Aggregated LDL and lipid dispersions induce lysosomal cholesteryl ester accumulation in macrophage foam cells

Griffin, Evelyn E.; Ullery, Jody C.; Cox, Brian E.; Jerome, W. Gray

doi:10.1194/jlr.m500059-jlr200

Cited by 48 publications

(72 citation statements)

References 54 publications

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“…1A ). As in previous studies ( 50 ), thin section electron microscopy of acid phosphatase-stained samples showed that >75% of the lipid volume was within lipid-engorged lysosomes. In contrast, coincubation of THP-1 with both aggLDL and VLDL resulted in a significant ( P < 0.05) reduction the accumulation of CE ( Fig.…”

Section: Resultsmentioning

confidence: 60%

“…by guest, on March 24, 2019 www.jlr.org Downloaded from particles, including oxidized LDL, aggLDL, and CE-DISP is, in large part, the result of inhibition of lysosomal CE hydrolysis in response to an initial accumulation of excess FC within the lysosome ( 45,50,51 ). Lysosomal CE hydrolysis is a key rate-limiting step in the cellular clearance of exogenously derived sterol.…”

Section: Resultsmentioning

confidence: 99%

“…These CE-containing particles must fi rst be processed within lysosomes. We have previously shown that this CE hydrolysis is inhibited in heavily cholesterol-laden foam cells due primarily to the accumulation of FC within the lysosome lumen and lysosome membrane ( 45,50 ). The lysosomally sequestered free and esterifi ed cholesterol is trapped and cannot be removed from the lysosome even under conditions that promote the removal of nonlysosomal cholesterol from membranes and intracellular droplets ( 16 ).…”

Section: Resultsmentioning

confidence: 99%

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Triglyceride alters lysosomal cholesterol ester metabolism in cholesteryl ester-laden macrophage foam cells

Ullery-Ricewick

Cox

Griffin

et al. 2009

Journal of Lipid Research

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Atherosclerosis is a complex, multifactorial disease. An early event in atherosclerosis is the development of macrophage foam cells. These are primarily formed through the uptake of modifi ed lipoproteins by macrophages within the artery wall ( 1-4 ). In late-stage atherosclerotic lesions, a large amount of both free cholesterol (FC) and cholesteryl ester (CE) accumulates in foam cell lysosomes. The presence of extensive amounts of CE suggests an interruption in the normal lysosomal hydrolysis of lipid particle-derived CE, while the accumulation of FC indicates an interruption in the normal removal of FC from lysosomes to other organelles, primarily the plasma membrane ( 5-7 ). Many studies indicate that lysosomal sequestration of cholesterol can have consequences for atherosclerotic lesion development (8)(9)(10)(11)(12)(13)(14)(15). In addition to a direct effect of accumulating sterol on lysosome function, trapping of sterol in lysosomes can prevent removal of cholesterol by effl ux. In fact, the cholesterol and CE in lysosomes remains trapped in lysosomes, even when further uptake of lipoproteins is halted and acceptor concentrations in the media are increased to levels that effl ux most of the nonlysosomal CE stores ( 16 ). Thus, the sequestration of sterol within lysosomes prevents effl ux and limits the availability of cholesterol to other intracellular processes ( 16 ). Therefore, factors that infl uence the removal of lysosomally sequestered sterol could have profound effects on foam cell biology and atherosclerotic lesion development.Many studies have examined macrophage foam cell metabolism in the presence of various CE-containing particles ( 2-4 ). However, triglyceride-rich particles (TRPs), including VLDL, are also present within the atherosclerotic Abbreviations: aggLDL, aggregated low density lipoprotein; CE, cholesteryl ester; DISP, lipid dispersions; FC, free cholesterol; LAMP-1, lysosomal-associated membrane protein; TG, triglyceride; TRP, triglyceride-rich particle; TPA, phorbol ester.

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Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Triglyceride alters lysosomal cholesterol ester metabolism in cholesteryl ester-laden macrophage foam cells

Ullery-Ricewick

Cox

Griffin

et al. 2009

Journal of Lipid Research

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“…54 Other modified LDLs, such as oxidized low-density lipoprotein (OxLDL) and LDL aggregates, are more important in the development of atherosclerosis. 55 OxLDL tends to be trapped in lysosomes, 56 suggesting that this lipoprotein does not enter LDs to be a substrate for lipophagy. Important to the consideration of autophagy as a therapeutic target is whether levels of autophagy are altered in macrophages as they progress to foam cells.…”

Section: Lipophagy Regulates Macrophage Cholesterol Effluxmentioning

confidence: 99%

Regulation of lipid stores and metabolism by lipophagy

2012

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Intracellular lipids are stored in lipid droplets (LDs) and metabolized by cytoplasmic neutral hydrolases to supply lipids for cell use. Recently, an alternative pathway of lipid metabolism through the lysosomal degradative pathway of autophagy has been described and termed lipophagy. In this form of lipid metabolism, LD triglycerides (TGs) and cholesterol are taken up by autophagosomes and delivered to lysosomes for degradation by acidic hydrolases. Free fatty acids generated by lipophagy from the breakdown of TGs fuel cellular rates of mitochondrial b-oxidation. Lipophagy therefore functions to regulate intracellular lipid stores, cellular levels of free lipids such as fatty acids and energy homeostasis. The amount of lipid metabolized by lipophagy varies in response to the extracellular supply of nutrients. The ability of the cell to alter the amount of lipid targeted for autophagic degradation depending on nutritional status demonstrates that this process is selective. Intracellular lipids themselves regulate levels of autophagy by unclear mechanisms. Impaired lipophagy can lead to excessive tissue lipid accumulation such as hepatic steatosis, alter hypothalamic neuropeptide release to affect body mass, block cellular transdifferentiation and sensitize cells to death stimuli. Future studies will likely identify additional mechanisms by which lipophagy regulates cellular physiology, making this pathway a potential therapeutic target in a variety of diseases. Open QuestionsHow does the autophagic machinery selectively target stored lipids for degradation in response to changes in nutrient levels? What are the relative contributions of cytosolic lipolysis and lipophagy to lipid metabolism in different cell types, and is there cross-talk between the two pathways? What are the mechanisms by which intracellular lipids and other factors regulate levels of lipophagy? Do defects in lipophagy underlie human disease and can lipophagy be a therapeutic target? Intracellular lipids are essential to cells as an energy source, structural components for membranes, synthetic building blocks for other molecules, such as hormones, and as mediators of cell signaling. The ability to safely store adequate, but not excessive, amounts of lipids and to metabolize them when needed is critical for cell function and survival. The recent finding that lipids can be selectively degraded by the lysosomal pathway of macroautophagy through a process termed lipophagy 1 has opened up a new understanding of how lipid metabolism regulates cellular physiology and pathophysiology. Many new functions for autophagic lipid metabolism have now been defined in diverse cellular processes ranging from transdifferentiation to resistance to death. Intracellular Lipids are Degraded by LipophagyTGs and cholesterol are safely stored as neutral lipids in specialized cellular organelles called LDs. 2,3 Until recently, the breakdown of LD-stored TG and cholesterol was attributed exclusively to the actions of cytosolic hydrolytic enzymes or lipases. The role of l...

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“…[13][14][15][16] Acetylated LDL (AcLDL) can induce the formation of foam cells in association with the accumulation of CE. 17) Much more CE was produced through the reesterification of FC induced by AcLDL than that induced by OxLDL.…”

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confidence: 99%

Inhibition of Cytosolic Phospholipase A2 Suppresses Production of Cholesteryl Ester through the Reesterification of Free Cholesterol but not Formation of Foam Cells in Oxidized LDL-Stimulated Macrophages

Hiromi

Oka

Yamashita

et al. 2008

Biological & Pharmaceutical Bulletin

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Aggregated LDL and lipid dispersions induce lysosomal cholesteryl ester accumulation in macrophage foam cells

Cited by 48 publications

References 54 publications

Triglyceride alters lysosomal cholesterol ester metabolism in cholesteryl ester-laden macrophage foam cells

Triglyceride alters lysosomal cholesterol ester metabolism in cholesteryl ester-laden macrophage foam cells

Regulation of lipid stores and metabolism by lipophagy

Inhibition of Cytosolic Phospholipase A2 Suppresses Production of Cholesteryl Ester through the Reesterification of Free Cholesterol but not Formation of Foam Cells in Oxidized LDL-Stimulated Macrophages

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