Overexpression of STARD3 in human monocyte/macrophages induces an anti-atherogenic lipid phenotype.
Dysregulated macrophage cholesterol homoeostasis lies at the heart of early and developing atheroma, and removal of excess cholesterol from macrophage foam cells, by efficient transport mechanisms, is central to stabilization and regression of atherosclerotic lesions. The present study demonstrates that transient overexpression of STARD3 {START [StAR (steroidogenic acute regulatory protein)-related lipid transfer] domain 3; also known as MLN64 (metastatic lymph node 64)}, an endosomal cholesterol transporter and member of the 'START' family of lipid trafficking proteins, induces significant increases in macrophage ABCA1 (ATP-binding cassette transporter A1) mRNA and protein, enhances [(3)H]cholesterol efflux to apo (apolipoprotein) AI, and reduces biosynthesis of cholesterol, cholesteryl ester, fatty acids, triacylglycerol and phospholipids from [(14)C]acetate, compared with controls. Notably, overexpression of STARD3 prevents increases in cholesterol esterification in response to acetylated LDL (low-density lipoprotein), blocking cholesteryl ester deposition. Thus enhanced endosomal trafficking via STARD3 induces an anti-atherogenic macrophage lipid phenotype, positing a potentially therapeutic strategy.
Borthwick
Faye
F
Vascular Biology Group, Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, UK.
Allen
Anne-Marie
AM
Taylor
Janice M
JM
Graham
Annette
A
D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D005487:Foam Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009000:Monocytes / Q000378:metabolism*; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics
D002352:Carrier Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C105684:STARD3 protein, human