The Influences Of PCSK9 On The Hepatocyte PUFAs Metabolism And Macrophage Inflammation

Atherosclerosis?AS?has become the leading cause of death worldwile.This desease is related to fatty acid metabolism,also closely associated with macrophages functions.PCSK9 is a kid of secreted protein,which can combine with LDLR on hepatocyte surface,and lead to its degaration.As a result PCSK9 will increase LDL-c level and promote AS development.It has been proved that PCSK9 in serum has negative correlation with n-6 and n-3 PUFAs intake,but the mechanism is still unkonw.N-6and n-3 PUFAs can take part in lipid metabolism balance,and prevent AS.It also has been porved that PCSK9 in serum can regulate macrophage functions through other factors,and finally influences AS.But there are few reports about PCSK9 and macrophage inflammation.In order to study the mechanism between PCSK9 and n-6 and n-3 PUFAs,and the influence between PCSK9 and macrophage inflammation,we used PCSK9 knockout mouse,detected liver fatty acids by GC.We isolated hepatocytes?HCs?by liver perfusion,and is analysised by iTRAQ.Then proteomics was used to find differently expressed proteins and pathways.And the results were proved by in vivo test.At the same time,peritoneal macrophage cells were purified.And the expression level of TNF-?,IL-6 and NF-?B was measured by RTFQ PCR.The results show that,PCSK9^-/-mice have a low LA and ALA level in liver.Proteomic data mapped n-6 and n-3 biosynthetic pathways,and find an up-regulation of FADS2protein.The in vivo test indicates that PCSK9 and FADS2 can be interacted by each other on regulation of LA.Meanwhile,the results show a significant increase of TNF-?,IL-6 and NF-?B in PCSK9^-/-mouse.That means PCSK9^-/-mouse can promote macrophages to release more inflammatory factors by NF-?B.This study proved that PCSK9 knocking out results out an up-regulation of FADS2,which promots the n-6 and n-3 PUFAs metabolism.But the interaction between PCSK9 and FADS2 need further study.This research also certified that PCSK9 knocking out promotes inflammatory cytokines expression by NF-?B.The mechanism of PCSK9 regulates macrophage inflammation need further investigate.PCSCK9 may influence AS process by taking part in n-6 and n-3 PUFAs metabolism and macrophage inflammation.