Abstract
Mechanisms of lipid homeostasis and its impairment are of crucial importance for atherogenesis, and their understanding is necessary for successful development of new therapeutic approaches. In the arterial wall, macrophages play a prominent role in intracellular lipid accumulation, giving rise to foam cells that populate growing atherosclerotic plaques. Under normal conditions, macrophages are able to process substantial amounts of lipids and cholesterol without critical overload of the catabolic processes. However, in atherosclerosis, these pathways become inefficient, leading to imbalance in cholesterol and lipid metabolism and disruption of cellular functions. In this review, we summarize the existing knowledge on the involvement of macrophage lipid metabolism in atherosclerosis development, including both the results of recent studies and classical concepts, and provide a detailed description of these processes from the moment of lipid uptake with lipoproteins to cholesterol efflux.
Highlights
Intracellular lipid accumulation associated with atherosclerosis can affect virtually any of the cell types that can be found in the subendothelial space of human arteries, including vascular smooth muscular cells (VSMCs), stellate pericyte-like cells, and macrophages
We presented the summarized knowledge obtained both by recent studies and classical works on the involvement of cholesterol metabolism in macrophages in atherosclerosis development and progression
They are faced with the difficult task of catabolism of excess lipids, which may interfere with the physiological cellular lipid metabolism
Summary
Intracellular lipid accumulation associated with atherosclerosis can affect virtually any of the cell types that can be found in the subendothelial space of human arteries, including vascular smooth muscular cells (VSMCs), stellate pericyte-like cells, and macrophages. Macrophages are recognized as a major precursor of foam cells These cells have their cytoplasm filled with lipid droplets, which gives them their specific microscopic appearance. LDL entering the cell through receptor-mediated endocytosis can be degraded in the lysosomes, which prevents excessive lipid accumulation. In case of free cholesterol excess, which is detected by cellular regulatory mechanisms described below, the amount of LDLR on the cell surface decreases, reducing the uptake of exogenous lipids with native LDL. Presence of atherogenic mLDL causes an imbalance of these processes due to the unregulated uptake of mLDL by macrophages, which leads to excessive accumulation of lipids by the cell and foam cell formation. LXRα, LXRβ, RXR, PPARγ, PCSK9, DAPK1, NF-κB, PKA, PKC, JAK2, miRNA-33, mTORC1, Keap1/Nrf pathway, IGF-1, PI3, and Akt signaling pathways, TLR2
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