Abstract
Hemojuvelin (HJV) enhances signaling to the iron hormone hepcidin and its deficiency causes iron overload, a risk factor for hepatocellular carcinoma (HCC). We utilized Hjv−/− mice to dissect mechanisms for hepatocarcinogenesis. We show that suboptimal treatment with diethylnitrosamine (DEN) triggers HCC only in Hjv−/− but not wt mice. Liver proteomics data were obtained by mass spectrometry. Hierarchical clustering analysis revealed that Hjv deficiency and DEN elicit similar liver proteomic responses, including induction of mitochondrial proteins. Dietary iron overload of wt mice does not recapitulate the liver proteomic phenotype of Hjv−/− animals, which is only partially corrected by iron depletion. Consistent with these data, primary Hjv−/− hepatocytes exhibit mitochondrial hyperactivity, while aged Hjv−/− mice develop spontaneous HCC. Moreover, low expression of HJV or hepcidin (HAMP) mRNAs predicts poor prognosis in HCC patients. We conclude that Hjv has a hepatoprotective function and its deficiency in mice promotes mitochondrial dysfunction and hepatocarcinogenesis.
Highlights
Hemojuvelin (HJV) enhances signaling to the iron hormone hepcidin and its deficiency causes iron overload, a risk factor for hepatocellular carcinoma (HCC)
We used Hjv−/− mice as a model of hemochromatosis to study the impact of iron overload on HCC pathogenesis following injection with DEN, an established hepatocarcinogen[15]
We did not observe any suppressive effects of DEN treatment on Hamp mRNA expression in female wild type mice (Fig. 1c), contrary to a previous report in which the sex of the mice was not specified[16]
Summary
Hemojuvelin (HJV) enhances signaling to the iron hormone hepcidin and its deficiency causes iron overload, a risk factor for hepatocellular carcinoma (HCC). Dietary iron overload of wt mice does not recapitulate the liver proteomic phenotype of Hjv−/− animals, which is only partially corrected by iron depletion Consistent with these data, primary Hjv−/− hepatocytes exhibit mitochondrial hyperactivity, while aged Hjv−/− mice develop spontaneous HCC. Disruption of the HJV gene results in severe hepcidin deficiency, which allows hyperabsorption of dietary iron by duodenal enterocytes and unrestricted iron entry into plasma from erythrophagocytic tissue macrophages These pathogenic responses underlie the development of juvenile hemochromatosis, a rare, early-onset form of hereditary hemochromatosis[9]. Hjv−/− mice recapitulate the iron overload phenotype of juvenile hemochromatosis[11,12] but do not develop spontaneous liver injury at young age They exhibit oxidative stress in the liver, early activation of profibrogenic hepatic stellate cells and increased sensitivity to CCl4-induced liver fibrosis[13]. They develop liver fibrosis in response to chronic feeding a high iron diet[14]
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