Torin-1 improves cognitive decline by regulating autophagic system and cholesterol metabolism in hepatic encephalopathy

Abstract

Patients with liver diseases, such as liver cirrhosis and liver failure, have a high likelihood of developing hepatic encephalopathy (HE). HE is characterised by neurological impairments ranging from mild cognitive dysfunction to severe coma. Hyperammonaemia, metabolic disruption, and inflammation are recognised as key factors in the onset of HE. Recently, impaired autophagy has also been suggested to contribute to the development of HE. Therefore, in this study, we aimed to examine whether the autophagy inducer torin-1 is effective in reducing signs of HE. In this study, C57BL/6 mice were subjected to bile duct ligation (BDL) for 14 days to establish a model of HE. Liver function and structure were assessed using aspartate aminotransferase, alanine aminotransferase, total bilirubin, and haematoxylin and eosin staining, respectively. Neurological function was evaluated through the elevated plus maze, novel object recognition test, marble-burying test, clasping test, and passive avoidance test. To evaluate the effects of torin-1, it was administrated intraperitoneally to mice daily for 14 days. Changes in autophagy, cholesterol metabolism, and the cytokine/chemokine profile in the cerebral cortex were measured with and without torin-1 treatment. We found that although systemic administration of torin-1 could not reduce the induction of jaundice and liver impairment caused by BDL, it appeared to delay the onset of HE. Torin-1 treatment reduced the BDL-induced elevation in serum cholesterol and ammonia levels. Furthermore, abnormal expression of autophagy-and cholesterol-associated molecules in the cerebral cortex was reduced by torin-1 treatment. Cognitive function was improved in mice undergoing BDL with torin-1 treatment. Conclusively, these findings indicate that the induction of autophagy was found to alleviate the adverse effects seen in HE by regulating cholesterol metabolism in the cerebral cortex. The autophagy inducer torin-1 might be a potential approach to alleviate alterations and symptoms in HE.