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

Background and aims PiZ mutation in alpha1-antitrypsin (AAT), a hepatocyte-made, secreted protein, causes AAT deficiency (AATD), a proteotoxic disease characterized by hepatocellular AAT accumulation. Since mTOR is a key regulator of proteostasis, we are investigating the role of mTOR signaling in AATD-related liver disease.

Methods PiZ mice, an experimental AATD model, were crossbred with rodents deficient in hepatocellular mTOR or its interaction partners RAPTOR (mTOR comples 1) or RICTOR (mTOR complex 2) as established proteostatic regulators.

Results 10 weeks old PiZ RaptorΔhep mice, but not PiZ RictorΔhep mice exhibited a lethal liver injury, while PiZ mTORΔhep mice showed a non-lethal phenotype. No increased AAT accumulation was seen. While PiZ RaptorΔhep displayed elevated apoptosis and increased levels of the pro-apoptotic protein CHOP, CHOP ablation did not rescue the phenotype. Serum proteomics revealed no obvious signs of impaired hepatocellular synthesis and PiZ RaptorΔhep mice harbored only minimal fibrosis. Metabolomic analysis revealed profound alterations in arginine metabolism as well as increased glutamate levels. Accordingly, spatial proteomics demonstrated an altered liver zonation that was particularly pronounced in pericentral hepatocytes and likely resulted in lethal hyperammonemia. The pericentral alterations included a decrease in cell-type specific pathways, for instance diminished glutamine synthetase and cytochrome P450 2E1, as well as ectopic activation of periportal processes such as oxidative phosphorylation. This is supported by changes in major regulatory pathways, i.e. Wnt or HNF4α.

Conclusion Our findings demonstrate that Raptor signaling constitutes an essential guardian of metabolic zonation and protects PiZ mice from lethal hyperammonemia.

Publication History

Article published online:
23 January 2024