Loss of the mechanistic target of rapamycin complexes 1 (mTORC1) causes a lethal alpha-1 antitrypsin deficiency associated liver disease

Background & aims: SERPINA1 mutations cause retention of the otherwise secreted alpha-1 antitrypsin (AAT) and lead to the proteotoxic AAT deficiency (AATD)-related liver disease (AATD-LD). As mechanistic target of rapamycin (mTOR) is a key coordinator of proteostasis, we studied its role in AATD-LD. Methods: PiZ mice overexpressing the characteristic SERPINA1 mutation were mated with rodents harboring a hepatocyte specific-ablation of the interaction partners regulatory-associated protein of mTOR (RAPTOR) or rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) corresponding to mTOR complexes 1 or 2 (mTORC1/2) or with mice lacking mTOR. Serum proteomics, liver bulk proteomics, spatial proteomics, and metabolomics were applied to characterize molecular and metabolic alterations. Results: At two months of age, PiZ-mTORΔhep and PiZ-RaptorΔhep but not PiZ-RictorΔhep mice showed signs of increased liver injury and mortality despite diminished hepatic AAT accumulation. PiZ-RaptorΔhep animals displayed increased levels of the pro-apoptotic protein C/EBP homologous protein (CHOP), but CHOP 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-RaptorΔhep mice. Spatial proteomics revealed alterations in liver zonation with increased ammonia levels as the likely cause of death in PiZ-RaptorΔhep animals. Conclusions: In summary, in AATD-related proteotoxic liver injury, Raptor preserves a liver zonation, thereby protecting from lethal metabolic dysregulation.