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Review
. 2002 Oct;110(7):905-11.
doi: 10.1172/JCI16452.

Consequences of cellular cholesterol accumulation: basic concepts and physiological implications

Ira Tabas  1
Affiliations
Review

Consequences of cellular cholesterol accumulation: basic concepts and physiological implications

Ira Tabas. J Clin Invest. 2002 Oct.
No abstract available

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Figures

Figure 1
Figure 1
Mechanisms that protect cells from excess accumulation of FC. Lipoprotein-derived cholesterol is distributed to peripheral cellular sites from a putative FC-sorting organelle, which may be a type of late endosome. The npc1 protein is depicted in this organelle as one of the molecules that are known to influence cholesterol trafficking. The cholesterol trafficking itineraries depicted here include transport to ACAT in the endoplasmic reticulum, leading to cholesterol esterification, and to sites of cholesterol efflux in the plasma membrane, leading to removal of cholesterol if appropriate extracellular cholesterol acceptors are present. Not depicted here are those pathways that downregulate the LDL receptor and cholesterol biosynthetic enzymes and those pathways in specialized cells that lead to the metabolism of cholesterol to other molecules, like bile acids and steroid hormones. As described in the text, FC accumulation can occur via inhibition of cholesterol transport to ACAT or to the plasma membrane, or by direct inhibition of ACAT or cholesterol efflux molecules. An increase in neutral cholesteryl esterase (NCEH) activity in the absence of compensatory re-esterification or efflux of cholesterol could also lead to FC accumulation.
Figure 2
Figure 2
Sequential responses of cultured macrophages to FC loading. In the initial, adaptive phase, CT is activated, leading to increased PC biosynthesis and PC mass and resulting in a normalization of the FC/phospholipid ratio. In addition, there is an increase in the degree of unsaturation of phospholipid fatty acids (FAs). With continued FC loading, death ensues by both apoptotic and necrotic processes. Apoptosis involves both activation of Fas ligand and release of cytochrome c (cyto c) from mitochondria, which may be related to the increased levels of mitochondria-associated Bax in FC-loaded macrophages. FC-induced mitochondrial dysfunction also leads to depletion of cellular ATP stores, which could trigger cellular necrosis.
Figure 3
Figure 3
Hypothetical model relating FC loading of lesional macrophages (Mφs) to acute events in advanced atheromata. Progressive FC loading of lesional macrophages leads to a series of phospholipid-related adaptive responses, as described in the text. These adaptive responses eventually fail, leading to macrophage death (see Figure 2). On the one hand, macrophage death may contribute to plaque instability by promoting lesional necrosis. On the other hand, safe disposal of apoptotic macrophages could decrease the number of macrophages that secrete matrix metalloproteinases (MMPs), tissue factor (TF), and inflammatory cytokines. Because these molecules are thought to contribute to plaque rupture and acute thrombosis, macrophage death in this particular context might be protective.
See this image and copyright information in PMC

References

    1. Dietschy JM, Turley SD, Spady DK. Role of the liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res. 1993;34:1637–1659. - PubMed
    1. Tabas, I., and Kreiger, M. 1999. Lipoprotein receptors and cellular cholesterol metabolism in health and disease. In Molecular basis of heart disease. K.R. Chien, editor. W.B. Saunders Co. New York, New York, USA. 428–457.
    1. Lin D, et al. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science. 1995;267:1828–1831. - PubMed
    1. Tall AR, Costet P, Wang N. Regulation and mechanisms of macrophage cholesterol efflux. J Clin Invest. 2002;110:899–904. doi:10.1172/JCI200216391. - PMC - PubMed
    1. Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell. 2001;104:503–516. - PubMed