title: SIRT6 reduces macrophage foam cell formation by inducing autophagy and cholesterol efflux under ox-LDL condition.
abstract: SIRT6 is a pivotal regulator of lipid metabolism. It is also closely connected to cardiovascular diseases, which are the main cause of death in diabetic patients. We observed a decrease in the expression of SIRT6 and key autophagy effectors (ATG5, LC3B, and LAMP1) in ox-LDL-induced foam cells, a special form of lipid-laden macrophages. In these cells, SIRT6 WT but not SIRT6 H133Y overexpression markedly reduced foam cell formation, as shown by Oil Red O staining, while inducing autophagy flux, as determined by both mRFP-GFP-LC3 labeling and transmission electron microscopy. Silencing the key autophagy initiation gene ATG5, reversed the autophagy-promoting effect of SIRT6 in ox-LDL-treated THP1 cells, as evidenced by an increase in foam cells. Cholesterol efflux assays indicated that SIRT6 overexpression in foam cells promoted cholesterol efflux, increased the levels of ABCA1 and ABCG1, and reduced miR-33 levels. By transfecting miR-33 into cells overexpressing SIRT6, we observed that reduced foam cell formation and autophagy flux induction were largely reversed. These data imply that SIRT6 plays an essential role in protecting against atherosclerosis by reducing foam cell formation through an autophagy-dependent pathway.
authors.affiliation: Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Jiangping
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Guangya
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Capital Medical University Electric Power Teaching Hospital, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Pang
authors.affiliation: Department of Ultrasound, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Fengling
authors.initials: F
authors.lastname: Chen
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008077:Lipoproteins, LDL / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D035683:MicroRNAs / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D000071187:Autophagy-Related Protein 5; D002784:Cholesterol; D008077:Lipoproteins, LDL; D008164:Luminescent Proteins; D051907:Lysosomal Membrane Proteins; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D037761:Sirtuins; C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C502778:ATG5 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C502070:MAP1LC3B protein, human; C550416:MIRN33a microRNA, human; C099252:oxidized low density lipoprotein; C516592:SIRT6 protein, human
keywords: SIRT6; atherosclerosis; autophagy; cholesterol efflux; foam cells