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Lack of macrophage fatty-acid–binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis

Nature Medicine volume 7, pages 699–705 (2001)Cite this article

Abstract

The adipocyte fatty-acid–binding protein, aP2, has an important role in regulating systemic insulin resistance and lipid metabolism. Here we demonstrate that aP2 is also expressed in macrophages, has a significant role in their biological responses and contributes to the development of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice also deficient for aP2 showed protection from atherosclerosis in the absence of significant differences in serum lipids or insulin sensitivity. aP2-deficient macrophages showed alterations in inflammatory cytokine production and a reduced ability to accumulate cholesterol esters when exposed to modified lipoproteins. Apoe−/− mice with Ap2+/+ adipocytes and Ap2−/− macrophages generated by bone-marrow transplantation showed a comparable reduction in atherosclerotic lesions to those with total aP2 deficiency, indicating an independent role for macrophage aP2 in atherogenesis. Through its distinct actions in adipocytes and macrophages, aP2 provides a link between features of the metabolic syndrome and could be a new therapeutic target for the prevention of atherosclerosis.

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Figure 1: Insulin sensitivity and atherosclerosis in Ap2+/+Apoe−/− and Ap2−/−Apoe−/− mice on chow diet.
Figure 2: Expression of fatty-acid binding proteins in macrophages.
Figure 3: Expression of inflammatory cytokines and cholesterol ester levels in Ap2−/− macrophages.
Figure 4: Lipoprotein distribution, immunochemistry and atherosclerosis in Ap2−/− BMT mice.

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Acknowledgements

This work was supported by National Institutes of Health grant HL65405-01. M.F.L., S.F., and J.S. are established investigators of the American Heart Association. J.B. is supported by a Diabetes Training Grant from the NIDDK (T32 DK7061). K.M. is supported by a postdoctoral fellowship from Manpei Suzuki Diabetes Foundation. G.S.H. is Pew Scholar in Biomedical Sciences.

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Author notes

  1. Liza Makowski and Jeffrey B. Boord: L.M. and J.B.B. contributed equally to this study.

Authors and Affiliations

  1. Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA

    Liza Makowski, Kazuhisa Maeda, K. Teoman Uysal & Gökhan S. Hotamisligil

  2. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Jeffrey B. Boord, Vladimir R. Babaev, Sergio Fazio & MacRae F. Linton

  3. Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Sergio Fazio

  4. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    MacRae F. Linton

  5. Department of Metabolic Research, Bristol-Myers Squibb PRI, Princeton, New Jersey, USA

    Maureen A. Morgan & Rex A. Parker

  6. Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA

    Jill Suttles

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Correspondence to Gökhan S. Hotamisligil or MacRae F. Linton.

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Makowski, L., Boord, J., Maeda, K. et al. Lack of macrophage fatty-acid–binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med 7, 699–705 (2001). https://doi.org/10.1038/89076

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