Manganese Transport and Toxicity

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ABSTRACT Manganese homeostasis must be balanced to prevent neurotoxic effects of excess metal while providing sufficient nutrition for growth and development. It has been established that manganese levels are strongly influenced by iron metabolism. We have found that blood manganese levels are reduced in individuals with hereditary hemochromatosis. Because this iron overload disease arises from genetic deficiencies in the hepcidin-ferroportin axis, we theorize that the iron regulatory hormone hepcidin also regulates manganese homeostasis. The balance between excess and sufficiency of manganese is regulated by hepatobiliary excretion of the metal, but insight into the molecular mechanism has only recently been obtained. Based on new information about manganese transporters in the liver, we propose an innovative model for hepatobiliary metal secretion. The proposed project will directly test our hypothetical model for vectorial manganese trafficking across the hepatocyte and further define hepcidin’s role in metal homeostasis. The goals are: 1) To identify the cellular localization of the Mn transporters Slc40a1 (ferroportin), Slc30a10 (ZnT10), Slc39a8 (Zip9) and Slc39a14 (Zip14) in polarized WIF-B hepatocytes; 2) To define the regulation of Mn transporters in WIF-B hepatocytes and HH patient liver samples; and 3) To determine the molecular function of Mn transporters in hepatobiliary transport model system using HepaRG hepatocytes in a “sandwich-culture” monolayer grown on Transwell filters.