Investigating the hepatic processing of the Z-variant of alpha-1-antitrypsin in a zebrafish model

The Z variant of alpha-1-antitrypsin (ZAAT) is associated with severe antitrypsin deficiency. Retention of ZAAT in the liver predispose individuals to develop liver disease, and limit its secretion into the circulation. A zebrafish model expressing ZAAT displays serum insufficiency but no liver accumulation, suggesting efficient mechanisms in the zebrafish liver to clear misfolded ZAAT. Collectively, our results suggest the processing of ZAAT by protein degradation machinery in hepatocytes lead to cholesterol homeostasis perturbation. Furthermore, the removal of a stress response factor enhances ZAAT secretion, thus providing a novel therapeutic strategy for treating antitrypsin deficiency.