Protective Function of Macrophage Nuclear Receptor Corepressor 1 in Atherosclerosis

S. Oppi1, S. Nusser-Stein1, P. Blyszczuk2, S. Marzolla1, E. Osto3, A. Othman2, T. Hornemann2, K. Schoonjans4, J. Auwerx4, M. Oosterveer5, T. Lüscher1, S. Stein1 (1Schlieren; 2Zurich; 3Schwerzenbach; 4Lausanne; 5Groningen)

Nuclear receptors and their cofactors regulate the expression of various target genes in different tissue and organs to orchestrate downstream (patho)physiological processes. Although the function of several nuclear receptors in atherosclerosis has been studied, the role of nuclear receptor corepressors in atherosclerosis is not known. Given its important role to suppress inflammatory processes, we speculated that macrophage nuclear receptor corepressor 1 (NCOR1) plays a protective function in atherosclerosis development. We demonstrate that myeloid cell-specific deletion of Ncor1 aggravates atherosclerosis development in male and female pro-atherogenic mice exposed to a high cholesterol diet. Myeloid cell Ncor1-deficient mice develop more atherosclerotic lesions along the aortae that are characterized by larger necrotic cores and thinner fibrous caps, a typical signature of unstable plaques. We demonstrate that the atherosclerosis phenotype is driven by enhanced foam cell formation that is secondary to an increased peroxisome proliferator-activated receptor gamma (PPARG)-driven expression of CD36. Our findings thus suggest that NCOR1 exerts protective functions by repressing PPARG-driven processes and identifies macrophage NCOR1 as a therapeutic target for atherosclerotic vascular disease.

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