Functional Study Of Hepatic APOA4 In Atherosclerosis And Liver Injury

APOA4 is a plasma lipoprotein,which is involved in the regulation of many metabolic pathways such as lipid and glucose metabolism.In rodents,APOA4 is primary synthesized by the liver and small intestine,followed by secretion into blood.APOA4 could enhance glucose stimulated insulin secretion and inhibit glucose production in the liver.APOA4 also enhances TG secretion from the liver.In addition,APOA4 has anti-oxidative and anti-inflammatory properties.The relationship between APOA4 and some diseases has also been found,such as the plasma APOA4 is a major factor in the prevention of atherosclerosis.As one of the synthetic organs of APOA4,the liver plays an important role in VLDL secretion,lipid and glucose metabolism.Liver is also sensitive to damage stimulation such as drugs,herbals and CCl4.However,whether hepatic APOA4 regulates atherosclerosis is largely unknown.In this study,we determine whether hepatic APOA4 regulates atherosclerosis by using variety of approaches.Firstly,to study whether hepatic APOA4 regulates atherosclerosis,we obtained ob/ob APOE-/-double knockout mice by hybridization and genotype identification.After feeding with HFD,we obtained HFD induced ob/ob APOE-/-double knockout atherosclerosis mouse model.Compared with the commonly used single knockout mice,the time required for the formation of atherosclerosis in HFD induced ob/ob APOE-/-double knockout mice is significantly shorter,and HFD induced ob/ob APOE-/-double knockout mice show much higher body weight and plasma lipid levels.Secondly,we found that the level of APOA4 in liver was increased abnormally by detecting HFD induced ob/ob APOE-/-double knockout atherosclerosis mouse model.These results suggest that APOA4 in the liver may be associated with atherosclerosis,therefore we specifically knock down APOA4 in the liver of model mice,then we detected blood lipid level,body weight,and the formation of atherosclerosis.The results showed that APOA4 in theliver could regulate the plasma TG level,but had no significant effect on the formation of atherosclerosis.Thirdly,we established CCl4-induced acute liver injury model,and found that the level of APOA4 in liver was increased abnormally.This result suggests that hepatic APOA4 may be involved in CCl4-induced liver injury process.In summary,we established HFD induced ob/ob APOE-/-double knockout atherosclerosis mouse model.Liver-specific knockdown of APOA4 significantly decreased plasma TG level,which is not sufficient to affect the formation of atherosclerosis.Hepatic APOA4 protein level is abnormally increased in CCl4-induced liver injury,which indicates that APOA4 may regulate liver injury.