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

Nature Medicine volume 7, pages 48–52 (2001)Cite this article

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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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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Authors and Affiliations

  1. The Salk Institute for Biological Studies, Howard Hughes Medical Institute, La Jolla, 90237, California, USA

    Ajay Chawla, Yaacov Barak, Debbie Liao & Ronald M. Evans

  2. Division of Endocrinology and Metabolism, University of California, San Diego, 92093, California, USA

    Ajay Chawla

  3. Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, 90095, California, USA

    Peter Tontonoz

  4. Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Nagyerdei krt. 98, Debrecen, H-4012, Hungary

    Laszlo Nagy

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  1. Ajay Chawla
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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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