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.Hemojuvelin (HJV), a BMP co-receptor promoting hepcidin expression in the liver, has a hepatoprotective function and its deficiency in mice triggers mitochondrial dysfunction and hepatocarcinogenesis.
Hemojuvelin deficiency promotes liver mitochondrial dysfunction and predisposes mice to hepatocellular carcinoma
Guido, Maria;
2022
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.Hemojuvelin (HJV), a BMP co-receptor promoting hepcidin expression in the liver, has a hepatoprotective function and its deficiency in mice triggers mitochondrial dysfunction and hepatocarcinogenesis.File | Dimensione | Formato | |
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