PGC1 deficiency reverses cholestasis-induced liver injury via attenuating hepatic inflammation and promoting bile duct remodeling

Objectives: Cholestatic liver diseases are characterized by hepatocellular damage, cholangiocyte proliferation, and progressive fibrosis. Bile duct ligation (BDL) is widely used to resemble liver injuries induced by cholestasis. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1 alpha) was reported to play a critical role in multiple biological responses. Nevertheless, whether PGC1 alpha is involved in bile acid metabolism and biliary disorders remains unclear. This study aimed to investigate the effect of PGC1 alpha on hepatic responses after cholestatic injury. Materials and methods: Wild-type mice were subjected to BDL or sham surgery for 14 days and human liver specimens from patients with primary biliary cholangitis (PBC) were collected to detect the expression of PGC1 alpha. Hepatic-specific PGC1 alpha knockout mice (HKO) were constructed and subjected to BDL, in which the effects of PGC1 alpha on cholestatic liver injury were demonstrated by biochemical and histopathological assessments, immunoblotting, and metabolomics. Results: The expression of PGC1 alpha was upregulated in the liver of PBC patients and murine models. Both in vivo and in vitro experiments supported the protective effects of PGC1 alpha on cholestasis-induced hepatocyte injury. Infiltrated inflammatory cells after BDL were decreased in HKO mice. Inhibited Wnt/beta-Catenin pathway and enhanced Notch signaling promoted transdifferentiation of hepatic progenitor cells (HPC)/ hepatocytes into cholangiocytes, leading to the greater ductular reaction observed in the HKO mice. But bile acids metabolism and mitochondrial function were not affected due to hepatic PGC1 alpha deficiency in cholestasis. Conclusions: Hepatic-specific deletion of PGC1 alpha regulated liver regeneration by promoting ductular reactions, thereby exerting protective effects against BDL-induced liver injury, which could be a new potential therapeutic target.