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

BACKGROUND

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by mutations in the SERPINA1 gene, leading to reduced levels or impaired alpha-1 antitrypsin (AAT) function. 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 proteins 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 the regulation of 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.

OBJECTIVE

This study explored the relationship between AATD and zinc metabolism through a combination of in vitro experiments and computational analysis.

RESULTS

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), a murine model of AATD, exhibited significant differences in mRNA levels related to zinc homeostasis and UPR when compared to wildtype mice. Bayesian network analysis of GEO data uncovered novel gene-to-gene interactions among zinc transporters, as well as between zinc homeostasis, UPR, and other associated genes.

CONCLUSIONS

The findings provide valuable insights into the role of zinc homeostasis genes in UPR processes linked to AATD.