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PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation

Abstract

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is highly expressed in lipid-accumulating macrophages of the coronary artery. In light of this, the wide-spread clinical use of thiazolidinediones (TZDs) in the treatment of type II diabetes raises concerns about the role of PPAR-γ in macrophage function and disease progression. To define the role of PPAR-γ in macrophage biology, we used homologous recombination to create embryonic stem cells that were homozygous for a null mutation in the PPAR-γ gene. We demonstrate here that PPAR-γ is neither essential for nor substantially affects the development of the macrophage lineage both in vitro and in vivo. In contrast, we show it is an important regulator of the scavenger receptor CD36, which has been genetically linked to lipid accumulation in macrophages. Both 15-deoxy-Δ12,14prostaglandin J2 and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-γ. We show that PPAR-γ is required for positive effects of its ligands in modulating macrophage lipid metabolism, but that inhibitory effects on cytokine production and inflammation may be receptor independent.

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Figure 1: PPAR-γ–deficient ES cells can differentiate into macrophages.
Figure 2: CD36 is a PPAR-γ target gene.
Figure 3: PPAR-γ is required for OxLDL uptake in NIH-3T3 cells, but not in differentiated macrophages.
Figure 4: PPAR-γ ligands can down regulate inflammatory response independent of PPAR-γ.
Figure 5: Model for gene regulation by PPAR-γ and its ligands.

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References

  1. 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 

  2. 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 

  3. 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 

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

    Article  CAS  Google Scholar 

  5. Forman, B.M. et al. 15-Deoxy-Δ 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR-γ. Cell 83, 803–812 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. 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 lipoprotein. Proc. Natl. Acad. Sci. USA 95, 7614–7619 (1998).

    Article  CAS  Google Scholar 

  8. Reginato, M.J. & Lazar, M.A. Mechanisms by which TZDs enhance insulin action. Trends Endocrinol. Metab. 10, 9–13 (1999).

    Article  CAS  Google Scholar 

  9. Nagy, L., Tontonoz, P., Alvarez, J.G., 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 

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

    Article  CAS  Google Scholar 

  11. 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 

  12. 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 

  13. Abbondanzo, S.J., Gadi, I. & Stewart, C.L. Derivation of embryonic stem cell lines. Methods Enzymol. 225, 803–823 (1993).

    Article  CAS  Google Scholar 

  14. Wiles, M.V. & Keller, G. Multiple hematopoietic lineages develop from embryonic stem (ES) cells in culture. Development 111, 259–267 (1991).

    CAS  PubMed  Google Scholar 

  15. Keller, G., Kennedy, M., Papayannopoulou, T. & Wiles, M.V. Hematopoietic commitment during embryonic stem cell differentiation in culture. Mol. Cell. Biol. 13, 473–486 (1993).

    Article  CAS  Google Scholar 

  16. McKnight, A.J. & Gordon, S. Membrane molecules as differentiation antigens of murine macrophages. Adv. Immunol. 68, 271–314 (1998).

    Article  CAS  Google Scholar 

  17. Tontonoz, P., Hu, E. & Spiegelman, B.M. Stimulation of adipogenesis in fibroblasts by PPAR-γ 2, a lipid-activated transcription factor. Cell 79, 1147–1156 (1994); erratum: 80, 957 (1995).

    Article  CAS  Google Scholar 

  18. McKnight, A.J. et al. Molecular cloning of F4/80, a murine macrophage-restricted cell surface glycoprotein with homology to the G-protein–linked transmembrane 7 hormone receptor family. J. Biol. Chem. 271, 486–489 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Straus, D.S. et al. 15-deoxy-Δ 12,14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc. Natl. Acad. Sci. USA 97, 4844–4849 (2000).

    Article  CAS  Google Scholar 

  22. Rocchi, S. & Auwerx, J. Peroxisome proliferator-activated receptor-gamma: a versatile metabolic regulator. Ann. Med. 31, 342–351 (1999).

    Article  CAS  Google Scholar 

  23. Tontonoz, P. & Nagy, L. Regulation of macrophage gene expression by peroxisome-proliferator-activated receptor γ: implications for cardiovascular disease. Curr. Opin. Lipidol. 10, 485–490 (1999).

    Article  CAS  Google Scholar 

  24. 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 

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Acknowledgements

We thank G. Keller for assistance with ES-cell differentiation and S. Gordon for assistance with macrophage analysis. This work was supported by NIH Grant #2 T32 HL07770 (to A.C.), the Boehringer Ingelheim Research Award (to L.N.), and a grant from the UCLA Jonsson Comprehensive Cancer Center (to P.T.).

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Correspondence to Ronald M. Evans.

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Chawla, A., Barak, Y., Nagy, L. et al. PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 7, 48–52 (2001). https://doi.org/10.1038/83336

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