Disparate β‐Catenin Activation Following Iron Overload is Responsible for Hepatocyte Proliferation in Male Mice

Abstract

Iron overload in diseases such as hemochromatosis is associated with development of hepatocellular cancer (HCC). Since β‐catenin signaling is a key molecular mechanism in HCC, we investigated the impact of high iron diet on mice with normal or absent β‐ catenin in hepatocytes. Male and female β‐catenin conditional knockouts (KO) or littermate controls (Con) were fed high iron diet for 3 months. Male and female Con and female KO tolerated the regimen, while male KO showed signs of morbidity. The liver weight to body weight ratio of KO males was 50% of controls. Serum biochemistry showed a mild elevation of serum bilirubin in KO. Histological analysis showed increased apoptotic hepatocytes and increase in CD45 cells in KO. There was no change in fibrosis. KO male mice show 1.6‐fold more liver iron (p=0.012), lower serum iron, and similar hepcidin and Id1. There was about 64‐fold increase in Saa‐1 (p=0.05) coinciding with inflammation. All controls & KO females showed an increase in cell proliferation and number of cyclin‐D1‐positive hepatocytes, while KO males did not show cell proliferation and cyclin‐D1. Compared to mice that did not receive iron diet, Con males showed increased levels of cyclin‐ D1; however, other β‐catenin mediated transcripts—cmyc and glutamine synthetase—decreased. Thus high iron diet appears to be affecting the activity of β‐catenin, resulting in association with different transcription factors.