title: Fat mass and obesity-associated protein attenuates lipid accumulation in macrophage foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice.
abstract: Genome-wide association studies have linked variants of fat mass and obesity-associated protein (FTO) to obesity. However, the molecular function of FTO remains unclear. In this study, we sought to investigate the potential effects of FTO in modulating cholesterol deposition in macrophage foam cells, as well as whether FTO exerts antiatherosclerotic properties in apolipoprotein E-deficient mice.
  
  
  
  We transfected RAW264.7 cells with plasmids encoding a wild-type or mutant FTO gene (I367F). The upregulation of FTO markedly attenuated cholesterol ester accumulation in macrophages loaded with oxidized LDL, whereas the downregulation of FTO reversed this effect. Moreover, FTO attenuated the mRNA and protein expression of a scavenger receptor, CD36, which was accompanied by the decline of peroxisome proliferator-activated receptor γ protein. In addition, FTO enhanced the phosphorylation of AMP-activated protein kinase (AMPK)α and acetyl-CoA carboxylase, which was effectively suppressed by FTO small interfering RNA. Pretreatment with compound C or transfection with a dominant-negative AMPKα blocked the FTO-mediated upregulation of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1. Furthermore, FTO suppressed IL-1β secretion independent of the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 inflammasome. In-vivo experiments were performed using apolipoprotein E-deficient mice that were infected with adeno-associated virus serotype 9-derived vectors encoding a wild-type or mutant FTO gene. FTO overexpression prevented the formation of atherosclerotic plaques and markedly reduced the content of plasma total cholesterol and LDL cholesterol. Notably, the antiatherosclerotic properties of FTO were observed only in male mice.
  
  
  
  We propose that the FTO-dependent control of cholesterol deposition may provide avenues for the treatment of atherosclerosis.
authors.affiliation: aLab for Aging Research, The Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversitybDepartment of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, ChinacDepartment of Molecular Genetics and Microbiology, Gene Therapy Center, University of Massachusetts School of Medicine, Worcester, Massachusetts, USA.
authors.forename: Chunfen
authors.initials: C
authors.lastname: Mo
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Han
authors.forename: Junhong
authors.initials: J
authors.lastname: Li
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.forename: Haoran
authors.initials: H
authors.lastname: Tai
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.forename: Hengyi
authors.initials: H
authors.lastname: Xiao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism; D047495:PPAR gamma; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D018955:CD36 Antigens; D058847:Inflammasomes; D053583:Interleukin-1beta; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase