Enhancement of hepatic autophagy increases ureagenesis and protects against hyperammonemia

Ammonia is a potent neurotoxin that is detoxified mainly by theurea cycle in the liver. Hyperammonemia is a common complicationof a wide variety of both inherited and acquired liver diseases. If nottreated early and thoroughly, it results in encephalopathy and death.Here, we found that hepatic autophagy is critically involved insystemic ammonia homeostasis by providing key urea-cycle intermediatesand ATP. Hepatic autophagy is triggered in vivo byhyperammonemia through an a-ketoglutarate-dependent inhibitionof the mammalian target of rapamycin complex 1, and deficiency ofautophagy impairs ammonia detoxification. In contrast, autophagyenhancement by means of hepatic gene transfer of the master regulatorof autophagy transcription factor EB or treatments with theautophagy enhancers rapamycin and Tat-Bedin-1 increased ureagenesisand protected against hyperammonemia in a variety of acuteand chronic hyperammonemia animal models, including acute liverfailure and ornithine transcarbamylase deficiency, the most frequenturea-cycle disorder. In conclusion, hepatic autophagy is an importantmechanism for ammonia detoxification because of its support ofurea synthesis, and its enhancement has potential for therapy ofboth primary and secondary causes of hyperammonemia.