Acetaminophen (APAP) overdose can induce liver injury and is generally accompanied by disruption of bile acid homeostasis. Physiologically, sodium taurocholate co-transporting polypeptide (NTCP) participates in the uptake of bile acids from portal blood into hepatocytes to maintain enterohepatic recirculation but its role in APAP-induced hepatotoxicity is unclear. Wild-type (WT) C57BL/6J and NTCP knockout (KO) mice were injected with 400mg/kg APAP and liver injury was evaluated by serum biochemical markers and histologic evaluation. RNA-seq analysis was performed to evaluate the liver gene expression profiles in APAP-treated mice. Compared with WT mice, the exposure to APAP overdose caused liver dysfunction, oxidative stress, inflammation and cell death, which were ameliorated by NTCP deficiency. APAP detoxification, metabolism, and elimination were significantly accelerated by the upregulation of UDP-glucuronosyltransferase (Ugt1a1, Ugt1a6 and Ugt1a9), sulfotransferase (Sult1a1 and Sult2a1) and bile acid efflux transporters (Abcc2/3/4) in NTCP KO mice compared with WT mice. Interestingly, APAP-induced hepatotoxicity was ameliorated using Irbesartan and Ezetimibe (NTCP inhibitors). In conclusion, NTCP deficiency attenuates APAP-induced hepatotoxicity by enhancing the metabolism and elimination of APAP. NTCP inhibitors protect against APAP-induced hepatotoxicity and thus are a potential therapeutic option.
