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Apolipoprotein CI aggravates atherosclerosis development in ApoE-knockout mice despite mediating cholesterol efflux from macrophages

  • Marit Westerterp
    Correspondence
    Corresponding author at: Leiden University Medical Center, Department of Endocrinology and Metabolism, C4-R, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Tel.: +31 71 526 3173; fax: +31 71 524 8136.
    Affiliations
    The Netherlands Organization for Applied Scientific Research-Quality of Life, Department of Biomedical Research, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden, The Netherlands

    Department of General Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

    Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
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  • Miranda Van Eck
    Affiliations
    Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Gorlaeus Laboratory, Einsteinweg 55, 2333 CC Leiden, The Netherlands
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  • Willeke de Haan
    Affiliations
    The Netherlands Organization for Applied Scientific Research-Quality of Life, Department of Biomedical Research, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden, The Netherlands

    Department of General Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

    Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
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  • Erik H. Offerman
    Affiliations
    The Netherlands Organization for Applied Scientific Research-Quality of Life, Department of Biomedical Research, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden, The Netherlands
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  • Theo J.C. Van Berkel
    Affiliations
    Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Gorlaeus Laboratory, Einsteinweg 55, 2333 CC Leiden, The Netherlands
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  • Louis M. Havekes
    Affiliations
    The Netherlands Organization for Applied Scientific Research-Quality of Life, Department of Biomedical Research, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden, The Netherlands

    Department of General Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

    Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

    Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
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  • Patrick C.N. Rensen
    Affiliations
    The Netherlands Organization for Applied Scientific Research-Quality of Life, Department of Biomedical Research, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden, The Netherlands

    Department of General Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

    Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
    Search for articles by this author

      Abstract

      Objective

      Apolipoprotein CI (apoCI) is expressed in the liver and in macrophages, and has several roles in lipid metabolism. Since macrophage apoCI expression might affect macrophage lipid homeostasis and atherosclerotic lesion development locally in the arterial wall, we investigated the effect of both systemic and macrophage apoCI on atherosclerotic lesion development.

      Methods and results

      To investigate whether physiological expression levels of apoCI affect atherosclerosis development, we first assessed the effect of systemic endogenous apoCI expression on atherosclerosis in apoe−/−apoc1+/+ as compared to apoe−/−apoc1−/− mice at 26 weeks of age. ApoCI expression increased plasma levels of triglycerides (TG) (+70%; P < 0.01) and cholesterol (+30%; P < 0.05), and increased the atherosclerotic lesion area in the aortic root (+87%; P < 0.05). Paradoxically, incubation of apoc1+/+ and apoc1−/− murine peritoneal macrophages with AcLDL (50 μg/mL; 48 h) revealed that macrophage apoCI decreased the accumulation of cellular cholesteryl esters (CE) relatively to free cholesterol (−22%; P < 0.05). Accordingly, exogenous human apoCI increased cholesterol efflux from AcLDL-laden wild-type macrophages, and to a similar extent as apoAI and apoE. To evaluate whether atherosclerosis development would be affected by macrophage apoCI expression in vivo, we assessed atherosclerotic lesion development at 16 weeks after transplantation of bone marrow from apoe−/−apoc1−/− or apoe−/−apoc1+/+ mice to apoe−/−apoc1+/+ mice. However, in the situation wherein the liver and adipose tissue still produce apoCI, macrophage apoCI expression did not affect plasma lipid levels or the atherosclerotic lesion area.

      Conclusions

      Systemic apoCI increases atherosclerosis, probably by inducing hyperlipidemia. Despite decreasing macrophage lipid accumulation in vitro, apoCI production by macrophages locally in the arterial wall does not affect atherosclerosis development in vivo.

      Keywords

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