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

## TL;DR

This study investigates how a genetic disorder called Alpha-1 Antitrypsin Deficiency affects zinc levels and gene interactions in liver cells.

## Contribution

The study reveals new gene interactions between zinc transporters and stress response genes in a mouse model of AATD.

## Key findings

- Expression of the mutant ATZ protein in mouse hepatocytes reduced labile zinc levels and disrupted zinc homeostasis genes.
- PiZ mice showed significant differences in mRNA levels related to zinc homeostasis and the unfolded protein response compared to wildtype mice.
- Bayesian network analysis identified novel gene interactions among zinc transporters and UPR-related genes.

## Abstract

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.