The Fatty Acid-binding Protein, aP2, Coordinates Macrophage Cholesterol Trafficking and Inflammatory Activity

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 ␥ activity, leading to elevated CD36 expression and enhanced uptake of modified low density lipoprotein. The increased peroxisome proliferatoractivated receptor ␥ activity in aP2-deficient macrophages is also accompanied by a significant stimulation of the liver X receptor ␣-ATP-binding cassette transporter A1-mediated cholesterol efflux pathway. In parallel, aP2-deficient macrophages display reduced IB kinase and NF-B 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.

Differential Effects of Lipoprotein Lipase on Tumor Necrosis Factor-α and Interferon-γ-mediated Gene Expression in Human Endothelial Cells

“…Macrophages deficient in aP-2 display enhanced free fatty acids, reduced IKK and NF-B activation, and suppression of inflammatory activities (40). It is likely that free fatty acids and their derivatives generated by LPL catalytic activity may inhibit I-B degradation and NF-B activation in HAECs.…”

A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease

“…In recent years, results obtained from experimental models demonstrated that FABPs integrate metabolic and immune responses and link the inflammatory and lipid-mediated pathways that are critical in metabolic syndrome (9). In particular, the adipocyte͞macrophage FABP isoform, aP2, when deleted in mice demonstrates three major phenotypes: moderately reduced triglyceride levels, protection against type 2 diabetes when the animals were made obese, and reduced atherosclerosis despite hypercholesterolemia (6,18).…”

“…In contrast, both isoforms are expressed at similar levels in activated macrophages (6) and regulated by a variety of inf lammatory and metabolic mediators (8,9). The precise physiological role of these small proteins has been recognized only upon the development of genetic models to examine their function in mice (4,10,11).…”

Role of the fatty acid-binding protein 4 in heart failure and cardiovascular disease

“…Similar to adipocytes, FABP4 expression is also induced during differentiation from monocytes to macrophages, and its expression in these cells is regulated by a wide range of proinflammatory stimuli (Pelton et al 1999, Fu et al 2000, Makowski et al 2001, Fu et al 2002, Kazemi et al 2005. In macrophages, FABP4 increases the accumulation of cholesterol ester and induces foam cell formation as well as inflammatory responses through the activation of the IKK-NF-κB and JNK-AP-1 pathways (Makowski et al 2005, Hui et al 2010). FABP4 expression is controlled at the transcriptional level by CEBP (CCAAT/enhancer-binding protein) (Christy et al 1989) and PPARγ (peroxisome proliferator-activated receptor γ) (Kletzien et al 1992, Cabre et al 2007.…”