title: Advanced glycation in macrophages induces intracellular accumulation of 7-ketocholesterol and total sterols by decreasing the expression of ABCA-1 and ABCG-1.
abstract: BACKGROUND
  Advanced glycation end products (AGE) alter lipid metabolism and reduce the macrophage expression of ABCA-1 and ABCG-1 which impairs the reverse cholesterol transport, a system that drives cholesterol from arterial wall macrophages to the liver, allowing its excretion into the bile and feces. Oxysterols favors lipid homeostasis in macrophages and drive the reverse cholesterol transport, although the accumulation of 7-ketocholesterol, 7alpha- hydroxycholesterol and 7beta- hydroxycholesterol is related to atherogenesis and cell death. We evaluated the effect of glycolaldehyde treatment (GAD; oxoaldehyde that induces a fast formation of intracellular AGE) in macrophages overloaded with oxidized LDL and incubated with HDL alone or HDL plus LXR agonist (T0901317) in: 1) the intracellular content of oxysterols and total sterols and 2) the contents of ABCA-1 and ABCG-1.
  
  
  METHODS
  Total cholesterol and oxysterol subspecies were determined by gas chromatography/mass spectrometry and HDL receptors content by immunoblot.
  
  
  RESULTS
  In control macrophages (C), incubation with HDL or HDL + T0901317 reduced the intracellular content of total sterols (total cholesterol + oxysterols), cholesterol and 7-ketocholesterol, which was not observed in GAD macrophages. In all experimental conditions no changes were found in the intracellular content of other oxysterol subspecies comparing C and GAD macrophages. GAD macrophages presented a 45% reduction in ABCA-1 protein level as compared to C cells, even after the addition of HDL or HDL + T0901317. The content of ABCG-1 was 36.6% reduced in GAD macrophages in the presence of HDL as compared to C macrophages.
  
  
  CONCLUSIONS
  In macrophages overloaded with oxidized LDL, glycolaldehyde treatment reduces the HDL-mediated cholesterol and 7-ketocholesterol efflux which is ascribed to the reduction in ABCA-1 and ABCG-1 protein level. This may contribute to atherosclerosis in diabetes mellitus.
authors.affiliation: Lipids Laboratory (LIM-10), Faculty of Medical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Iborra
authors.forename: Adriana
authors.initials: A
authors.lastname: Machado-Lima
authors.forename: Gabriela
authors.initials: G
authors.lastname: Castilho
authors.forename: Valeria S
authors.initials: VS
authors.lastname: Nunes
authors.forename: Dulcinéia S P
authors.initials: DS
authors.lastname: Abdalla
authors.forename: Edna R
authors.initials: ER
authors.lastname: Nakandakare
authors.forename: Marisa
authors.initials: M
authors.lastname: Passarelli
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002460:Cell Line; D003925:Diabetic Angiopathies / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D008401:Gas Chromatography-Mass Spectrometry; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007653:Ketocholesterols / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000819:agonists; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D013261:Sterols / Q000378:metabolism*
chemical_list: C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D017127:Glycation End Products, Advanced; D007653:Ketocholesterols; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D016877:Oxidants; D013261:Sterols; C099252:oxidized low density lipoprotein; D000079:Acetaldehyde; C003001:7-ketocholesterol; C010972:glycolaldehyde