Highlights
- •IL-4-polarized macrophages show a lipid-sequestering phenotype dependent on PPARγ.
- •PPARγ-dependent expression of lipoprotein lipase is attenuated by FABP4 inhibition.
- •FABP4 inhibition decreases VLDL-triggered lipid accumulation in macrophages.
Abstract
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
Abbreviations:
CCL (chemokine (C-C motif) ligand), FABP (fatty acid binding protein), LDL (low density lipoprotein), LPL (lipoprotein lipase), M-CSF (macrophage colony-stimulating factor), Mo (monocyte), oxLDL (oxidized LDL), PPAR (peroxisome proliferator-activated receptor), TG (triglyceride), VLDL (very low density lipoprotein)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets.Nat. Rev. Drug Discov. 2008; 7: 489-503
- Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture.Atherosclerosis. 2013; 226: 74-81
- Fatty acid binding protein 4 is associated with carotid atherosclerosis and outcome in patients with acute ischemic stroke.PLoS One. 2011; 6: e28785
- Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein.Science. 1996; 274: 1377-1379
- Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2.Nature. 2007; 447: 959-965
- mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.Genes Dev. 1994; 8: 1224-1234
- PPARgamma activation induces the expression of the adipocyte fatty acid binding protein gene in human monocytes.Biochem. Biophys. Res. Commun. 1999; 261: 456-458
- PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation.Biochim. Biophys. Acta. 2011; 1812: 1007-1022
- Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma.J. Clin. Investig. 2004; 114: 1564-1576
- PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties.Cell Metab. 2007; 6: 137-143
- Delayed activation of PPARgamma by LPS and IFN-gamma attenuates the oxidative burst in macrophages.FASEB J. 2001; 15: 535-544
- PPARs and lipid ligands in inflammation and metabolism.Chem. Rev. 2011; 111: 6321-6340
- PPAR gamma and the control of adipogenesis.Biochimie. 1997; 79: 111-112
- Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.N. Engl. J. Med. 2007; 356: 2457-2471
- STAT6 transcription factor is a facilitator of the nuclear receptor PPARgamma-regulated gene expression in macrophages and dendritic cells.Immunity. 2010; 33: 699-712
- Orchestration of metabolism by macrophages.Cell Metab. 2012; 15: 432-437
- MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA destabilization.J. Biol. Chem. 2010; 285: 11846-11853
- PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL.Cell. 1998; 93: 241-252
- Endoplasmic reticulum stress controls m2 macrophage differentiation and foam cell formation.J. Biol. Chem. 2012; 287: 11629-11641
- PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion.Diabetes. 2003; 52: 291-299
- Lipoprotein lipase: from gene to obesity.Am. J. Physiol. Endocrinol. Metab. 2009; 297: E271-E288
- Lipoprotein lipase enhances binding of lipoproteins to heparan sulfate on cell surfaces and extracellular matrix.J. Clin. Investig. 1992; 90: 2013-2021
- AICAR inhibits PPARgamma during monocyte differentiation to attenuate inflammatory responses to atherogenic lipids.Cardiovasc Res. 2013; 98: 479-487
- Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARgamma by FABP4.Biochemistry. 2007; 46: 6744-6752
- Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription.Mol. Cell. Biol. 2002; 22: 5114-5127
- Role of adipocyte lipid-binding protein (ALBP) and acyl-coA binding protein (ACBP) in PPAR-mediated transactivation.Mol. Cell. Biochem. 2002; 239: 157-164
- FABP4 attenuates PPARgamma and adipogenesis, and is inversely correlated with PPARgamma in adipose tissues.Diabetes. 2013; 63: 900-911
- Phospholipase A2-modified low-density lipoprotein activates macrophage peroxisome proliferator-activated receptors.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 313-320
- Attenuated suppression of the oxidative burst by cells dying in the presence of oxidized low density lipoprotein.J. Lipid Res. 2009; 50: 2173-2181
- Adipocyte-type fatty acid-binding protein as inter-compartmental shuttle for peroxisome proliferator activated receptor gamma agonists in cultured cell.Biochim. Biophys. Acta. 2006; 1761: 172-181
- Identification and characterization of a small molecule inhibitor of fatty acid binding proteins.J. Med. Chem. 2009; 52: 6024-6031
- Activation of peroxisome proliferator-activated receptor delta inhibits human macrophage foam cell formation and the inflammatory response induced by very low-density lipoprotein.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 2919-2928
- Postprandial VLDL lipolysis products increase monocyte adhesion and lipid droplet formation via activation of ERK2 and NFkappaB.Am. J. Physiol. Heart Circ. Physiol. 2014; 306: H109-H120
- Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARgamma and LXRalpha pathways.Circ. Res. 2011; 108: 985-995
- Human ATP-binding cassette G1 controls macrophage lipoprotein lipase bioavailability and promotes foam cell formation.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 2223-2231
- Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis.Nat. Med. 2009; 15: 1383-1391
- PPARdelta activation attenuates hepatic steatosis in Ldlr-/- mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity.J. Lipid Res. 2014; 55: 1254-1266
- Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice.J. Clin. Investig. 2008; 118: 2640-2650
- Lipid storage by adipose tissue macrophages regulates systemic glucose tolerance.Am. J. Physiol. Endocrinol. Metab. 2014; 307: E374-E383
Article info
Publication history
Published online: April 02, 2015
Accepted:
March 30,
2015
Received in revised form:
February 26,
2015
Received:
November 18,
2014
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
