title: Homozygosity for an allele encoding deacetylated FoxO1 protects macrophages from cholesterol-induced inflammation without increasing apoptosis.
abstract: OBJECTIVE
  Insulin resistance renders macrophages more prone to cholesterol-induced apoptosis by promoting nuclear localization of transcription factor forkhead box transcription factor (Fox) O1. However, FoxO1 also decreases macrophage inflammation, raising the question of how the balance between proapoptotic and antiinflammatory effects is determined. We sought to identify the mechanism whereby FoxO1 dampens inflammation without promoting apoptosis. We hypothesized that nutrient-dependent FoxO1 acetylation plays a role in this process.
  
  
  RESULTS
  We generated knock-in mice bearing alleles that encode constitutively deacetylated FoxO1 and studied the ex vivo response of primary peritoneal macrophages. We show that macrophages derived from mice homozygous for constitutively deacetylated FoxO1 alleles retain antiinflammatory properties in response to free cholesterol loading, without increasing apoptosis. Deacetylated FoxO1 inhibits free cholesterol-induced Akt phosphorylation and increases levels of the nuclear factor-κB precursor p105, decreasing nuclear translocation of nuclear factor-κB p65 subunit and dampening mitogen-activated protein/extracellular signal-regulated kinase activation to prevent inflammation.
  
  
  CONCLUSIONS
  Deacetylated FoxO1 regulates p105 to prevent macrophage inflammation without causing apoptosis, suggesting a potential novel therapeutic approach to atherosclerosis through FoxO1 deacetylation.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Kyoichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Banks
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Liang
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000107:Acetylation; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000009:adverse effects* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C073701:Nfkb1 protein, mouse; D002784:Cholesterol; D051057:Proto-Oncogene Proteins c-akt