Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

Abstract

Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet-induced ER stress using Zip14 −/− (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders.unfolded protein response | p-eIF2α/ATF4/CHOP pathway | apoptosis | steatosis | zinc metabolism

Non-Alcoholic Fatty Liver Disease, Diabetes Mellitus, and Zinc/ Zinc Transporters: Is there a Connection?

“…The authors conclude from this that ZIP14 may have a relevance analogue to that of ZnT8 regarding the diagnosis and treatment of type 2 Dm and NAFLD. Current findings by Kim et al [45] showed the relevance of zinc trafficking and the functional ZIP14 activity for adaptation to endoplasmic reticulum (ER) stress connected to metabolic diseases. According to Zhang [46], zinc restriction in the cells triggers ER stress, which highlights the relevance of zinc for maintaining a normal ER function.…”

“…Zinc and zinc transporters are involved in the development of ER stress and impairment of the protein synthesis, the unfold protein response (UPR; 45). UPR could be triggered in yeasts and in some mammals by zinc restriction UPR [45,52,53]. In the liver, impaired apoptosis leads to dysregulation of the lipid metabolism, causing hepatic steatosis [54].…”

“…In the liver, impaired apoptosis leads to dysregulation of the lipid metabolism, causing hepatic steatosis [54]. Kim et al [45] were able to show that the ZIP14mediated zinc transport is critical for the prevention of prolonged apoptotic cell death and steatosis during ER stress, that is, for hepatocellular adaptation to ER stress.…”

Endoplasmic reticulum targeting fluorescent probes to image mobile Zn2+

“…11,12 For example, it has been found that zinc can be released from thapsigargin-and inositol 1,4,5-trisphosphate (IP3)-sensitive ER storage in cortical neurons. 13 In light of this, it is unsurprising that a large number of reports demonstrate that the depletion of zinc transporters and zinc deciency can cause ER stress and upregulate the UPR, [14][15][16][17][18] however, the role of 'free' or 'mobile' zinc in this process is little understood due to the lack of suitable molecular tools to image this subcellular region that exist.…”

Lipid perturbation-activated IRE-1 modulates autophagy and lipolysis during endoplasmic reticulum stress

“…In the event of an acute response to excessive ER stress, the UPR is known to elicit cell death response mediated through IRE1 and PERK (Harding et al, 2003, Novoa et al, 2001. In addition, chronic ER stress characterised by the continual burden on the ER function has surprisingly resulted to an adaptative response by the UPR (Rutkowski et al, 2006, Kim et al, 2017. Contrary to the apoptotic response observed in acute ER stress, adaptation to chronic ER stress is characterised by resistance to apoptosis resulting from differential expression of pro-survival signals and stabilisation of UPR components (Rubio et al, 2011).…”