FABP4 inhibition suppresses PPARγ activity and VLDL-induced foam cell formation in IL-4-polarized human macrophages

Atherosclerosis. 2015 Jun;240(2):424-30. doi: 10.1016/j.atherosclerosis.2015.03.042. Epub 2015 Apr 3.


Objective: Macrophages, converted to lipid-loaded foam cells, accumulate in atherosclerotic lesions. Macrophage lipid metabolism is transcriptionally regulated by peroxisome proliferator-activated receptor gamma (PPARγ), and its target gene fatty acid binding protein 4 (FABP4) accelerates the progression of atherosclerosis in mouse models. Since expression of PPARγ and FABP4 is increased upon interleukin-4 (IL-4)-induced macrophage polarization, we aimed to investigate the role of FABP4 in human IL-4-polarized macrophages.

Methods and results: We investigated the impact of FABP4 on PPARγ-dependent gene expression in primary human monocytes differentiated to macrophages in the presence of IL-4. IL-4 increased PPARγ and its target genes lipoprotein lipase (LPL) and FABP4 compared to non-polarized or LPS/interferon γ-stimulated macrophages. LPL expression correlated with increased very low density lipoprotein (VLDL)-induced triglyceride accumulation in IL-4-polarized macrophages, which was sensitive to inhibition of lipolysis or PPARγ antagonism. Inhibition of FABP4 during differentiation using chemical inhibitors BMS309403 and HTS01037 or FABP4 siRNA decreased the expression of FABP4 and LPL, and reduced lipid accumulation in macrophages treated with VLDL. FABP4 or LPL inhibition also reduced the expression of inflammatory mediators chemokine (C-C motif) ligand 2 (CCL2) and IL-1β in response to VLDL in IL-4-polarized macrophages. PPARγ luciferase reporter assays confirmed that FABP4 supports fatty acid-induced PPARγ activation.

Conclusion: Our findings suggest that IL-4 induces a lipid-accumulating macrophage phenotype by activating PPARγ and subsequent LPL expression. Inhibition of FABP4 decreases VLDL-induced foam cell formation, indicating that anti-atherosclerotic effects achieved by FABP4 inhibition in mouse models may be feasible in the human system as well.

Keywords: Fatty acid binding proteins; Foam cell formation; Lipoprotein lipase; PPARγ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents / pharmacology*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / prevention & control*
  • Biphenyl Compounds / pharmacology*
  • Cells, Cultured
  • Down-Regulation
  • Fatty Acid-Binding Proteins / antagonists & inhibitors*
  • Fatty Acid-Binding Proteins / genetics
  • Fatty Acid-Binding Proteins / metabolism
  • Foam Cells / drug effects*
  • Foam Cells / metabolism
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / prevention & control*
  • Inflammation Mediators / metabolism
  • Interferon-gamma / pharmacology
  • Interleukin-4 / pharmacology*
  • Lipopolysaccharides / pharmacology
  • Lipoprotein Lipase / genetics
  • Lipoprotein Lipase / metabolism
  • Lipoproteins, VLDL / metabolism
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • PPAR gamma / agonists*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phenotype
  • Pyrazoles / pharmacology*
  • RNA Interference
  • Transfection


  • 2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid
  • Anti-Inflammatory Agents
  • Biphenyl Compounds
  • FABP4 protein, human
  • Fatty Acid-Binding Proteins
  • Inflammation Mediators
  • Lipopolysaccharides
  • Lipoproteins, VLDL
  • PPAR gamma
  • Pyrazoles
  • Interleukin-4
  • Interferon-gamma
  • LPL protein, human
  • Lipoprotein Lipase