Introduction Alpha1-antitrypsin (AAT) mutations lead to the retention of the otherwise secreted
protein in the endoplasmic reticulum (ER) thereby giving rise to AAT deficiency (AATD).
Liver disease arising due to the proteotoxic stress is the second leading cause of
mortality in AATD.
Aims & methodology Our aim was to assess the importance of mTOR signaling in AATD as the central proteostatic
regulator. Animals overexpressing the characteristic AAT mutation (PiZ mice) were
cross-bred with rodents harboring a hepatocyte specific-ablation of the interaction
partners RAPTOR/RICTOR corresponding to mTOR complexes 1/2 (mTORC1/2) or with mice
lacking mTOR.
Results At two month of age, PiZ-mTORΔhep and PiZ-RAPTORΔhep but not PiZ-RICTORΔhep mice
showed signs of increased liver injury and apoptosis despite diminished AAT accumulation.
While PiZ-RAPTORΔhep animals displayed increased levels of the pro-apoptotic protein
CHOP, CHOP ablation did not rescue the phenotype. As a potential underlying mechanism,
we observed reduced levels of several chaperones, i. e. Hsp90 or Grp94.
Conclusions mTORC1 but not mTORC2 plays an important role in PiZ induced liver injury.
