The alcoholic liver injury (ALI) commonly occurs among people, typically the young and the middle-aged, who drink heavily. The ALI is extremely harmful and can induce severe disease states such as hepatitis, liver fibrosis, cirrhosis or even liver cancer. Recent studies found that the pathological changes of hepatocytes and hepatic stellate cell showed significant connection between endoplasmic reticulum (ER) stress which is the key factor to aggravate the development of liver pathology in patients with ALI. However, the detailed mechanism needs to be further studied. Schisandra chinensis, a member of TCM, has been used as a Chinese folk medicine for treatments of chronic or acute diseases especially the liver diseases, and especially Schisandra chinensis (S. chinensis) derived lignans (SCDLs) have been shown to alleviate liver pathological changes.This study sought to elucidate the mechanisms underlying SCDLs-mediated hepatoprotection.We first used in silico target prediction and computational simulation methods to identify putative lignans binding targets relative to the hepatoprotective effect. The gene microarray analysis was also performed in this study to identify differently expressed genes which may have significance in disease pathological process; we then used histological analyses in a mice hepatotoxicity model to test the effectiveness of SCDLs in vivo, and hepatocellular toxicity model to analyze the candidate compound mediated hepatoprotection and expression states of the key targets in vitro.In silico analysis results showed endothelin receptor B (ETBR/EDNRB) is likely a significant node during the liver pathological change process and a promising key target for the SCDLs compound Schisantherin D on the hepatoprotective effect; experimental studies showed that Schisantherin D alleviated HL-7702 cell (belongs to liver parenchymal cell lines) injury ratio, decreased expression of ETBR, and inhibited ECMs and ET-1 secretion in LX-2 cells (one form of hepatic stellate cells); SCDLs ameliorated the fibrosis formation in mice liver tissue. Liver tissue western blots of SCDLs treated mice showed down-regulated α-SMA, ETBR, PLCβ, CHOP, Bax, and the apoptotic factors of cleaved-caspase 12, cleaved-caspase 9 and cleaved-caspase 3 indicating the anti-apoptosis and hepatoprotective effect. SCDLs treatment also elevated serum glutathione (GSH) and reduced serum transforming growth factor-β1 (TGF-β1) level.SCDLs appears to prevent hepatotoxicity by the anti-fibrotic, anti-oxidance, and anti-apoptosis properties. ETBR may be the key factor in EtOH induced long term liver degeneration.
