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Insulin Downregulates the Expression of ATP-binding Cassette Transporter A-I in Human Hepatoma Cell Line HepG2 in a FOXO1 and LXR Dependent Manner

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Abstract

ATP-binding cassette transporter A-I (ABCA1) is an ubiquitously expressed protein whose main function is the transmembrane transport of cholesterol and phospholipids. Synthesis of ABCA1 protein in liver is necessary for high-density lipoprotein (HDL) formation in mammals. Thus, the mechanism of ABCA1 gene expression regulation in hepatocytes are of critical importance. Recently, we have found the insulin-dependent downregulation of other key player in the HDL formation—apolipoprotein A-I gene (J. Cell. Biochem., 2017, 118:382-396). Nothing is known about the role of insulin in the regulation of ABCA1 gene. Here we show for the first time that insulin decreases the mRNA and protein levels of ABCA1 in human hepatoma cell line HepG2. PI3K, p38, MEK1/2, JNK and mTORC1 signaling pathways are involved in the insulin-mediated downregulation of human ABCA1 gene. Transcription factors LXRα, LXRβ, FOXO1 and NF-κB are important contributors to this process, while FOXA2 does not regulate ABCA1 gene expression. Insulin causes the decrease in FOXO1, LXRα and LXRβ binding to ABCA1 promoter, which is likely the cause of the decrease in the gene expression. Interestingly, the murine ABCA1 gene seems to be not regulated by insulin in hepatocytes (in vitro and in vivo). We suggest that the reason for this discrepancy is the difference in the 5ʹ-regulatory regions of human and murine ABCA1 genes.

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Acknowledgements

We thank Prof. A. D. Denisenko (Institute of Experimental Medicine, Russia) for useful discussion.

Author Contributions

V.S.S. wrote the manuscript; V.S.S., A.V.B., E.V.N. carried out the experiments and analyzed the results; A.V.L. performed the gene engineering manipulations; E.B.D. and G.N.O. performed the cell cultivation and the cell transfection experiments; S.V.O. designed the study, wrote the manuscript. All authors revised the manuscript and agreed to be accountable for all aspects of the presented work.

Funding

This work was supported by Russian Science Foundation (Grant No. 17-15-01326).

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Authors and Affiliations

  1. Department of Biochemistry, Institute of Experimental Medicine, St. Petersburg, Russia

    Vladimir S. Shavva, Anna V. Babina, Ekaterina V. Nekrasova, Alexey V. Lisunov, Ella B. Dizhe, Galina N. Oleinikova & Sergey V. Orlov

  2. Department of Embryology, St. Petersburg State University, St. Petersburg, Russia

    Alexey V. Lisunov & Sergey V. Orlov

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  1. Vladimir S. Shavva
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Shavva, V.S., Babina, A.V., Nekrasova, E.V. et al. Insulin Downregulates the Expression of ATP-binding Cassette Transporter A-I in Human Hepatoma Cell Line HepG2 in a FOXO1 and LXR Dependent Manner. Cell Biochem Biophys 81, 151–160 (2023). https://doi.org/10.1007/s12013-022-01109-w

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