Interleukin-6 (IL-6) up-regulates the
ZIP14 gene expression ZIP14 (Slc39a14)., which in turn, is responsible for an excess of intracellular zinc and, at the same time, for hypozincemia that accompanies the acute phase response to inflammation and infection. Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia.
Interleukin-6 regulates the zinc transporter Zip14 in the liver and contributes to the hypozincemia of the acute-phase response. https://www.pnas.org/doi/10.1073/pnas.0502257102
Cellular stress induced by the abnormal accumulation of unfolded or misfolded proteins at the endoplasmic reticulum (ER). Unresolved endoplasmic reticulum (ER) stress corresponds with various chronic diseases, including cancer, diabetes, obesity and neurodegeneration, hepatic steatosis.
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, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression.) 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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530682/
Expanded quote from above:
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
IFN-y is also induced by intense exercise,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849644/ and
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484649/
IFN-y increases expression of GRP78, which is the same GRP78 that increases WASF3 levels. The 24 hr delay for PEM correlates with IFN-y levels that are known to rise ~24 hrs after exertion.
https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2443910
As Datadragon mentioned and I’m seeing in the literature is there is a known connection between IFNs and ER function/UPR
Interferon-y (intensive exercise also is ifn-y), Interferon-α (IFN-a) and inflammatory cytokines IL-1β, IL-6 and TNF-a, have all been shown to induce metallothioneins in the research, which can all reduce zinc availability and uptake. NLRP3 activation also leads to IL-1b (and Il-6) and IL-18. Interleukin-18 (IL-18) synergizes with IL-2 to enhance cytotoxicity, interferon-gamma (IFN-y) production, and expansion of natural killer cells.
The protein WASF3 is boosted in response to ER Stress as one reason, and this disrupts the cells energy production when WASF3 was increased, while blocking the WASF3 increase through blocking ER Stress lowered WASF3 levels and restored mitochondrial function. They discovered that the ME/CFS patients had higher levels of WASF3, lower levels of Mitochondrial cytochrome c oxidase (MTCO1) (a sign that oxygen wasn’t being metabolized well) and higher levels of the ER stress protein, PERK.
https://medicalnewsbulletin.com/jou...c-encephalomyelitis-chronic-fatigue-syndrome/ Note
Cytochrome c oxidase, the terminal
oxidase in the electron transport
chain, is
copper dependent which requires ceruloplasmin to make our copper and iron bio-available (usable). Zinc is involved in Vitamin A metabolism and vice versa and Zinc, Vitamin A ,and Magnesium are needed for ceruloplasmin production that Ive covered more elsewhere. Other mechanisms may also be at play.
Glucose deprivation strongly inhibited IFN-gamma gene expression (increased by ifn-a, heavy exercise), optimal induction of IFN-gamma transcription is a glucose-dependent process. IFN-γ rapidly increases protein synthesis and causes the unfolded protein response (UPR), as evidenced by the increased expression of glucose-regulated protein 78 (GRP78). IFN-y is also upregulated from intensive exercise.
https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2443910
High glucose treatment, but not the osmotic control mannitol, induces csGRP78 expression through an ER stress–dependent mechanism (which increases WASF3 levels). There are many 'roads' to increase NLRP3 and/or ER Stress.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514638/ GRP78 levels were positively correlated with HbA1c and AGEs.
https://pubmed.ncbi.nlm.nih.gov/34591271/
