Gender Difference In The Effect Of Omega-3 Polyunsaturated Fatty Acids On Acetaminophen-induced Acute Liver Failure

Paracetamolum(acetaminophen,APAP)is one of most commonly used drugs in the treatment of pain and fever all over the world.APAP is safe and has an effective use at the recommended dosage,but APAP overdose can lead to dose-related liver cell necrosis,and it’s toxicity is a worldwide main reason that causes drug-induced liver injury(DILI).DILI is accomplied with mitochondrial dysfunction,oxidative stress,and it is closely related to inflammation,it can further cause acute liver damage.When liver damage occures,it causes a large amount of accumulation of reactive oxygen species(ROS),changes in mitochondrial membrane potential,phosphorylation of JNK,and autophagy,which are the main reasons that drug-induced liver injury leads to the death of liver parenchymal cells.Thus,it is of great significance to explore the mechanism of APAP-induced liver cell injury and observe the involvement and regulation of relevant molecules in this injury process.PUFAs(polyunsaturated fatty acids)refers to the PUFAs with multiple unsaturated double bond,and they can be divided into n-3 series and n-6 series polyunsaturated PUFAs according to the position of the unsaturated bond.PUFAs are essential for human’s normal growth.And they cannot be synthesized by themselves and must be obtained from diet or nutritional supplements.DHA is the most common n-3 polyunsaturated PUFAs found in plants and deep-sea fish.Studies in clinical trials and in animal models have shown that omega-3 polyunsaturated fatty acids(n-3 PUFAs)can affect the progression of various liver damage.It is worth noting that n-3 PUFAs have a gender-dependent effect on human health,however,it is not clear whether supplementation of n-3 PUFAs is gender-specific to the pathogenesis of APAP-induced liver failure in mice of different genders.Our study found that both endogenous and exogenous n-3 PUFAs have similar regulatory effects and mechanisms on APAP-induced liver injury.In vivo experiments,endogenous expression of n-3 PUFAs in mice significantly aggravated APAP-induced liver injury in male mice,while the opposite phenomenon was observed in female mice,that n-3 PUFAs had a damage-relieving effect on APAP-induced liver injury.We found that n-3 PUFAs’ regulation of APAP-induced liver inj ury,the production of oxidative stress and autophagy in liver cells also showed significant differences between male and female mice,and this difference was related to the activation of GSK-3β regulated β-catenin signaling pathway.Compared with C57BL/6 mice in the normal diet group,the C57BL/6 mice that were given a n-3 PUFAs intensive diet for 3 weeks had a more severe liver injury induced by APAP,as the same phenomenon was observed in WT mice and fat-1 mice after.In vitro trials,human liver cell line HepaRG cells were stimulated by APAP,and it was found that compared with the cell group not treated with n-3 PUFAs,the presence of n-3 PUFAs aggravated APAP-induced liver injury by promoting mitochondrial damage,production of ROS,activation of JNK in oxidative stress signaling pathway,and autophagy in liver.In summary,we found that n-3 PUFAs supplementation had sex difference effect on APAP-induced liver toxicity as it played a role of liver injury in males and a protective role of liver in females,and estrogen was involved in the regulation of n-3 PUFAs on the toxicity induced by APAP.Mechanism studies have shown that estrogen is involved in the regulation of n-3 PUFAs on APAP-induced liver toxicity by affecting GSK-3β-mediated β-catenin pathway.This result explained the significant differences in the pathological process of APAP-induced liver injury in mice of different genders in detail,which may provide new insights and theoretical basis for the common clinical treatment of APAP-induced liver injury.