Enhancement of hepatic autophagy increases ureagenesis and protects against hyperammonemia

Abstract

Ammonia is a potent neurotoxin that is detoxified mainly by the urea cycle in the liver. Hyperammonemia is a common complication of a wide variety of both inherited and acquired liver diseases. If not treated early and thoroughly, it results in encephalopathy and death. Here, we found that hepatic autophagy is critically involved in systemic ammonia homeostasis by providing key urea-cycle intermediates and ATP. Hepatic autophagy is triggered in vivo by hyperammonemia through an α-ketoglutarate-dependent inhibition of the mammalian target of rapamycin complex 1, and deficiency of autophagy impairs ammonia detoxification. In contrast, autophagy enhancement by means of hepatic gene transfer of the master regulator of autophagy transcription factor EB or treatments with the autophagy enhancers rapamycin and Tat-Beclin-1 increased ureagenesis and protected against hyperammonemia in a variety of acute and chronic hyperammonemia animal models, including acute liver failure and ornithine transcarbamylase deficiency, the most frequent urea-cycle disorder. In conclusion, hepatic autophagy is an important mechanism for ammonia detoxification because of its support of urea synthesis, and its enhancement has potential for therapy of both primary and secondary causes of hyperammonemia.

Retinal Degeneration in MPS-IIIA Mouse Model

“…In all experiments, we used as control aged-matched littermates of MPS-IIIA mice. For CQ assays, WT and MPS-IIIA mice at 9 months of age underwent to single intraperitoneal injection of 120 mg/kg CQ as previously described (Soria et al, 2018) and analyzed 4 h after the injection.…”

Ammonia and autophagy: An emerging relationship with implications for disorders with hyperammonemia

“…At elevated concentrations (above 20 mM), ammonia impairs lysosomal function because it increases lysosomal pH and water influx which secondarily result in defective substrate degradation and lysosome swelling, respectively . In contrast, ammonia strongly activates autophagy at lower concentrations (from 0.2 to 10 mM) both in vitro and in vivo . Ammonia derived from glutamine catabolism also strongly induces autophagy in cancer cells …”

“…Moreover, activation of AMPK and components of the unfolded protein response (UPR) have been involved in ammonia‐mediated induction of autophagy . In addition, induced autophagy in vivo was observed in livers and skeletal muscles of mice with hyperammonemia . The reasons underlying such differences in mTORC1 response to ammonia are unknown but they could depend on cell and tissue contexts.…”

“…Recent studies revealed that ammonia activates autophagy in several disease conditions . Ammonia is generated as a bioproduct of the catabolism of nitrogen‐containing molecules, is highly diffusible and neurotoxic at high concentrations.…”

Acute Liver Failure

“…137 Moreover, as hepatic autophagy is an essential mechanism for ammonia detoxification because of its support of urea synthesis, its augmentation has the potential for the treatment of both primary and secondary causes of hyperammonemia. 138 CONCLUSIONS ALF still remains a rather rare but often fatal entity, which requires high clinical suspicion and alertness. The sooner a patient is identified with ALF, the sooner the transfer to specialized centers with the capability of a highlevel multidisciplinary intensive care, and the more the possibilities exist for a favorable outcome.…”