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.

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.
Authors	Liza Makowski, Katherine C Brittingham, Joseph M Reynolds, Jill Suttles, Gökhan S Hotamisligil
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 13 Pg. 12888-95 (Apr 01 2005) ISSN: 0021-9258 [Print] United States
PMID	15684432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	CD36 Antigens Carrier Proteins Cytokines DNA-Binding Proteins Fatty Acid-Binding Proteins Liver X Receptors NF-kappa B Nr1h3 protein, mouse Orphan Nuclear Receptors PPAR gamma Proteins RNA, Messenger Receptors, Cytoplasmic and Nuclear CD40 Ligand Cholesterol Nitric Oxide Synthase Nitric Oxide Synthase Type II Nos2 protein, mouse Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Protein Serine-Threonine Kinases Chuk protein, mouse I-kappa B Kinase Ikbkb protein, mouse Ikbke protein, mouse Glucose
Topics	Animals Arteriosclerosis (metabolism) Biological Transport CD36 Antigens (biosynthesis) CD40 Ligand (biosynthesis) CHO Cells Carrier Proteins (chemistry, 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 Liver X Receptors Macrophages (cytology, 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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!