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

Ekaterina V. Nekrasova1, Ekaterina E. Larionova1, Katerina Danko2, Darya O. Kuzmina2, Vladimir S. Shavva1, Igor V. Kudriavtsev1, and Sergey V. Orlov1,2,a,b*

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

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

* To whom correspondence should be addressed.

Received July 1, 2021; Revised July 18, 2021; Accepted July 23, 2021
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.
KEY WORDS: atherosclerosis, oxLDL, macrophages, THP-1 cells, foam cells, TLR4, gene expression regulation, apoA-I gene

DOI: 10.1134/S0006297921100047