title: Tribbles Homolog 3 Promotes Foam Cell Formation Associated with Decreased Proinflammatory Cytokine Production in Macrophages: Evidence for Reciprocal Regulation of Cholesterol Uptake and Inflammation.
abstract: BACKGROUND
  Insulin resistance is central in the pathophysiology of cardiometabolic disease; however, common mechanisms that explain the parallel development of both type 2 diabetes and atherosclerosis have not been elucidated. We have previously shown that tribbles homolog 3 (TRB3) can exert a chronic pathophysiological role in promoting insulin resistance and also has an acute physiological role to alternatively regulate glucose uptake in fat and muscle during short-term fasting and nutrient excess. Since TRB3 is expressed in human atherosclerotic plaques, we explored its role in foam cell formation to assess its potential contribution to atherogenesis.
  
  
  METHODS
  We have used human THP-1 monocytes, which transition to lipid-laden macrophage foam cells when exposed to oxidized low-density lipoprotein (ox-LDL).
  
  
  RESULTS
  We first observed that TRB3 was upregulated by more than twofold (P < 0.01) within 24 hr of treatment with ox-LDL. To determine whether TRB3 actively participated in foam cell formation, we overexpressed TRB3 in THP-1 monocytes and found that this led to a 1.5-fold increase in cholesterol accumulation after 48 hr (P < 0.01), compared with controls. At the same time, TRB3 overexpression suppressed inflammation in macrophages as evidenced by reduced expression and secretion of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) (both P < 0.01).
  
  
  CONCLUSIONS
  (1) TRB3 is upregulated in macrophages upon treatment with ox-LDL; (2) TRB3 promotes lipid accumulation and suppresses cytokine expression; and (3) inflammation and foam cell formation can be reciprocally regulated, and TRB3 orients the macrophage to assume a more primary role for lipid accumulation while maintaining a secondary role as an inflammatory immune cell.
authors.affiliation: 1 Department of Pathology, University of Alabama at Birmingham , Birmingham Alabama.|2 Department of Nutrition Sciences, University of Alabama at Birmingham , Birmingham Alabama.
authors.forename: Dennis
authors.initials: D
authors.lastname: Steverson
authors.affiliation: 2 Department of Nutrition Sciences, University of Alabama at Birmingham , Birmingham Alabama.
authors.forename: Ling
authors.initials: L
authors.lastname: Tian
authors.affiliation: 2 Department of Nutrition Sciences, University of Alabama at Birmingham , Birmingham Alabama.
authors.forename: Yuchang
authors.initials: Y
authors.lastname: Fu
authors.affiliation: 2 Department of Nutrition Sciences, University of Alabama at Birmingham , Birmingham Alabama.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 2 Department of Nutrition Sciences, University of Alabama at Birmingham , Birmingham Alabama.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ma
authors.affiliation: 2 Department of Nutrition Sciences, University of Alabama at Birmingham , Birmingham Alabama.|3 Birmingham Veterans Affairs Medical Center , Birmingham, Alabama.
authors.forename: William Timothy
authors.initials: WT
authors.lastname: Garvey
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000067996:RAW 264.7 Cells; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; C508585:IL1B protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008077:Lipoproteins, LDL; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D017346:Protein Serine-Threonine Kinases