Protective Effects Of MBL On APAP-induced Liver Injury And Its Potential Mechanism

Acetaminophen(APAP)overdose is a frequent cause of drug-induced liver injury(DILI)and the most frequent cause of acute liver failure.Overdose of APAP can mediate necrosis of hepatocyte,and the activation of innate immune response induced by hepatocyte necrosis is also an important cause of liver injury.Therefore,to elucidate the stability and regulation of the immune microenvironment in the liver is necessary,and it will lay the foundation for the exploration of the new strategies for the prevention and treatment of drug induced liver injury(DILI).Mannan-binding lectin(MBL)is a key molecule in the innate immune system,which plays an immunomodulatory role in infectious and inflammatory diseases by activating the complement lectin pathway and participating in the anti-infective immune response.However,it has not been reported that whether the innate immune system is involved in drug metabolism affecting the disease progression of DILI.Our study found that,after APAP treatment,MBL deficient mice had enhanced liver injury,the increased APAP protein adduct formation and levels of cytochrome P450 2E1(CYP2E1)protein expression were observed in livers of APAP-treated MBL deficient mice,compared to those of control mice.However,there was no significant difference in the extent of hepatic GSH depletion between the two groups.It is indicated that MBL affects the metabolism of APAP by inhibiting the expression of metabolic enzyme CYP2E1,thus protecting APAP induced acute liver injury.The study found that,the expression and nuclear translocation of transcription factor SP1 increased in livers of MBL deficient mice after APAP treatment,compared with control mice.Inhibition of SP1 could abrogate the inhibitory effect of MBL on CYP2E1.Further studies have found that higher levels of ROS were produced in livers of APAP-treated MBL deficient mice compared to that of control mice.When pretreated WT and MBL deficient mice with NAC,an inhibitor of ROS,there was no significant difference in APAP induced liver injury between two groups.Meanwhile,the nuclear translocation of SP1 was obviously inhibited,the inhibition of MBL to CYP2E1 also disappeared.In addition,in vitro study of stimulation of human hepatocyte line HepaRG cells by APAP showed that MBL could down regulate intracellular ROS level and inhibit nuclear translocation of SP1,resulting in the inhibition of CYP2E1 expression.Taken together,the study suggested that MBL played a protective role in APAP induced liver injury.Mechanism investigation demonstrated that the ROS/SP1/CYP2E1 pathway is involved in the inhibitory effect of MBL on CYP2E1 expression.This may provide new insights and theoretical basis for clinical medication guidance and DILI clinical adjuvant therapy,especially for people with MBL defeciency.