Scientific Papers

PGC1α deficiency reverses cholestasis-induced liver injury via attenuating hepatic inflammation and promoting bile duct remodeling

Human cholestatic liver diseases are a group of biliary disorders caused by heterogeneous reasons, which mainly comprise primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) (Alvaro and Mancino, 2008). During that progression, bile acids accumulate in the liver due to aberrant flux and metabolism, leading to hepatocellular necrosis and apoptosis, cholangiocyte proliferation, progressive fibrosis, and cirrhosis at the end stage (Hirschfield, Heathcote et al., 2010). Bile duct ligation (BDL) was a classic experimental model of cholestatic injuries by imitating biliary obstruction (Saito and Maher, 2000). Although new evidence for therapeutic strategies has been given (Trauner and Fuchs, 2022), the understanding of the pathogenesis of biliary injury still obscure.

Bile acid (BA) homeostasis was important in maintaining liver functions (Halilbasic et al., 2013). In cholestatic liver diseases, the balance was ruined due to intrahepatic biliary obstruction, thus resulting in a toxic attack when the body failed to compensate (Li et al., 2021). In addition, ductular reaction, characterized by the proliferation of reactive cholangiocytes, was considered a crucial factor for liver regeneration during liver and bile duct injuries (Sato et al., 2019). Deficiency in the ductular reaction was reported to aggravate cholestasis-related liver injuries (Kim et al., 2015, Pihlajoki et al., 2021).

Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) is a member of PGC1s, known as a transcription coactivator involved in multiple biological responses associated with energy homeostasis (Handschin and Spiegelman, 2006), thermal production (Lin et al., 2002), and lipid and glucose metabolism (Yoon et al., 2001, Haemmerle et al., 2011, Lee et al., 2018). Liver is the key organ where a wide variety of metabolic reactions would be in process (Piñeiro-Carrero and Piñeiro, 2004, Jones, 2016) and PGC1α has been reported to play a central role in a spectrum of liver diseases (Wang et al., 2018, Piccinin et al., 2019, Liu et al., 2020). Our previous study showed that hepatic-specific overexpression of PGC1α contributed to improving hepatic steatosis and insulin resistance in mice fed with a high-fat diet (Wan et al., 2020). However, whether PGC1α participated in BA metabolism and cholestatic liver diseases was little investigated.

Nevertheless, little is known about whether PGC1α is involved in bile acid metabolism and biliary disorders. In this study, we aimed to investigate the role of PGC1α in cholestatic liver injury induced by BDL and the underlying mechanism. It was elucidated that PGC1α deficiency may prevent the progress of cholestatic liver injury via regulating the bile duct endothelial cells (BECs) proliferation. These findings implied that PGC1α may represent a viable therapeutic target in cholestatic liver injury.

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