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Sci Adv. 2019 Oct 30;5(10):eaax9183. doi: 10.1126/sciadv.aax9183. eCollection 2019 Oct.

Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion.

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Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA 19104-5158, USA.
Department of Cardiovascular Sciences, University of Leicester and NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Temesvari korut 62, Szeged H-6726, Hungary.
Departments of Biochemistry and Medical Chemistry, University of Pecs, Medical School, Szigeti ut 12, Pecs H-7624, Hungary.
Division of Biomedical Services, University of Leicester, Leicester, UK.
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London and the Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, UK.


Macrophages drive atherosclerotic plaque progression and rupture; hence, attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low-density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.

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