Investigation of the function of Zip14-mediated transient zinc-uptake into the liver during normal infection and sepsis

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Zinc is an essential trace element for numerous body functions. This is underlined by the observation that zinc deficiency, caused by malnutrition or as a consequence of ageing or pregnancy, disturbs immune cell functions as well as it accelerates onset and progression of inflammatory diseases such as sepsis. In contrast, zinc supplementation had beneficial effects during treatment of liver fibrosis or cirrhosis, viral hepatitis or alcoholic liver disease. During acute infection, zinc is taken up by the liver, causing a transient decrease in serum zinc. Recent results indicate that the hepatic zinc importer Zip14 is responsible for this transfer of zinc into the liver. However, the functional significance of this process as well as the underlying mechanisms are not entirely clear. By blocking Zip14-mediated zinc uptake through Zip14 knockout in mice, we will clarify if zinc is vital for the liver metabolism. Moreover, we will investigate, if low serum zinc concentrations are necessary to establish a pro-inflammatory immune response or to inhibit microbial proliferation. We will also investigate how pre-existing zinc deficiency contributes to the onset and development of sepsis, focusing on the mechanisms responsible for the hyper-inflammatory response, which is responsible in part for tissue destruction. Finally, we will examine if zinc supplementation after sepsis onset can be beneficial. This will include analyses of different treatment strategies using various doses, time points and repeats of zinc administration.