Loss of the Mechanistic Target of Rapamycin Complex 1 Causes a Lethal Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

SERPINA1 mutations cause retention of the otherwise secreted alpha-1 antitrypsin and lead to the proteotoxic alpha-1 antitrypsin deficiency-related liver disease. As mechanistic target of rapamycin is a key coordinator of proteostasis, we studied its role in alpha-1 antitrypsin deficiency-related liver disease.

PiZ mice overexpressing the characteristic SERPINA1 mutation were mated with rodents harboring a hepatocyte specific-ablation of the interaction partners regulatory-associated protein of mechanistic target of rapamycin or rapamycin-insensitive companion of mammalian target of rapamycin, corresponding to mechanistic target of rapamycin complexes 1 or 2, or with mice lacking mechanistic target of rapamycin. Serum proteomics, liver bulk proteomics, spatial proteomics, and metabolomics were applied to characterize molecular and metabolic alterations.

At 2 months of age, PiZ-mTOR^Δhep and PiZ-Raptor^Δhep but not PiZ-Rictor^Δhep mice showed signs of increased liver injury and mortality despite diminished hepatic alpha-1 antitrypsin accumulation. PiZ-Raptor^Δhep animals displayed increased levels of the proapoptotic protein C/EBP homologous protein, but C/EBP homologous protein ablation did not rescue the phenotype. Serum proteomics revealed no signs of advanced synthetic liver failure but immature hepatocellular products. Liver bulk proteomics and small metabolite measurement demonstrated a metabolic reprogramming of PiZ-Raptor^Δhep mice. Spatial proteomics revealed alterations in liver zonation with increased ammonia levels as the likely cause of death in PiZ-Raptor^Δhep animals.

In summary, in alpha-1 antitrypsin deficiency-related proteotoxic liver injury, regulatory-associated protein of mechanistic target of rapamycin preserves a liver zonation, thereby protecting from lethal metabolic dysregulation.