Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress
Significance Unresolved endoplasmic reticulum (ER) stress corresponds with various chronic diseases, such as hepatic steatosis and diabetes. Although cellular zinc deficiency has been implicated in causing ER stress, the effect of disturbed zinc homeostasis on hepatic ER stress and a role for zinc during stress are unclear. This study reveals that ER stress increases hepatic zinc accumulation via enhanced expression of metal transporter ZIP14. Unfolded protein response-activated transcription factors ATF4 and ATF6α regulate Zip14 expression in hepatocytes. During ER stress, ZIP14-mediated zinc transport is critical for preventing prolonged apoptotic cell death and steatosis, thus leading to hepatic cellular adaptation to ER stress. These results highlight the importance of normal zinc transport for adaptation to ER stress and to reduce disease risk.