Lysosomal Cholesterol Accumulation Inhibits Subsequent Hydrolysis of Lipoprotein Cholesteryl Ester

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

doi:10.1017/s1431927608080069

Cited by 56 publications

(56 citation statements)

References 48 publications

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“…Jerome et al (38) have demonstrated that oxidized LDL accumulation within lysosomes inhibits subsequent lipoprotein hydrolysis and that lipid-engorged lysosomes failed to maintain an acidic pH. We proposed that the Hp genotype-dependent oxidative effect on LDL accumulated within lysosomes may further increase its pH leading to more lysosomal dysfunction.…”

Section: Demonstration That the Increased Oxidative Stress In Lysosommentioning

confidence: 82%

Haptoglobin Genotype-dependent Differences in Macrophage Lysosomal Oxidative Injury

Asleh

Ward

Levy

et al. 2014

Journal of Biological Chemistry

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Background:The haptoglobin genotype is a determinant of atherosclerotic plaque oxidation and instability. Results: The amount of lysosomal iron and membrane injury is haptoglobin genotype-dependent. Conclusion: Hemoglobin-mediated lysosomal oxidative injury of the macrophage is haptoglobin genotype-dependent. Significance: The haptoglobin genotype may modulate plaque stability by determining the macrophage response to free hemoglobin within the atherosclerotic plaque.

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Section: Demonstration That the Increased Oxidative Stress In Lysosommentioning

confidence: 82%

Haptoglobin Genotype-dependent Differences in Macrophage Lysosomal Oxidative Injury

Asleh

Ward

Levy

et al. 2014

Journal of Biological Chemistry

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“…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%

“…Furthermore, TG can prevent subsequent cellular cholesterol accumulation and can mobilize preexisting stores of cellular CE, including the large volume of sterol that accumulates in cellular lysosomes ( 50 ). This is in stark contrast to direct stimulation of extralysosomal cholesterol mobilization, which does not affect the cholesterol trapped within lysosomes ( 16,51 ).…”

Section: Resultsmentioning

confidence: 99%

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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“…Aliquots were stored at −80°C for lipid/chemical determinations while the HDL fraction (d = 1.063 to 1.22 g/ml) was isolated from fresh plasma by density gradient ultracentrifugation (DGUC). 23 Because of their size and small volume, we were initially concerned that the DGUR method would yield insufficient HDL fraction and began the studies using samples (three from each group) obtained by precipitating the apoB fraction with polyethylene glycol (PEG) solution as described. 24 HDL isolation method did not influence results of migration and cytokine expression studies and results were combined.…”

Section: Methodsmentioning

confidence: 99%

Dysfunctional high-density lipoproteins in children with chronic kidney disease

et al. 2015

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Objectives Our aim was to determine if chronic kidney disease (CKD) occurring in childhood impairs the normally vasoprotective functions of high-density lipoproteins (HDL). Materials and Methods HDL were isolated from children with end-stage renal disease on dialysis (ESRD), children with moderate CKD and controls with normal kidney function. Macrophage response to HDL was studied as expression of inflammatory markers (MCP-1, TNF-α, IL-1β) and chemotaxis. Human umbilical vein endothelial cells were used for expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and adhesion. Cellular proliferation, apoptosis, and necrosis of endothelial cells was measured by MTS/PMS reagent-based assay, flow cytometry, and ELISA. Cholesterol efflux was assessed by gas chromatographic measurements of cholesterol in macrophages exposed to HDL. Results Compared with HDLControl, HDLCKD and HDLESRD heightened the cytokine response and disrupted macrophage chemotaxis. HDLControl reduced endothelial expression of ICAM-1, VCAM-1, E-selectin, whereas HDLCKD and HDLESRD were less effective and showed reduced capacity to protect endothelial cells against monocyte adhesion. Compared with a dramatically enhanced endothelial proliferation following injurious stimulus by HDLControl, neither HDLCKD nor HDLESRD caused proliferative effects. HDL of all three groups were equally protective against apoptosis assessed by flow cytometry and cleaved caspase-3 activity. Compared to HDLControl, HDLCKD and HDLESRD trended toward reduced capacity as cholesterol acceptors. Conclusion CKD in children impairs HDL function. Even in the absence of long-standing and concomitant risk factors, CKD alters specific HDL functions linked to control of inflammation and endothelial responses.

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Lysosomal Cholesterol Accumulation Inhibits Subsequent Hydrolysis of Lipoprotein Cholesteryl Ester

Cited by 56 publications

References 48 publications

Haptoglobin Genotype-dependent Differences in Macrophage Lysosomal Oxidative Injury

Haptoglobin Genotype-dependent Differences in Macrophage Lysosomal Oxidative Injury

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

Dysfunctional high-density lipoproteins in children with chronic kidney disease

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