Effect of Alpha-1 Antitrypsin Deficiency on Zinc Homeostasis Genes Regulation and Interaction with Endoplasmic Reticulum Stress Response Associated Genes

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by mutations in the SERPINA1 gene, leading to reduced levels or impaired function of alpha-1 antitrypsin (AAT). This condition predominantly affects the lungs and liver. The Z allele, a specific mutation in the SERPINA1 gene, is the most severe form and results in the production of misfolded AAT proteins. The misfolded peptides accumulate in the endoplasmic reticulum (ER) of liver cells, triggering ER stress and activating the unfolded protein response (UPR), a cellular mechanism designed to restore ER homeostasis. Currently, there is limited knowledge regarding specific nutritional recommendations for patients with AATD. The liver is essential for regulating zinc homeostasis, with zinc widely recognized for its hepatoprotective properties. However, the effects of AATD on zinc metabolism remain poorly understood. Similarly, the potential benefits of zinc supplementation for individuals with AATD have not been thoroughly investigated. This study explored the relationship between AATD and zinc metabolism through a combination of in vitro experiments and in silico analyses. The expression of the mutant Z variant of ATT (ATZ) in cultured mouse hepatocytes was associated with decreased labile zinc levels in cells and dysregulation of zinc homeostasis genes. Analysis of two data series from the Gene Expression Omnibus (GEO) revealed that mice expressing ATZ (PiZ mice) exhibited significant differences in mRNA levels related to zinc homeostasis and UPR-associated genes when compared to wild-type mice. Bayesian network analysis of GEO data revealed novel gene-to-gene interactions among zinc transporters, as well as between zinc homeostasis, UPR, and other associated genes. These findings offer valuable insights into the role of zinc homeostasis genes in UPR processes linked to AATD.