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

Nature Medicine volume 7, pages 41–47 (2001)Cite this article

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.

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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.

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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)].

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Authors and Affiliations

  1. Department of Medicine, Lipid Metabolism Unit, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Kathryn J. Moore, Michael L. Fitzgerald, Lorna P. Andersson & Mason W. Freeman

  2. Harvard Medical School, Boston, 02115, Massachusetts, USA

    Kathryn J. Moore, Evan D. Rosen, Michael L. Fitzgerald, Felix Randow, Lorna P. Andersson, David S. Milstone, Bruce M. Spiegelman & Mason W. Freeman

  3. Department of Cell Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Evan D. Rosen & Bruce M. Spiegelman

  4. Department of Molecular Biology, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Felix Randow & David Altshuler

  5. Whitehead Institute/MIT Center for Genome Research, Cambridge, 02139, Massachusetts, USA

    David Altshuler

  6. Vascular Research Division, Dept of Pathology, Brigham & Women's Hospital, Boston, 02115, Massachusetts, USA

    David S. Milstone

  7. Department of Physiology, Endocrine Division, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Richard M. Mortensen

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Correspondence to Mason W. Freeman.

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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

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