Inactivation of major hepcidin pathways leads to systemic and hepatic iron overload during development of chemically-induced liver cirrhosis in rats.

Hepatic iron overload is a common complication of human chronic liver diseases, including liver cirrhosis; however, the underlying mechanisms remain unclear. In the present study, we investigated the temporal changes in iron metabolism and the expression of iron-regulatory molecules during thioacetamide-induced liver cirrhosis in rats. Histopathological and biochemical analyses revealed that iron overload develops concurrently with the suppression of hepcidin expression in advanced cirrhosis. Hepatic expression of genes involved in cellular iron intake, storage, and export increased persistently in cirrhotic livers. The IL6-STAT3 and BMP6-SMAD pathways, which are the major intracellular mechanisms that induce hepcidin transcription, were inactivated in advanced cirrhosis. Furthermore, microRNA-135b-5p (miR-135b-5p), which targets JAK2 and SMAD5, key molecules of the IL6-STAT3 and BMP6-SMAD pathways, respectively, was highly upregulated in parallel with the progression of cirrhosis. These results indicate that inactivation of multiple hepcidin pathways, possibly mediated by miR-135b-5p upregulation, is responsible for hepatic iron overload in advanced cirrhosis. Our findings provide new insights into the mechanisms underlying iron dysregulation in liver cirrhosis.