Effection Of Acipimox On Expression And Regulation Of ATP Binding Cassette Transporter A1in Macrophages

Background：The overload of cholesterol ester in mononuclear macrophages makesthem form foam cells, which is the early characteristics ofAtherosclerosis(AS). So,enhancement of reverse cholesterol transport (RCT)can delay the progression of AS, which is one of the important mechanismsof anti-AS.RCT is defined as the process of efflux of excess cholesterolfrom the peripheral cells via transporters,then binding with apo A-I toproduce HDLs, which are transported to the liver and bile, followed byexcretion in the feces. ATP binding cassette transporter A1(ABCA1) canmediate efflux of cholesterol,then initiate RCT,which is an importanttransporter. Many factors can modulate the expression of ABCA1,such asLiver X receptor(LXR), including two subtypes-αand β. LXRα binds toRetinoid X receptor(RXR) to form heterodimer,and upregulates expressionof ABCA1.Niacin is the first lipid-regulating agent in clinical practice, and acipimox, as a derivative of niacin, is superior to it due to less adversereaction. Niacin has the most significant effect of upregulation of HDL,compared with other lipid-regulating drugs, but a couple of adverse effectsrestrict its application. At present, niacin is revalued because of emergenceof extended-release agents. Some researches verified that niacin couldstrengthen the efflux of cholesterol, but the mechanisms are unclear.Objectives：The aim of this project is to work on RAW264.7macrophages as thecell model, and to investigate the changes of mRNA and protein expressionof ABCA1and its upstream regulatory factors LXRα induced by acipimox atdifferent concentrations in vitro. At last, the probable mechanisms ofanti-AS via RCT which caused by acipimox are discussed.Methods：1Vitro cultured RAW264.7macrophages.2We isolated total RNA and protein of macrophages followedincubation with acipimox of different concentrations for24h.3We investigated mRNA of ABCAl and LXRα by RT-PCR.4We detected protein expression of ABCA1and LXRα by Westernblot.5Cellular cholesterol efflux rate detected by scintillation counting.6Statistical analysis. Results：1Detected by RT-PCR,the intervention of acipimox significantlyincreased the mRNA of ABCA1and LXRα in macrophages, and this effectswere dose-dependent（P<0.05）.2Detected by Western blot,the intervention of acipimox significantlyincreased the protein expression of ABCA1and LXRα in macrophages, andthis effects were dose-dependent（P<0.05）.3Acipimox could dose-dependently increase cholesterol efflux fromRAW264.7（p<0.05）.Conclusion:Acipimox as a derivative of niacin could upregulate the levels ofmRNA and protein expression of ABCA1,and this effects weredose-dependent.Furthermore,the changes of its upstream regulatory factorsLXRα was similar to acipimox.In Conclusion, acipimox maybe upregulateABCA1expression via LXRα pathway to promote RCT and inhibit theformation of foam cells to anti-AS.