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Regulation of Apolipoprotein A-I Gene Expression in Human Macrophages by Oxidized Low-Density Lipoprotein

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Abstract

Apolipoprotein A-I (ApoA-I) is a key component of reverse cholesterol transport in humans. In the previous studies, we demonstrated expression of the apoA-I gene in human monocytes and macrophages; however, little is known on the regulation of the apoA-I expression in macrophages during the uptake of modified low-density lipoprotein (LDL), which is one of the key processes in the early stages of atherogenesis leading to formation of foam cells. Here, we demonstrate a complex nature of the apoA-I regulation in human macrophages during the uptake of oxidized LDL (oxLDL). Incubation of macrophages with oxLDL induced expression of the apoA-I gene within the first 24 hours, but suppressed it after 48 h. Both effects depended on the interaction of oxLDL with the TLR4 receptor, rather than on the oxLDL uptake by the macrophages. The oxLDL-mediated downregulation of the apoA-I gene depended on the ERK1/2 and JNK cascades, as well as on the NF-κB cascade.

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Abbreviations

ApoA-I:

apolipoprotein A-I

BSA:

bovine serum albumin

ER:

endoplasmic reticulum

FCS:

fetal calf serum

LDL:

low-density lipoprotein

oxLDL:

oxidized low-density lipoprotein

PBS:

phosphate buffered saline

PMA:

phorbol 12-myristate 13-acetate (activator of cell differentiation and/or apoptosis in cancer models)

THP-1:

human monocytic cell line derived from an acute monocytic leukemia patient

TNFα:

tumor necrosis factor α

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Funding

This work was financially supported by the Russian Science Foundation (project no. 17-15-01326).

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Authors and Affiliations

  1. Institute of Experimental Medicine, 197376, St. Petersburg, Russia

    Ekaterina V. Nekrasova, Ekaterina E. Larionova, Vladimir S. Shavva, Igor V. Kudriavtsev & Sergey V. Orlov

  2. St. Petersburg State University, 199034, St. Petersburg, Russia

    Katerina Danko, Darya O. Kuzmina & Sergey V. Orlov

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  1. Ekaterina V. Nekrasova
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  2. Ekaterina E. Larionova
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Correspondence to Sergey V. Orlov.

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Nekrasova, E.V., Larionova, E.E., Danko, K. et al. Regulation of Apolipoprotein A-I Gene Expression in Human Macrophages by Oxidized Low-Density Lipoprotein. Biochemistry Moscow 86, 1201–1213 (2021). https://doi.org/10.1134/S0006297921100047

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