Metabolomic analysis of cholestatic liver damage in mice

Abstract Cholestasis is characterized by the obstruction of bile duct, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The complicated etiology and injury mechanism greatly limits the development of new drugs for its treatment. To better understand the mechanism of cholestatic liver damage, ultra-performance liquid chromatography-linked electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) and multivariate data analysis were used to determine the metabolic changes in three recognized mouse cholestasis models. The cholestatic liver damage was generated by alphanaphthyl isothiocyanate (ANIT), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and lithocholic acid (LCA). The results indicated that the levels of bile acids were commonly increased in plasma of three mouse cholestasis models, while arginine was decreased. The level of plasma glutathione was decreased in ANIT- and LCA-induced intrahepatic PBC and PSC, respectively. But, the liver glutathione was decreased in DDC induced extrahepatic PSC. The level of plasma phospholipids was elevated in ANIT and DDC models, whereas that was depleted in LCA model. And protoporphyrin IX was significantly increased in the liver of DDC model. These metabolomics data could potentially distinguish the metabolic differences of three types of cholestasis, contributing to the understanding of the potential mechanism of cholestatic liver damage.