Multi-omics profiling reveals protective function of Schisandra lignans against acetaminophen-induced hepatotoxicity

The action principles of traditional Chinese medicines (TCMs) feature multi-active components, multi-target sites, and weak combination with action targets. In the present study, we performed an integrated analysis of metabonomics, proteomics and lipidomics to establish a scientific research system on the underlying mechanism of TCMs, and Schisandra lignan extract (SLE) was selected as a model TCM. In metabonomics, several metabolic pathways were found to mediate the liver injury induced by acetaminophen (APAP), and SLE could regulate the disorder of lipid metabolism. The proteomic study further proved that the hepatoprotective effect of SLE was closely related to the regulation of lipid metabolism. Indeed, the results of lipidomics demonstrated that SLE-dosing has an obvious callback effect on APAP-induced lipidic profile shift. The contents of 25 diglycerides (DAGs) and 21 triglycerides (TAGs) were enhanced significantly by APAP-induced liver injury, which could further induce liver injury and inflammatory response by up-regulating protein kinase C (PKCβ, PKCγ, PKCδ and PKCθ). The up-regulated lipids and PKCs could be reversed to the normal level by SLE-dosing. More importantly, phosphatidic acid phosphatase (lipin1), fatty acid transport protein 5 (FATP5) and diacylglycerol acyltransferase 2 (DGAT2) were proved to be positively associated with the regulation of DAGs and TAGs. Significance Statement Integrated multi-omics was first used to reveal the mechanism of APAP-induced acute liver failure (ALF) and hepatoprotective role of SLE. The results showed that the ALF caused by APAP was closely related to lipid regulation and SLE-dosing could exert hepatoprotective role by reducing intrahepatic DAG and TAG levels. Our research can not only promote the application of multi-component technology in the study of the mechanism of TCMs, but also provide an effective approach for the prevention and treatment of ALF.

Keywords: drug-induced hepatotoxicity; lipids; metabolomics; proteomics.