Small Dense LDL Enhances THP-1 Macrophage Foam Cell Formation

DOI PubMed 6 Citations 24 References
  • Tani Mariko
    Life Science and Bioethics Research Center, Tokyo Medical and Dental University. Institute of Environmental Science for Human Life, Ochanomizu University.
  • Kawakami Akio
    Geriatrics and Vascular Medicine, Tokyo Medical and Dental University.
  • Mizuno Yuki
    Life Science and Bioethics Research Center, Tokyo Medical and Dental University.
  • Imase Reina
    Life Science and Bioethics Research Center, Tokyo Medical and Dental University.
  • Ito Yasuki
    Research and Development Department, Denka Seiken Co., Ltd.
  • Kondo Kazuo
    Institute of Environmental Science for Human Life, Ochanomizu University.
  • Ishii Hideto
    Life Science and Bioethics Research Center, Tokyo Medical and Dental University.
  • Yoshida Masayuki
    Life Science and Bioethics Research Center, Tokyo Medical and Dental University.

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Abstract

Aim: Increased levels of small dense low-density lipoproteins (sd-LDL) have been reported more atherogenic compared to total low-density lipoprotein (LDL); however, no definitive experiments using macrophages have examined this concept in vitro.<BR>Method and Result: In this study, we isolated fractions of total LDL (density 1.019-1.063g/ml) and sd-LDL (density 1.044-1.063g/ml) from the plasma of subjects with modest hypertriglycidemia. Oxidizabilty as assessed by copper-induced generation (1.6 µmol/L CuSO4,12 h) of thiobarbituric acid reactive substances (TBARS) was significantly greater (7-fold higher, p < 0.01) for sd-LDL (4.3±1.1 nmol/mg) than for total LDL (0.6±0.2 nmol/mg) at the same cholesterol concentrations. Moreover, oxidized sd-LDL induced more lipid staining in macrophages than oxidized total LDL. When non-oxidized sd-LDL were incubated with THP1 macrophages, there was much greater lipid accumulation as assessed by oil red O staining, and more than a 2-fold increase (p < 0.05) in intracellular triglyceride content as compared to non-oxidized total LDL. Furthermore, non-oxidized sd-LDL in contrast to non-oxidized total LDL enhanced macrophage lectin-like oxidized LDL receptor-1 (LOX-1) protein expression and significantly LOX-1 mRNA levels (+158%, p < 0.05), with no effect on scavenger receptor A or CD36 gene expression. These effects of non-oxidized sd-LDL on LOX-1 gene expression were suppressed when Toll-like receptor 4 was inactivated either by RNAi or antibody.<BR>Conclusion: Our data indicate for the first time that sd-LDL is much more effective in promoting macrophage triglyceride accumulation and LOX-1 gene expression than total LDL.

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