PMID:15684432

Citation	Makowski, L, Brittingham, KC, Reynolds, JM, Suttles, J and Hotamisligil, GS (2005) The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. J. Biol. Chem. 280:12888-95
Abstract	Fatty acid-binding proteins are cytosolic fatty acid chaperones, and the adipocyte isoform, aP2, plays an important role in obesity and glucose metabolism. Recently, this protein has been detected in macrophages where it strongly contributes to the development of atherosclerosis. Here, we investigated the role of aP2 in macrophage biology and the molecular mechanisms underlying its actions. We demonstrate that aP2-deficient macrophages display defects in cholesterol accumulation and alterations in pro-inflammatory responsiveness. Deficiency of aP2 alters the lipid composition in macrophages and enhances peroxisome proliferator-activated receptor gamma activity, leading to elevated CD36 expression and enhanced uptake of modified low density lipoprotein. The increased peroxisome proliferator-activated receptor gamma activity in aP2-deficient macrophages is also accompanied by a significant stimulation of the liver X receptor alpha-ATP-binding cassette transporter A1-mediated cholesterol efflux pathway. In parallel, aP2-deficient macrophages display reduced IkappaB kinase and NF-kappaB activity, resulting in suppression of inflammatory function including reduced cyclooxygenase-2 and inducible nitric-oxide synthase expression and impaired production of inflammatory cytokines. Our results demonstrate that aP2 regulates two central molecular pathways to coordinate macrophage cholesterol trafficking and inflammatory activity.
Links	PubMed Online version:10.1074/jbc.M413788200
Keywords	Animals; Antigens, CD36/biosynthesis; Arteriosclerosis/metabolism; Biological Transport; CD40 Ligand/biosynthesis; CHO Cells; Carrier Proteins/chemistry; Carrier Proteins/physiology; Cell Line; Cholesterol/metabolism; Cricetinae; Cyclooxygenase 2; Cytokines/metabolism; DNA-Binding Proteins/metabolism; Fatty Acid-Binding Proteins; Genes, Reporter; Glucose/metabolism; I-kappa B Kinase; Inflammation; Lipid Metabolism; Macrophages/cytology; Macrophages/metabolism; Mice; Models, Biological; Models, Genetic; NF-kappa B/metabolism; Nitric Oxide Synthase/antagonists & inhibitors; Nitric Oxide Synthase Type II; Orphan Nuclear Receptors; PPAR gamma/metabolism; Promoter Regions, Genetic; Prostaglandin-Endoperoxide Synthases/metabolism; Protein-Serine-Threonine Kinases/metabolism; Proteins/metabolism; RNA, Messenger/metabolism; Receptors, Cytoplasmic and Nuclear/metabolism; Time Factors
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