Schisandrol B protects against cholestasis through Parkin‐Drp1 signaling pathway involved in mitochondrial dynamics

Till now, only two drugs were approved by FDA in treating cholestatic liver diseases. Exploring potential novel targets or candidates is crucial in the development of therapeutic drug for the treatment of cholestasis. It has been shown that mitochondrial dynamics (fission‐fusion) plays a vital role in various conditions‐induced hepatocyte injury. Our previous study demonstrated that Schisandrol B (SolB) exerts significant hepato‐protection effect against lithocholic acid (LCA)‐induced acute liver injury. In this study, anti‐cholestasis effect of SolB and the possible molecular mechanism were investigated. We found that SolB pretreatment (200 mg/kg/d) alleviated LCA‐induced liver injury as evidenced by histological and biochemical analyses. Transmission electron microscope analysis showed that LCA elicited small, fragmented morphology in mitochondria, and SolB pretreatment had no effects on the mitochontrial morphology. However, western blot analysis showed that proteins associated with mitochondrial dynamics such as dynamin‐related protein1 (DRP1), optic atrophy 1 (OPA1), mitofusin 1 (MFN1) and MFN2 were significantly downregulated after LCA treatment. However, pretreatment with SolB significantly increased DRP1 and mitochondrial fission factor (MFF), which are crucial to regulate mitochondrial fission. Additionally, the E3 ubiquitin protein ligase (Parkin), a protein that promotes the proteasome dependent degradation of Drp1, was decreased after SolB pretreatment. In summary, this study demonstrate that hepato‐protection effect of SolB against LCA‐induced cholestastic liver injury is related to Parkin‐Drp1 mediated mitochondrial fission, and provide a new insight to understand hepato‐protective mechanism of SolB.