Sortilin promotes macrophage cholesterol accumulation and aortic atherosclerosis through lysosomal degradation of ATP-binding cassette transporter A1 protein  

作　　者：Yuncheng Lv Jing Yang Anbo Gao Sha Sun Xilong Zheng Xi Chen Wei Wan Chaoke Tang Wei Xie Suyun Li Dongming Guo Tianhong Peng Guojun Zhao Liyuan Zhong 

机构地区：[1]Clinical Anatomy and Reproductive Medicine Application Institute,University of South China,Hengyang 421001,China [2]Clinical Medical Research Institute of the First Affiliated Hospital,University of South China,Hengyang 421001,China [3]Department of Biochemistry and Molecular Biology,The Libin Cardiovascular Institute of Alberta,The University of Calgary,Health Sciences Center,Calgary T2N 4N1,Canada [4]Institute of Cardiovascular Research,Medical Research Center,University of South China,Hengyang 421001,China [5]Department of Histology and Embryology,Guilin Medical University,Guilin 541004,China

出　　处：《Acta Biochimica et Biophysica Sinica》2019年第5期471-483,共13页生物化学与生物物理学报（英文版）

摘　　要：Sortilin is closely associated with hyperlipidemia and the risk of atherosclerosis(AS).The role of sortilin and the underlying mechanism in peripheral macrophage are not fully understood.In this study,we investigated the effect of macrophage sortilin on ATP-binding cassette transporter A1(ABCA1)expression,ABCA1-mediated cholesterol efflux,and aortic AS.Macrophage sortilin expression was upregulated by oxidized low-density lipoproteins(ox-LDLs)in both concentration-and time-dependent manners.Its expression reached the peak level when cells were incubated with 50μg/ml ox-LDL for 24 h.Overexpression of sortilin in macrophage reduced cholesterol efflux,leading to an increase in intracellular total cholesterol,free cholesterol,and cholesterol ester.Sortilin was found to bind with ABCA1 protein and suppress macrophage ABCA1 expression,resulting in a decrease in cholesterol efflux from macrophages.The inhibitory effect of sortilin in cholesterol efflux was partially reversed by treatment with chloroquine,a lysosomal inhibitor.On the contrary,the ABCA1 protein level and ABCA1-mediated cholesterol efflux is increased by sortilin short hairpin RNA transfection.The fecal and biliary cholesterol 3H-sterol from cholesterol-laden mouse peritoneal macrophage was reduced by sortilin overexpression through lentivirus vector(LV)-sortilin in low-density lipoprotein receptor knockout mice,which was prevented by co-treatment with chloroquine.Treatment with LV-sortilin reduced plasma high-density lipoprotein and increased plasma ox-LDL levels.Accordingly,aortic lipid deposition and plaque area were exacerbated,and ABCA1 expression was reduced in mice in response to infection with LV-sortilin alone.These effects of LV-sortilin were partially reversed by chloroquine.Sortilin enhances lysosomal degradation of ABCA1 protein and suppresses ABCA1-mediated cholesterol efflux from macrophages,leading to foam cell formation and AS development.

关 键 词：SORTILIN ABCA1 MACROPHAGE CHOLESTEROL EFFLUX ATHEROSCLEROSIS 

分 类 号：Q[生物学]