Selenium and copper belong to the group of essential trace elements, both affecting cellular redox homeostasis as being components of antioxidant enzymes. Additionally, it is known that copper inhibits the enzymatic activity of the selenoproteins glutathione peroxidases and thioredoxin reductase. Regarding serum concentrations, there is an inverse relationship present between copper and selenium with copper being high and selenium low upon various conditions such as aging, inflammation and in cancer patients. In serum the majority of selenium is present as selenoprotein P (SELENOP) which is mainly secreted by the liver and subsequently supplies peripheral tissues with selenium. Based on these notions, we wanted to investigate if the reduction of serum selenium concentration is a result of direct interference of copper with hepatic SELENOP secretion.

Treatment of HepG2 cells or primary murine hepatocytes with non-toxic copper concentrations revealed a strong reduction of SELENOP release from the cells. This was confirmed by performing an untargeted secretome approach in HepG2 cells identifying SELENOP as one of the most downregulated proteins. Furthermore, analyzing serum samples of patients with Wilson’s disease and corresponding rats, which are characterized by a strong hepatic copper accumulation due to mutations in the main hepatic copper exporter ATP7B, the decline in serum SELENOP was validated. Using a copper chelator in the Wilson’s rat model the effect on SELENOP could be reversed. Importantly these effects are not a general effect of a divalent metal or increased oxidative stress, as neither zinc, iron nor hydrogen peroxide treatment showed comparable results.

Overall, we observed for the first time that copper affects hepatic SELENOP release and thus peripheral selenium supply of target organs such as the brain could be impaired, especially under condition of hepatic copper accumulation.