Hepatic processing of Z variant a-1-antitrypsin alters ERAD capacity to regulate cholesterol biosynthesis in a zebrafish model

Homozygosity for the Z allele of a1-antitrypsin (ZAAT) predisposes affected individuals to developing liver disease as the serpin misfolds and forms insoluble polymers that accumulate in the endoplasmic reticulum (ER) of hepatocytes, resulting in gain-of-function hepatotoxicity. This prevents secretion of ZAAT leading to serum insufficiency. A zebrafish model expressing human ZAAT in the liver shows no signs of hepatic accumulation despite displaying serum insufficiency, suggesting defect in ZAAT secretion occurs independently of its tendency to accumulate in hepatocytes. In this study, global transcriptomic approach was used to identify pathways activated and operating in the ZAAT-expressing zebrafish liver. The analysis provided strong evidence of suppressed Srebp2-mediated cholesterol biosynthesis. qPCR confirms this observation in the human liver cell line stably expressing ZAAT. We proposed that the engagement of misfolded ZAAT by the ER-associated degradation (ERAD) system inhibits the turnover of Srebp2-repressing elements therefore hindering the activation of Srebp2. Overall design: Comparative gene expression profiling analysis of RNA-seq data for transgenic zebrafish liver expressing wildtype or Z-mutant human antitrypsin, and their non-transgenic siblings.