Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The role of PPAR-γ in macrophage differentiation and cholesterol uptake

Abstract

Peroxisome proliferator-activated receptor-γ (PPAR-γ), the transcription factor target of the anti-diabetic thiazolidinedione (TZD) drugs, is reported to mediate macrophage differentiation and inflammatory responses. Using PPAR-γ–deficient stem cells, we demonstrate that PPAR-γ is neither essential for myeloid development, nor for such mature macrophage functions as phagocytosis and inflammatory cytokine production. PPAR-γ is required for basal expression of CD36, but not for expression of the other major scavenger receptor responsible for uptake of modified lipoproteins, SR-A. In wild-type macrophages, TZD treatment divergently regulated CD36 and class A macrophage-scavenger receptor expression and failed to induce significant cellular cholesterol accumulation, indicating that TZDs may not exacerbate macrophage foam-cell formation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: PPAR-γ–deficient ES cells differentiate into macrophages in vitro and respond to inflammatory stimuli.
Figure 2: Modified LDL uptake and degradation is compromised in PPAR-γ–deficient macrophages.
Figure 3: Regulation of CD36 and SR-A expression in PPAR-γ–deficient and wild-type macrophages.
Figure 4: Troglitazone treatment does not alter OxLDL uptake and degradation in wild-type macrophages.

Similar content being viewed by others

References

  1. Kliewer, S.A., Umesono, K., Noonan, D.J., Heyman, R.A. & Evans, R.M. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358, 771–774 (1992).

    Article  CAS  Google Scholar 

  2. Kliewer, S.A., Umesono, K., Mangelsdorf, D.J. & Evans, R.M. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature 355, 446–449 (1992).

    Article  CAS  Google Scholar 

  3. Spiegelman, B.M. Peroxisome proliferator-activated receptor γ: A key regulator of adipogenesis and systemic insulin sensitivity. Eur. J. Med. Res. 2, 457–464 (1997).

    CAS  PubMed  Google Scholar 

  4. Law, R.E. et al. Expression and function of PPAR-γ in rat and human vascular smooth muscle cells. Circulation 101, 1311–1318 (2000).

    Article  CAS  Google Scholar 

  5. Clark, R.B. et al. The nuclear receptor PPAR-γ and immunoregulation: PPAR-γ mediates inhibition of helper T cell responses. J. Immunol. 164, 1364–1371 (2000).

    Article  CAS  Google Scholar 

  6. Forman, B.M. et al. 15-Deoxy-Δ12,14prostaglandin J2 is a ligand for the adipocyte determination factor PPAR-γ. Cell 83, 803–812 (1995).

    Article  CAS  Google Scholar 

  7. Lehmann, J.M. et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPAR-γ). J. Biol. Chem. 270, 12953–12956 (1995).

    Article  CAS  Google Scholar 

  8. Kliewer, S.A. et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proc. Natl. Acad. Sci. USA 94, 4318–4323 (1997).

    Article  CAS  Google Scholar 

  9. Tontonoz, P., Nagy, L., Alvarez, J.G.A., Thomazy, V.A. & Evans, R. PPAR-γ promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93, 241–252 (1998).

    Article  CAS  Google Scholar 

  10. Nagy, L., Tontonoz, P., Alvarez, J.G.A., Chen, H. & Evans, R.M. Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR-γ. Cell 93, 229–240 (1998).

    Article  CAS  Google Scholar 

  11. Ricote, M., Li, A.C., Willson, T.M., Kelly, C.J. & Glass, C.K. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391, 79–82 (1998).

    Article  CAS  Google Scholar 

  12. Jiang, C., Ting, A.T. & Seed, B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86 (1998).

    Article  CAS  Google Scholar 

  13. Marx, N., Sukhova, G., Murphy, C., Libby, P. & Plutzky, J. Macrophages in human atheroma contain PPAR-γ: differentiation-dependent peroxisomal proliferator-activated receptor γ (PPAR-γ) expression and reduction of MMP-9 activity through PPAR-γ activation in mononuclear phagocytes in vitro. Am. J. Pathol. 153, 17–23 (1998).

    Article  CAS  Google Scholar 

  14. Ricote, M. et al. Expression of the peroxisome proliferator-activated receptor γ (PPAR-γ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoproteins. Proc. Natl. Acad. Sci. USA 95, 7614–7619 (1998).

    Article  CAS  Google Scholar 

  15. Chinetti, G. et al. CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation 101, 2411–2417 (2000).

    Article  CAS  Google Scholar 

  16. Kersten, S., Desvergne, B. & Wahli, W. Roles of PPARs in health and disease. Nature 405, 421–424 (2000).

    Article  CAS  Google Scholar 

  17. Willoughby, D.A., Moore, A.R. & Colville-Nash, P.R. Cyclopentenone prostaglandins—new allies in the war on inflammation [news]. Nature Med. 6, 137–138 (2000).

    Article  CAS  Google Scholar 

  18. Rossi, A. et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 403, 103–108 (2000).

    Article  CAS  Google Scholar 

  19. Straus, D.S. et al. 15-Deoxy-Δ12,14prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway [In Process Citation]. Proc. Natl. Acad. Sci. US A 97, 4844–4849 (2000).

    Article  CAS  Google Scholar 

  20. Vaidya, S., Somers, E.P., Wright, S.D., Detmers, P.A. & Bansal, V.S. 15-Deoxy-Δ12,14prostaglandin J2 inhibits the β-2 integrin-dependent oxidative burst: involvement of a mechanism distinct from peroxisome proliferator-activated receptor γ ligation. J. Immunol. 163, 6187–6192 (1999).

    CAS  PubMed  Google Scholar 

  21. Pasceri, V., Wu, H.D., Willerson, J.T. & Yeh, E.T. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-γ activators. Circulation 101, 235–238 (2000).

    Article  CAS  Google Scholar 

  22. Spiegelman, B.M. PPAR-γ in monocytes: less pain, any gain? Cell 93, 153–155 (1998).

    Article  CAS  Google Scholar 

  23. Barak, Y. et al. PPAR-γ is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585–595 (1999).

    Article  CAS  Google Scholar 

  24. Rosen, E.D. et al. PPAR-γ is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell 4, 611–617 (1999).

    Article  CAS  Google Scholar 

  25. Kubota, N. et al. PPAR-γ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol. Cell 4, 597–609 (1999).

    Article  CAS  Google Scholar 

  26. Moore, K.J., Fabunmi, R.P., Andersson, L.P. & Freeman, M.W. In vitro-differentiated embryonic stem cell macrophages: a model system for studying atherosclerosis-associated macrophage functions. Arterio. Thromb. Vasc. Biol. 18, 1647–1654 (1998).

    Article  CAS  Google Scholar 

  27. Thieringer, R. et al. Activation of peroxisome proliferator-activated receptor γ does not inhibit IL-6 or TNF-α responses of macrophages to lipopolysaccharide in vitro or in vivo. J. Immunol. 164, 1046–1054 (2000).

    Article  CAS  Google Scholar 

  28. Huang, J.T. et al. Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase. Nature 400, 378–382 (1999).

    Article  CAS  Google Scholar 

  29. Feng, J. et al. Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-γ. J. Lipid Res. 41, 688–696 (2000).

    CAS  PubMed  Google Scholar 

  30. de Villiers, W.J., Fraser, I.P., Hughes, D.A., Doyle, A.G. & Gordon, S. Macrophage-colony-stimulating factor selectively enhances macrophage scavenger receptor expression and function. J. Exp. Med. 180, 705–709 (1994).

    Article  CAS  Google Scholar 

  31. Armesilla, A.L., Calvo, D. & Vega, M.A. Structural and functional characterization of the human CD36 gene promoter: identification of a proximal PEBP2/CBF site. J. Biol. Chem. 271, 7781–7787 (1996).

    Article  CAS  Google Scholar 

  32. Febbraio, M. et al. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J. Biol. Chem. 274, 19055–19062 (1999).

    Article  CAS  Google Scholar 

  33. Febbraio, M. et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J. Clin. Invest. 105, 1049–1056 (2000).

    Article  CAS  Google Scholar 

  34. Calvo, D., Gomez-Coronado, D., Suarez, Y., Lasuncion, M.A. & Vega, M.A. Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. J. Lipid Res. 39, 777–788 (1998).

    CAS  PubMed  Google Scholar 

  35. Huh, H.Y., Pearce, S.F., Yesner, L.M., Schindler, J.L. & Silverstein, R.L. Regulated expression of CD36 during monocyte-to-macrophage differentiation: potential role of CD36 in foam cell formation. Blood 87, 2020–2028 (1996).

    CAS  PubMed  Google Scholar 

  36. Repa, J.J. et al. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers [see comments]. Science 289, 1524–1529 (2000).

    Article  CAS  Google Scholar 

  37. Li, A.C. et al. Peroxisome proliferator-activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J. Clin. Invest. 106, 523–531 (2000).

    Article  CAS  Google Scholar 

  38. Ghazzi, M.N. et al. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. Diabetes 46, 433–439 (1997).

    Article  CAS  Google Scholar 

  39. Noguchi, N. et al. Inhibition of oxidation of low density lipoprotein by troglitazone. Atherosclerosis 123, 227–234 (1996).

    Article  CAS  Google Scholar 

  40. Minamikawa, J., Yamauchi, M., Inoue, D. & Koshiyama, H. Another potential use of troglitazone in noninsulin-dependent diabetes mellitus [letter; comment]. J. Clin. Endocrinol. Metab. 83, 1041–1042 (1998).

    Article  CAS  Google Scholar 

  41. Law, R.E. et al. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J. Clin. Invest. 98, 1897–1905 (1996).

    Article  CAS  Google Scholar 

  42. Shinohara, E. et al. Troglitazone suppresses intimal formation following balloon injury in insulin-resistant Zucker fatty rats. Atherosclerosis 136, 275–279 (1998).

    Article  CAS  Google Scholar 

  43. Freeman, M. et al. An ancient, highly conserved family of cysteine-rich protein domains revealed by cloning type I and type II murine macrophage scavenger receptors. Proc. Natl. Acad. Sci. USA 87, 8810–8814 (1990).

    Article  CAS  Google Scholar 

  44. Milstone, D.S., Bradwin, G. & Mortensen, R.M. Simultaneous Cre catalyzed recombination of two alleles to restore neomycin sensitivity and facilitate homozygous mutations. Nucleic Acids Res. 27, 10 (1999).

    Article  Google Scholar 

  45. Lindblad-Toh, K. et al. Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse. Nature Genet. 24, 381–386 (2000).

    Article  CAS  Google Scholar 

  46. Jacobs, N.L. et al. Analysis of a Chinese hamster ovary cell mutant with defective mobilization of cholesterol from the plasma membrane to the endoplasmic reticulum. J. Lipid Res. 38, 1973–1987 (1997).

    CAS  PubMed  Google Scholar 

  47. Ashkenas, J. et al. Structures and high and low affinity ligand binding properties of murine type I and type II macrophage scavenger receptors. J. Lipid. Res. 34, 983–1000 (1993).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Liscum for help in performing the cellular cholesterol measurements by gas chromatography; L. Shang and R. Lane for their technical assistance; and B. Seed and H. Kronenberg for comments. This work was supported by grants from the NHLBI [(45098 (MWF), 56985 (MWF), HL5409 (DSM)] and NIDDK [50305 (MWF)].

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mason W. Freeman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moore, K., Rosen, E., Fitzgerald, M. et al. The role of PPAR-γ in macrophage differentiation and cholesterol uptake. Nat Med 7, 41–47 (2001). https://doi.org/10.1038/83328

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/83328

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing