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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1220.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Mahmood R. Kazemi; Carol M. McDonald; Judy K. Shigenaga; Carl Grunfeld; Kenneth R. Feingold

From the Metabolism Section, Department of Veterans Affairs Medical Center, San Francisco, Calif; and the Department of Medicine, University of California, San Francisco.

Correspondence to Mahmood R. Kazemi, SFVAMC—Metabolism Section, 4150 Clement St, 111F, San Francisco, CA 94121. E-mail mkazemi{at}medicine.ucsf.edu

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 1500-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 5-fold greater in the presence of low-density lipoprotein, and triglyceride content was 2-fold greater in the absence of exogenous lipid than control or poly I:C–treated cells.

Conclusions— Expression of macrophage aP2 is induced on TLR activation and parallels increases in cholesteryl ester and triglyceride levels. These results provide a molecular link between the known roles of TLR and aP2 in foam cell formation.

Given the key role of macrophage aP2 in atherosclerosis, we studied aP2 expression in macrophages stimulated with LPS and 2 other TLR ligands: zymosan and poly I:C. Treatment with LPS or zymosan, but not poly I:C, leads to significant increases in aP2 mRNA and protein, which parallel cholesteryl ester and triglyceride accumulation.

Key Words: atherosclerosis • foam cell • macrophage • toll-like receptor • aP2

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