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Mechanisms of foam cell formation in atherosclerosis

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Abstract

Low-density lipoprotein (LDL) and cholesterol homeostasis in the peripheral blood is maintained by specialized cells, such as macrophages. Macrophages express a variety of scavenger receptors (SR) that interact with lipoproteins, including SR-A1, CD36, and lectin-like oxLDL receptor-1 (LOX-1). These cells also have several cholesterol transporters, including ATP-binding cassette transporter ABCA1, ABCG1, and SR-BI, that are involved in reverse cholesterol transport. Lipids internalized by phagocytosis are transported to late endosomes/lysosomes, where lysosomal acid lipase (LAL) digests cholesteryl esters releasing free cholesterol. Free cholesterol in turn is processed by acetyl-CoA acetyltransferase (ACAT1), an enzyme that transforms cholesterol to cholesteryl esters. The endoplasmic reticulum serves as a depot for maintaining newly synthesized cholesteryl esters that can be processed by neutral cholesterol ester hydrolase (NCEH), which generates free cholesterol that can exit via cholesterol transporters. In atherosclerosis, pro-inflammatory stimuli upregulate expression of scavenger receptors, especially LOX-1, and downregulate expression of cholesterol transporters. ACAT1 is also increased, while NCEH expression is reduced. This results in deposition of free and esterified cholesterol in macrophages and generation of foam cells. Moreover, other cell types, such as endothelial (ECs) and vascular smooth muscle cells (VSMCs), can also become foam cells. In this review, we discuss known pathways of foam cell formation in atherosclerosis.

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Authors and Affiliations

  1. Department of Neurochemistry, Division of Basic and Applied Neurobiology, Serbsky Federal Medical Research Center of Psychiatry and Narcology, Moscow, Russia, 119991

    Dimitry A. Chistiakov

  2. Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, Russia, 125315

    Alexandra A. Melnichenko & Alexander N. Orekhov

  3. Skolkovo Innovative Center, Institute for Atherosclerosis Research, Moscow, Russia, 121609

    Veronika A. Myasoedova & Alexander N. Orekhov

  4. Federal Scientific Clinical Center for Resuscitation and Rehabilitation, Moscow, Russia, 109240

    Andrey V. Grechko

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  1. Dimitry A. Chistiakov
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  2. Alexandra A. Melnichenko
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  3. Veronika A. Myasoedova
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Correspondence to Alexander N. Orekhov.

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This work was supported by Russian Science Foundation (Grant no. 14-15-00112).

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Chistiakov, D.A., Melnichenko, A.A., Myasoedova, V.A. et al. Mechanisms of foam cell formation in atherosclerosis. J Mol Med 95, 1153–1165 (2017). https://doi.org/10.1007/s00109-017-1575-8

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