fe from hepatic steatosis, injury and fibrosis, and suppressed phosphorylation of AKT and NFkB. Conclusions We provide evidence that lack of hepatic b‐catenin predisposes mice to hepatic injury and fibrosis following iron overload thus phenocopying disease in patients. This is chiefly due to lack of antioxidant response in the absence of b‐catenin demonstrating its role in hepatic redox homeostasis. Lastly, antioxidant therapy may have a chemopreventive role in the management of chronic iron overload.