Adipocyte Fatty Acid–Binding Protein Expression and Lipid Accumulation Are Increased During Activation of Murine Macrophages by Toll-Like Receptor Agonists

Abstract

Objective-Toll-like receptors (TLRs) recognize pathogens and mediate signaling pathways important for host defense.Recent studies implicate TLR polymorphisms in atherosclerosis risk in humans. Adipocyte fatty acid-binding protein (aP2) is present in macrophages and has an important role in atherosclerotic plaque development. We investigated aP2 expression in RAW 264.7 cells treated with lipopolysaccharide (LPS) and other TLR agonists and assessed lipid accumulation in these activated murine macrophages. Methods and Results-Stimulation with LPS, a TLR4 ligand, resulted in a 56-fold increase in aP2 mRNA expression, and zymosan, a TLR2 ligand, induced an Ϸ1500-fold increase. Polyinosine: polycytidylic acid (poly I:C), a TLR3 ligand, led to a 9-fold increase. Levels of aP2 protein were significantly increased in LPS or zymosan-treated macrophages compared with control or poly I:C-treated cells. In addition, the cholesteryl ester content of LPS or zymosan-treated macrophages was Ϸ5-fold greater in the presence of low-density lipoprotein, and triglyceride content was Ϸ2-fold greater in the absence of exogenous lipid than control or poly I:C-treated cells. Conclusions-Expression

Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon-α and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque

“…Moreover, TLR4 signaling promotes foam cell formation by increasing cholesteryl ester and triglyceride levels in macrophages. 38,39 These severe consequences for inducing full-blown immune activation via simultaneous triggering of TLR4 and TLR9 raise the question of which situation may elicit this threatening outcome. Recognition of at least 2 "danger signals" corresponds well with the assumption that not 1 pathogen but the total infectious burden is relevant for atherosclerotic lesion progression.…”

Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?

“…In addition, LPS-induced JNK phosphorylation, activator protein-1 stimulation and production of proinflammatory cytokines are significantly attenuated by pharmacological or genetic AFABP suppression in macrophages [49]. Besides TLR4-agonistic LPS, the TLR2 ligand zymosan and the TLR3 ligand polyinosine:polycytidylic acid significantly upregulate AFABP in murine macrophages [47]. Furthermore, saturated fatty acids including palmitate induce AFABP production in macrophages [50].…”

“…In addition, AFABP-deficient mice are resistant to several inflammatory disorders, including allergic airway inflammation [45] and experimental autoimmune encephalomyelitis/multiple sclerosis [46]. Several proinflammatory stimuli induce AFABP production, including phorbol myristate acetate, oxidised (ox)LDL and toll-like receptor (TLR) agonists [4,35,47,48]. Among these, oxLDL upregulates AFABP during the transformation of macrophages into foam cells [4].…”

“…This AFABP elevation involves activation of PPARγ by components of oxLDL that function as PPARγ ligands [4]. Lipopolysaccharides (LPS) are potent TLR4 agonists that induce AFABP production in macrophages [47]. LPS stimulates AFABP transcription through Jun N-terminal kinase (JNK), which in turn induces c-Jun recruitment to a highly conserved activator protein-1 recognition site within the proximal region of the AFABP promoter [49].…”

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

“…FABP4 expression is strongly induced during adipocyte differentiation (Bernlohr et al 1985a), which has led to proposals of this molecule as an adipocyte differentiation marker (Bernlohr et al 1985b, Smith et al 1988, Yang et al 1989. 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).…”