Glycosylation of low-density lipoprotein enhances cholesteryl ester synthesis in human monocyte-derived macrophages

Lopes‐Virella, Maria F.; Klein, Richard L.; Lyons, Timothy; Stevenson, Henry C.; Witztum, Joseph L.

doi:10.2337/diabetes.37.5.550

Cited by 94 publications

(52 citation statements)

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“…LDL obtained from diabetic patients is less well metabolized by cultured human skin fibroblasts [2,6] and enhances cholesteryl ester synthesis in human monocyte-derived macrophages [4]. Lopes-Virella et al [16] reported that in vitro glycation enhances LDL metabolism by monocyte-derived macrophages.…”

Section: Discussionmentioning

confidence: 99%

Glycation Accelerates the Oxidation of Low Density Lipoprotein by Copper Ions.

et al. 1995

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Section: Discussionmentioning

confidence: 99%

Glycation Accelerates the Oxidation of Low Density Lipoprotein by Copper Ions.

et al. 1995

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“…18,20,26,27 Also, LDL particles, modified by advanced glycation, promote cholesterol accumulation in cultured macrophages. 19,28 Consequently, enhancement of LAL activity in macrophages could provide a means to decrease accumulated, pathologic cholesteryl esters and triglycerides (TGs) that are causally related to atherosclerosis. …”

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confidence: 99%

Reduction of Atherosclerotic Plaques by Lysosomal Acid Lipase Supplementation

Du¹,

Schiavi²,

Wan³

et al. 2004

ATVB

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Objective-Proof of principle is presented for targeted enzyme supplementation by using lysosomal acid lipase to decrease aortic and coronary wall lipid accumulation in a mouse model of atherosclerosis. Methods and Results-Mice with LDL receptor deficiency were placed on an atherogenic diet and developed predictable aortic and coronary atheroma. ␣-Mannosyl-terminated human lysosomal acid lipase (phLAL) was produced in Pichia pastoris, purified, and administered intravenously to such mice with either early or late lesions. phLAL injections reduced plasma, hepatic, and splenic cholesteryl esters and triglycerides in affected mice. phLAL was detected in hepatic Kupffer cells and in atheromatous foam cells. Repeated enzyme injections were well tolerated, with no obvious adverse effects. In addition, the coronary and aortic atheromatous lesions were (1) eliminated in their early stages and (2) quantitatively and qualitatively reduced in their advanced stages. A therosclerosis is the number 1 cause of mortality and morbidity in the developed countries. A number of interventions or preventions delay the consequences of atherosclerosis, eg, low cholesterol diet and exercise, HMG-CoA reductase inhibitors, and coronary artery bypass. However, they are not suitable for all patients, and few have been shown to promote regression of lesions. Therefore, new approaches are needed for the treatment and prevention of atherosclerosis. Several stages characterize the progression of atherosclerotic lesions. 1,2 The earliest lesion is the "fatty streak," an aggregation of lipid-rich macrophages and T-lymphocytes within the intimae layer of an artery. The fatty streaks evolve into intermediate lesions that have a layer of foamy macrophages and smooth muscle cells. This develops into complex and occlusive lesions, as well as fibrous plaques. These plaques have a dense cap of connective tissue, with embedded smooth muscle cells overlaying a core of lipid and necrotic debris. Macrophages are present at all lesional stages with excessive cholesterol and cholesteryl esters in lysosomes. Continuing development of atherosclerotic plaques requires progressive macrophage processing of cholesteryl esters in and through the lysosomes. Perpetuation and maturation of the plaques depends on additional complex inflammatory and scarring processes. Lysosomal acid lipase (LAL) is the only hydrolase for cleavage of cholesteryl esters delivered to the lysosomes. 3 The receptors that mediate cholesteryl ester uptake into macrophage include those for LDL and oxidized LDL (oxLDL), ie, LDL receptor (LDL-R), the scavenger receptors type AI and AII (SR-AI and SR-AII), 4 -6 the scavenger receptor type B1 (SR-BI), 7-9 CD36, 10 and the LDL receptor related protein (LRP). 11 All of these, except SR-BI, direct associated lipids to the lysosome. 12-15 Furthermore, modification of LDL by oxidation, aggregation, and glycation occurs in the atherosclerotic lesions by histochemical and biochemical studies. 16 -20 The delivery of oxidized LDL to lysosomes of macropha...

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“…Regarding the metabolism of glycosylated LDL without Cu++ modification, it remains controversial as to whether the glycosylated LDL alone is capable of enhancing the CE synthesis. The LDL that is extensively glycosylated in vitro has been shown to enhance the CE synthesis by human monocyte-derived macrophages [26] but not that by murine macrophages [27,28] Therefore, in the present study employing mouse peritoneal macrophages, the modification by Cu++ was added to diabetic LDL, and this procedure successfully led to the enhancement of CE synthesis. When the trichloroacetic-acid-soluble products were measured, indicating the degradation of ['25I]-labeled apoprotein in Cu-modified diabetic LDL, the amount of degradation was the same as that of Cu-modified normal LDL.…”

Section: Discussionmentioning

confidence: 99%

Copper-Modified Low Density Lipoprotein from Diabetic Patients Enhances Cholesteryl Ester Synthesis by Mouse Peritoneal Macrophages.

Hiramatsu

Pajor

Nakazawa

et al. 1992

J. Clin. Biochem. Nutr.

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SummaryIn this study, the capability of superoxide production by LDL either without stimulation or under the stimulation of Fe-ADP and the manner of modification of low density lipoprotein (LDL) by copper (Cu) in diabetic patients were examined and compared with those of healthy subjects. The amount of superoxide generated by diabetic LDL was similar to that of healthy subjects both at the basal level and following stimulation by Fe-ADP. LDL from healthy subjects and diabetic patients was modified in the presence of 10 ji M CuSO4. When the level of thiobarbituric acid-reactive substance was determined in the Cu-modified LDL, no difference was found. On the other hand, when the incorporation of ['4C]oleate into cholesteryl ester (CE) by mouse peritoneal macrophages was stimulated by the Cu-modified LDL, we found that the modified diabetic LDL significantly enhanced the CE synthesis compared with the modified healthy LDL (p <0.01). To clarify the mechanism of the enhanced CE synthesis, the rate of degradation of ['25I]Cu-modified ++diabetic LDL was measured. We found that this rate was similar to that of healthy subjects. These data suggest that the degree of oxidation does not differ among patients although diabetic LDL is modified by Cu++ in a manner such that it preferentially promotes the activity of CE synthesis in macrophages by some unknown intracellular metabolic mechanism.

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Glycosylation of low-density lipoprotein enhances cholesteryl ester synthesis in human monocyte-derived macrophages

Cited by 94 publications

References 0 publications

Glycation Accelerates the Oxidation of Low Density Lipoprotein by Copper Ions.

Glycation Accelerates the Oxidation of Low Density Lipoprotein by Copper Ions.

Reduction of Atherosclerotic Plaques by Lysosomal Acid Lipase Supplementation

Copper-Modified Low Density Lipoprotein from Diabetic Patients Enhances Cholesteryl Ester Synthesis by Mouse Peritoneal Macrophages.

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