RT Journal Article SR Electronic T1 Mouse models of hereditary hemochromatosis do not develop early liver fibrosis in response to a high fat diet JF bioRxiv FD Cold Spring Harbor Laboratory SP 319442 DO 10.1101/319442 A1 John Wagner A1 Carine Fillebeen A1 Tina Haliotis A1 Jeannie Mui A1 Hojatollah Vali A1 Kostas Pantopoulos YR 2018 UL http://biorxiv.org/content/early/2018/05/10/319442.abstract AB Hepatic iron overload, a hallmark of hereditary hemochromatosis (HH), triggers progressive liver disease. There is also increasing evidence for a pathogenic role of iron in non-alcoholic fatty liver disease (NAFLD), which may progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular cancer. Mouse models of HH and NAFLD can be used to explore potential interactions between iron and lipid metabolic pathways. Hfe−/− mice, a model of moderate iron overload, were reported to develop early liver fibrosis in response to a high fat diet. However, this was not the case with Hjv−/− mice, a model of severe iron overload. These data raised the possibility that the Hfe gene may protect against liver injury independently of its iron regulatory function. Herein, we addressed this hypothesis in a comparative study utilizing wild type, Hfe−/−, Hjv−/− and double Hfe−/−Hjv−/− mice. The animals, all in C57/BL6 background, were fed with a high fat diet for 14 weeks and developed hepatic steatosis, associated with mild iron overload. Hfe co-ablation did not sensitize steatotic Hjv-deficient mice to liver injury. Moreover, we did not observe any signs of liver inflammation or fibrosis even in single steatotic Hfe−/− mice. Ultrastructural studies revealed a reduced lipid and glycogen content in Hjv−/− hepatocytes, indicative of a metabolic defect. Interestingly, glycogen levels were restored in double Hfe−/−Hjv−/− mice, which is consistent with a metabolic function of Hfe. We conclude that hepatocellular iron excess does not aggravate diet-induced steatosis to steatohepatitis or early liver fibrosis in mouse models of HH, irrespectively of the presence or lack of Hfe.