Accumulation and metabolism of low density lipoprotein-derived cholesteryl linoleate hydroperoxide and hydroxide by macrophages

Kritharides, Leonard; Upston, Joanne M.; Jessup, Wendy; Dean, Roger T.

doi:10.1016/s0022-2275(20)33318-6

Cited by 18 publications

(4 citation statements)

References 60 publications

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“…The high levels of lipid hydroperoxides present in LDL oxidized by iron at lysosomal pH may confer atherogenic properties to the LDL, which differ from those of copper-oxidized LDL. Kritharides et al 31 showed that treatment of murine peritoneal macrophages with acetylated or aggregated LDL, subjected to mild oxidation, led to a lysosomal or prelysosomal accumulation of CLOOH and CLOH, which impaired the breakdown of cholesteryl esters. The accumulation of lipid hydroperoxides within the lysosome might therefore compromise lysosomal function.…”

Section: ■ Discussionmentioning

confidence: 99%

Oxidation of Low-Density Lipoprotein by Iron at Lysosomal pH: Implications for Atherosclerosis

Satchell

Leake

2012

Biochemistry

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Low-density lipoprotein (LDL) has recently been shown to be oxidized by iron within the lysosomes of macrophages, and this is a novel potential mechanism for LDL oxidation in atherosclerosis. Our aim was to characterize the chemical and physical changes induced in LDL by iron at lysosomal pH and to investigate the effects of iron chelators and α-tocopherol on this process. LDL was oxidized by iron at pH 4.5 and 37 °C and its oxidation monitored by spectrophotometry and high-performance liquid chromatography. LDL was oxidized effectively by FeSO4 (5–50 μM) and became highly aggregated at pH 4.5, but not at pH 7.4. The level of cholesteryl esters decreased, and after a pronounced lag, the level of 7-ketocholesterol increased greatly. The total level of hydroperoxides (measured by the triiodide assay) increased up to 24 h and then decreased only slowly. The lipid composition after 12 h at pH 4.5 and 37 °C was similar to that of LDL oxidized by copper at pH 7.4 and 4 °C, i.e., rich in hydroperoxides but low in oxysterols. Previously oxidized LDL aggregated rapidly and spontaneously at pH 4.5, but not at pH 7.4. Ferrous iron was much more effective than ferric iron at oxidizing LDL when added after the oxidation was already underway. The iron chelators diethylenetriaminepentaacetic acid and, to a lesser extent, desferrioxamine inhibited LDL oxidation when added during its initial stages but were unable to prevent aggregation of LDL after it had been partially oxidized. Surprisingly, desferrioxamine increased the rate of LDL modification when added late in the oxidation process. α-Tocopherol enrichment of LDL initially increased the rate of oxidation of LDL but decreased it later. The presence of oxidized and highly aggregated lipid within lysosomes has the potential to perturb the function of these organelles and to promote atherosclerosis.

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Section: ■ Discussionmentioning

confidence: 99%

Oxidation of Low-Density Lipoprotein by Iron at Lysosomal pH: Implications for Atherosclerosis

Satchell

Leake

2012

Biochemistry

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“…Lysosomal accumulation of cholesteryl linoleate hydroperoxides and hydroxides occurs in macrophages incubated with mildly oxidized AcLDL, associated with retarded lysosomal hydrolysis of unoxidized cholesteryl esters (49). This probably reflects general inactivation of acid esterase activity by such early oxidation products.…”

Section: Discussionmentioning

confidence: 97%

Cholesterol and oxysterol metabolism and subcellular distribution in macrophage foam cells: accumulation of oxidized esters in lysosomes

Brown

Mander

Gelissen

et al. 2000

Journal of Lipid Research

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Cholesterol-and cholesteryl ester-rich macrophage foam cells, characteristic of atherosclerotic lesions, are often generated in vitro using oxidized low density lipoprotein (OxLDL). However, relatively little is known of the nature and extent of sterol deposition in these cells or of its relationship to the foam cells formed in atherosclerotic lesions. The purpose of this study was to examine the content and cellular processing of sterols in OxLDL-loaded macrophages, and to compare this with macrophages loaded with acetylated LDL (AcLDL; cholesteryl ester-loaded cells containing no oxidized lipids) or 7-ketocholesterol-enriched acetylated LDL (7KCAcLDL; cholesteryl ester-loaded cells selectively supplemented with 7-ketocholesterol (7KC), the major oxysterol present in OxLDL). Both cholesterol and 7KC and their esters were measured in macrophages after uptake of these modified lipoproteins. Oxysterols comprised up to 50% of total sterol content of OxLDL-loaded cells. Unesterified 7KC and cholesterol partitioned into cell membranes, with no evidence of retention of either free sterol within lysosomes. The cells also contained cytosolic, ACAT-derived, cholesteryl and 7-ketocholesteryl esters. The proportion of free cholesterol and 7KC esterified by ACAT was 10-fold less in OxLDL-loaded cells than in AcLDL or 7KCAcLDL-loaded cells. This poor esterification rate in OxLDL-loaded cells was partly caused by fatty acid limitation. OxLDL-loaded macrophages also contained large ( ϳ 40-50% total cell sterol content) pools of oxidized esters, containing cholesterol or 7KC esterified to oxidized fatty acids. These were insensitive to ACAT inhibition, very stable and located in lysosomes, indicating resistance to lysosomal esterases. Macrophages loaded with OxLDL do not accumulate free sterols in their lysosomal compartment, but do accumulate lysosomal deposits of OxLDL-derived cholesterol and 7-ketocholesterol esterified to oxidized fatty acids. The presence of similar deposits in lesion foam cells would represent a pool of sterols that is particularly resistant to removal. -Brown, A.

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“…A final possibility, consistent with a delay in suppression of hydrolysis, is that oxidized lipids continue to accumulate until they reach a point that inhibits the acid lipase. Recent studies (53) showed that hydrolysis of unoxidized CE is compromised in mouse peritoneal macrophages incubated with mildly oxidized acLDL. It was proposed that this impairment resulted from accumulation of cholesteryl linoleate hydroperoxides that inhibit acid lipase (53,54).…”

Section: Clearance Of Acldl and Oxldl Cholesteryl Estermentioning

confidence: 99%

“…Recent studies (53) showed that hydrolysis of unoxidized CE is compromised in mouse peritoneal macrophages incubated with mildly oxidized acLDL. It was proposed that this impairment resulted from accumulation of cholesteryl linoleate hydroperoxides that inhibit acid lipase (53,54). In our current studies, mildly oxidized LDL, which should contain lipid hydroperoxides (13), was used.…”

Section: Clearance Of Acldl and Oxldl Cholesteryl Estermentioning

confidence: 99%

Lysosomal cholesterol derived from mildly oxidized low density lipoprotein is resistant to efflux

Yancey

Jerome

2001

Journal of Lipid Research

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In atherosclerotic lesions, macrophages store lipid in cytoplasmic inclusions and lysosomes. Regression studies show that lysosomal lipid is not as easily cleared as cytoplasmic inclusion lipid. Macrophages enriched with mildly oxidized low density lipoprotein (oxLDL) accumulate cholesteryl ester (CE) and free cholesterol (FC) in lysosomes. We examined whether lysosomal stores of cholesterol from oxLDL are cleared from THP-1 and mouse macrophages. As in previous studies, oxLDL-enriched THP-1 macrophages accumulated substantial lysosomal cholesterol. Surprisingly, less than 12% of oxLDL-derived lysosomal CE was cleared to efficient FC acceptors (e.g., cyclodextrins, apolipoprotein/phosphatidylcholine vesicles, and fetal bovine serum). Filipin staining showed that lysosomes of oxLDL-treated THP-1 cells contained FC, and despite removal of most of the cell FC (70-80%) by incubation with cyclodextrins, filipin staining of FC in lysosomes did not diminish. Also, when THP-1 macrophages were incubated with [ 3 H]CE oxLDL, 73-76% of the [ 3 H]CE was retained in a lysosomal hydrolysis resistant pool. In contrast, greater than 90% of acetylated low density lipoprotein (acLDL) [ 3 H]CE was hydrolyzed. Furthermore, [ 3 H]FC liberated from oxLDL [ 3 H]CE was released at a slower rate to cyclodextrins than was [ 3 H]FC from acLDL [ 3 H]CE. In contrast, only 27% of oxLDL [ 3 H]CE was resistant to hydrolysis in mouse macrophages, and the [ 3 H]FC generated from oxLDL and acLDL [ 3 H]CE was released to cyclodextrins at similar rates. We conclude that lack of hydrolysis and efflux of oxLDL cholesterol is not exclusively inherent in oxLDL, but also requires specific cell factors present in one cell type but not the other. -Yancey, P. G., and W. G. Jerome. Lysosomal cholesterol derived from mildly oxidized low density lipoprotein is resistant to efflux.

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Accumulation and metabolism of low density lipoprotein-derived cholesteryl linoleate hydroperoxide and hydroxide by macrophages

Cited by 18 publications

References 60 publications

Oxidation of Low-Density Lipoprotein by Iron at Lysosomal pH: Implications for Atherosclerosis

Oxidation of Low-Density Lipoprotein by Iron at Lysosomal pH: Implications for Atherosclerosis

Cholesterol and oxysterol metabolism and subcellular distribution in macrophage foam cells: accumulation of oxidized esters in lysosomes

Lysosomal cholesterol derived from mildly oxidized low density lipoprotein is resistant to efflux

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