Oxidized LDL level is related to gene expression of tumour necrosis factor super family members in children and young adults with familial hypercholesterolaemia

Authors

  • I. Narverud,

    1. Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway
    2. Department of Health, Nutrition and Management, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway
    3. Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • B. Halvorsen,

    1. Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Faculty of Medicine, University of Oslo, Oslo, Norway
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  • M. S. Nenseter,

    1. Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • K. Retterstøl,

    1. Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway
    2. Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • A. Yndestad,

    1. Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Faculty of Medicine, University of Oslo, Oslo, Norway
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  • T. B. Dahl,

    1. Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Faculty of Medicine, University of Oslo, Oslo, Norway
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  • S. M. Ulven,

    1. Department of Health, Nutrition and Management, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway
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  • O. K. Olstad,

    1. Department of Medical Biochemistry, Oslo University Hospital Ullevål, Oslo, Norway
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  • L. Ose,

    1. Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway
    2. Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • K. B. Holven,

    Corresponding author
    1. Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway
    • Correspondence: Kirsten B Holven, Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, PO Box 1046, Blindern, 0316 Oslo, Norway. (fax: +4722851341; e-mail: kirsten.holven@medisin.uio.no).

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  • P. Aukrust

    1. Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Faculty of Medicine, University of Oslo, Oslo, Norway
    3. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
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Abstract

Objective

Familial hypercholesterolaemia (FH) is associated with increased risk of premature atherosclerosis. Inflammation is a key event in atherogenesis, and we have previously reported an inflammatory imbalance between tumour necrosis factor (TNF)α and interleukin-10 in children with FH. Based on the potential role of TNF-related molecules in inflammation, we investigated the regulation of other members of the TNF superfamily (TNFSF)/TNF receptor superfamily (TNFRSF) in children and young adults with FH and matched healthy controls.

Methods

Expression of TNFSF/TNFRSF genes in peripheral blood mononuclear cells (PBMCs) was quantified in children and young adults with FH prior to (= 42) and after statin treatment (= 10) and in controls (= 25) by quantitative real-time polymerase chain reaction.

Results

First we found that, compared with controls, the mRNA levels of OX40L, BAFFR and TRAILR1 were significantly higher, whereas TRAIL and TRAILR3 were significantly lower in children and young adults with FH. Secondly, levels of oxidized low-density lipoprotein (oxLDL) were significantly raised in the FH group, and correlated with the expression of OX40L, BAFFR and TRAILR1. Thirdly, oxLDL increased mRNA levels of BAFFR, TRAILR1 and TRAILR4 in PBMCs ex vivo from individuals with FH. Fourthly, OX40, acting through OX40L, enhanced the oxLDL-induced expression of matrix metalloproteinase-9 in THP-1 monocytes in vitro. Finally, after statin treatment in children with FH (= 10), mRNA levels of OX40L and TRAILR1 decreased, whereas levels BAFF, TRAIL and TRAILR3 increased.

Conclusion

Our findings suggest the involvement of some TNFSF/TNFRSF members and oxLDL in the early stages of atherogenesis; this may potentially contribute to the accelerated rate of atherosclerosis observed in individuals with FH.

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