Mouse models of hereditary hemochromatosis do not develop early liver fibrosis in response to a high fat diet

Abstract

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.

Propionic acid and not caproic acid, attenuates nonalcoholic steatohepatitis and improves (cerebro) vascular functions in obese Ldlr −/− .Leiden mice

“…Interestingly, HFD treatment strongly lowered the hepatic glycogen content, and both CA and PA significantly prevented this reduction indicating an effect of both CA and PA on liver metabolism. A reduction in hepatic glycogen content appears to be indicative of a defect in liver metabolism, impaired liver function, and hepatic insulin resistance as reported by others, 52,53 an effect that has not been reported earlier in the HFD-fed Ldlr −/− .Leiden model of NASH. The hepatic glycogen augmenting effect of CA was paralleled by an insignificant reduction of lobular inflammation (by about 50%), whereas similar increases of hepatic glycogen with PA were associated with a reduction in liver inflammation.…”