Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome caused by liver dysfunction resulting in hyperammonemia-induced cerebral osmotic disturbances, oxidative/nitrosative stress, and cellular dysfunction. Whether impairing cellular quality control processes are involved in HE pathogenesis is unclear. Using primary rat astrocytes and an in-vivo rat HE model we determined whether hyperammonemia modulates autophagy. We performed gene expression analyses in post mortem brain samples of liver cirrhosis patients with HE in comparison to controls. We show that at pathologically high concentrations of ammonia autophagic flux is efficiently inhibited. This inhibition of autophagic flux occurs in a fast, reversible, time-, and dose-dependent manner. Mechanistically this is mediated by ammonia-induced changes in intralysosomal pH and depends on the formation of ROS. Conversely, at only moderately increased ammonia concentrations, autophagy is triggered. Consistent with this we find autophagy to be modulated in the in-vitro and the in-vivo HE models as well as in post mortem brain samples of liver cirrhosis patients with HE, but not without HE. We further demonstrate strategies reducing the observed negative effects of ammonia on autophagy flux in astrocytes as well as hyperammonemia in intoxicated rats. Overall, we show that autophagy is strongly altered in glial cells in various models of HE. We propose that modulating autophagy in the brain represents a novel strategy to treat liver diseases associated with hyperammonemia.
