title: Targeting mitochondrial 18 kDa translocator protein (TSPO) regulates macrophage cholesterol efflux and lipid phenotype.
abstract: The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein (TSPO) as a potential therapeutic target, capable of increasing macrophage cholesterol efflux to (apo)lipoprotein acceptors. Expression and activity of TSPO in human (THP-1) macrophages were manipulated genetically and by the use of selective TSPO ligands. Cellular responses were analysed by quantitative PCR (Q-PCR), immunoblotting and radiolabelling, including [3H]cholesterol efflux to (apo)lipoprotein A-I (apoA-I), high-density lipoprotein (HDL) and human serum. Induction of macrophage cholesterol deposition by acetylated low-density lipoprotein (AcLDL) increased expression of TSPO mRNA and protein, reflecting findings in human carotid atherosclerosis. Transient overexpression of TSPO enhanced efflux (E%) of [3H]cholesterol to apoA-I, HDL and human serum compared with empty vector (EV) controls, whereas gene knockdown of TSPO achieved the converse. Ligation of TSPO (using PK11195, FGIN-1-27 and flunitrazepam) triggered increases in [3H]cholesterol efflux, an effect that was amplified in TSPO-overexpressing macrophages. Overexpression of TSPO induced the expression of genes [PPARA (peroxisome-proliferator-activated receptor α), NR1H3 (nuclear receptor 1H3/liver X receptor α), ABCA1 (ATP-binding cassette A1), ABCG4 (ATP-binding cassette G4) and APOE (apolipoprotein E)] and proteins (ABCA1 and PPARα) involved in cholesterol efflux, reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL. Thus, targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation, via enhanced cholesterol efflux to (apo)lipoprotein acceptors.
authors.affiliation: *Department of Life Sciences and the Diabetes Research Group, Institute for Applied Health Research, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 0BA, U.K.
authors.forename: Janice M W
authors.initials: JM
authors.lastname: Taylor
authors.affiliation: *Department of Life Sciences and the Diabetes Research Group, Institute for Applied Health Research, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 0BA, U.K.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Allen
authors.affiliation: *Department of Life Sciences and the Diabetes Research Group, Institute for Applied Health Research, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 0BA, U.K.
authors.forename: Annette
authors.initials: A
authors.lastname: Graham
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D018079:Receptors, GABA / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D008077:Lipoproteins, LDL; D047493:PPAR alpha; D018079:Receptors, GABA; C499229:TSPO protein, human; C032629:acetyl-LDL; D002784:Cholesterol