Macrophage mal1 deficiency suppresses atherosclerosis in low-density lipoprotein receptor-null mice by activating peroxisome proliferator-activated receptor-γ-regulated genes

Vladimir R. Babaev, Robert P. Runner, Daping Fan, Lei Ding, Youmin Zhang, Huan Tao, Ebru Erbay, Cem Z. Görgün, Sergio Fazio, Gökhan S. Hotamisligil, MacRae F. Linton

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    28 Scopus citations

    Abstract

    Objective- The adipocyte/macrophage fatty acid-binding proteins aP2 (FABP4) and Mal1 (FABP5) are intracellular lipid chaperones that modulate systemic glucose metabolism, insulin sensitivity, and atherosclerosis. Combined deficiency of aP2 and Mal1 has been shown to reduce the development of atherosclerosis, but the independent role of macrophage Mal1 expression in atherogenesis remains unclear. Methods and Results- We transplanted wild-type (WT), Mal1, or aP2 bone marrow into low-density lipoprotein receptor-null (LDLR) mice and fed them a Western diet for 8 weeks. Mal1→LDLR mice had significantly reduced (36%) atherosclerosis in the proximal aorta compared with control WT→LDLR mice. Interestingly, peritoneal macrophages isolated from Mal1-deficient mice displayed increased peroxisome proliferator-activated receptor-γ (PPARγ) activity and upregulation of a PPARγ-related cholesterol trafficking gene, CD36. Mal1 macrophages showed suppression of inflammatory genes, such as COX2 and interleukin 6. Mal1→LDLR mice had significantly decreased macrophage numbers in the aortic atherosclerotic lesions compared with WT→LDLR mice, suggesting that monocyte recruitment may be impaired. Indeed, blood monocytes isolated from Mal1→LDLR mice on a high-fat diet had decreased CC chemokine receptor 2 gene and protein expression levels compared with WT monocytes. Conclusion- Taken together, our results demonstrate that Mal1 plays a proatherogenic role by suppressing PPARγ activity, which increases expression of CC chemokine receptor 2 by monocytes, promoting their recruitment to atherosclerotic lesions.

    Original languageEnglish (US)
    Pages (from-to)1283-1290
    Number of pages8
    JournalArteriosclerosis, thrombosis, and vascular biology
    Volume31
    Issue number6
    DOIs
    StatePublished - Jun 1 2011

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    Keywords

    • CCR2
    • CD36
    • PPARγ
    • macrophages

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

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