FIGURE 7.

Potential mechanism of ZnT8 KO protection against APAP-induced liver injury. Zip4 and Zip14 are localized to the plasma membrane of hepatocytes and are dramatically upregulated after APAP treatment. ZnT8 KO mice displayed higher levels of hepatic IL6, Zip4, and Zip14 expression than wild-type mice after APAP overdose, accompanied by increased zinc uptake. Accumulation of hepatic Zn²⁺ and IL6 upregulates the antioxidant proteins MT1/2. Accumulation of MT1/2 attenuates APAP-induced inflammation, ROS, and necrosis. Zip4 and Zip14 may play a major role in the mechanisms responsible for the protective effects of ZnT8 KO mice. In addition, higher levels of IL6 also lead to enhanced hepatocyte proliferation in ZnT8 KO mice.