Advanced Glycation in macrophages induces intracellular accumulation of 7-ketocholesterol and total sterols by decreasing the expression of ABCA-1 and ABCG-1

Lipids in Health and Disease

Marisa Passarelli²  Edna R Nakandakare²  Dulcinéia SP Abdalla¹  Valeria S Nunes²  Gabriela Castilho²  Adriana Machado-Lima²  Rodrigo T Iborra² 

[1] Department of Clinical and Toxicology Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil;Lipids Laboratory (LIM-10), Faculty of Medical Sciences, University of São Paulo. São Paulo, Brazil

关键词: ABCG-1;    ABCA-1;    7-ketocholesterol;    oxysterols;    diabetes mellitus;    advanced glycation;   

Others  :  1212492
DOI  :  10.1186/1476-511X-10-172

 received in 2011-09-09, accepted in 2011-09-29,  发布年份 2011

【 摘 要 】

Background

Advanced glycation end products (AGE) alter lipid metabolism and reduce the macrophage expression of ABCA-1 and ABCG-1 which impairs the reverse cholesterol transport, a system that drives cholesterol from arterial wall macrophages to the liver, allowing its excretion into the bile and feces. Oxysterols favors lipid homeostasis in macrophages and drive the reverse cholesterol transport, although the accumulation of 7-ketocholesterol, 7alpha- hydroxycholesterol and 7beta- hydroxycholesterol is related to atherogenesis and cell death. We evaluated the effect of glycolaldehyde treatment (GAD; oxoaldehyde that induces a fast formation of intracellular AGE) in macrophages overloaded with oxidized LDL and incubated with HDL alone or HDL plus LXR agonist (T0901317) in: 1) the intracellular content of oxysterols and total sterols and 2) the contents of ABCA-1 and ABCG-1.

Methods

Total cholesterol and oxysterol subspecies were determined by gas chromatography/mass spectrometry and HDL receptors content by immunoblot.

Results

In control macrophages (C), incubation with HDL or HDL + T0901317 reduced the intracellular content of total sterols (total cholesterol + oxysterols), cholesterol and 7-ketocholesterol, which was not observed in GAD macrophages. In all experimental conditions no changes were found in the intracellular content of other oxysterol subspecies comparing C and GAD macrophages. GAD macrophages presented a 45% reduction in ABCA-1 protein level as compared to C cells, even after the addition of HDL or HDL + T0901317. The content of ABCG-1 was 36.6% reduced in GAD macrophages in the presence of HDL as compared to C macrophages.

Conclusion

In macrophages overloaded with oxidized LDL, glycolaldehyde treatment reduces the HDL-mediated cholesterol and 7-ketocholesterol efflux which is ascribed to the reduction in ABCA-1 and ABCG-1 protein level. This may contribute to atherosclerosis in diabetes mellitus.

【 授权许可】

   
2011 Iborra et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Björkhem I: Do oxysterols control cholesterol homeostasis? J Clin Invest 2002, 110(6):725-30.
• [2]Schroepfer GJ Jr: Oxysterols: modulators of cholesterol metabolism and other processes. Physiological Reviews 2000, 80(1):361-554.
• [3]Berthier A, Lemaire-Ewing S, Prunet C, Montange T, Vejux A, Pais de Barros JP, Monier S, Gambert P, Lizard G, Néel D: 7-Ketocholesterol-induced apoptosis. Involvement of several pro-apoptotic but also anti-apoptotic calcium-dependent transduction pathways. Febs J 2005, 272(12):3093.
• [4]Machado AP, Pinto RS, Moysés ZP, Nakandakare ER, Quintão EC, Passarelli : Aminoguanidine and metformin prevent the reduced rate of HDL-mediated cell cholesterol efflux induced by formation of advanced glycation end products. M Int J Biochem Cell Biol 2006, 38(3):392.
• [5]Matsuki K, Tamasawa N, Yamashita M, Tanabe J, Murakami H, Matsui J, Imaizumi T, Satoh K, Suda T: Metformin restores impaired HDL-mediated cholesterol efflux due to glycation. Atherosclerosis 2009, 206(2):434.
• [6]Isoda K, Folco EJ, Shimizu K, Libby P: AGE-BSA decreases ABCG1 expression and reduces macrophage cholesterol efflux to HDL. Atherosclerosis 2007, 192(2):298.
• [7]Passarelli M, Catanozi S, Nakandakare ER, Rocha JC, Morton RE, Shimabukuro AF, Quintão EC: Plasma lipoproteins from patients with poorly controlled diabetes mellitus and "in vitro" glycation of lipoproteins enhance the transfer rate of cholesteryl ester from HDL to apo-B-containing lipoproteins. Diabetologia 1997, 40(9):1085-93.
• [8]Steinbrecher UP, Witztum JL, Parthasarathy S, Steinberg D: Decrease in reactive amino groups during oxidation or endothelial cell modification of LDL. Correlation with changes in receptor-mediated catabolism. Arteriosclerosis 1987, 7(2):135.
• [9]Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 1951, 193(1):265-75.
• [10]Ferderbar S, Pereira EC, Apolinário E, Bertolami MC, Faludi A, Monte O, Calliari LE, Sales JE, Gagliardi AR, Xavier HT, Abdalla DS: Cholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus. Diabetes Metab Res Rev 2007, 23(1):35.
• [11]Peppa M, Raptis SA: Advanced glycation end products and cardiovascular disease. Curr Diabetes Rev 2008, 4(2):92.
• [12]Shibata N, Glass CK: Macrophages, Oxysterols and Atherosclerosis. Circ J 2010, 74(10):2045-51.
• [13]Adorni MP, Zimetti F, Billheimer JT, Wang N, Rader DJ, Phillips MC, Rothblat GH: The roles of different pathways in the release of cholesterol from macrophages. J Lipid Res 2007, 48(11):2453-62.
• [14]Castilho G, Philipson PB, Pinto RS, Nakandakare ER, Quintão ECR, Passarelli M: Glycoxidation reduces cholesterol biosynthesis and increases cholesterol esterification in J-774 macrophages. Diabetes 2007, 56(suppl 1):728-P.
• [15]Kritharides L, Jessup W, Mander EL, Dean RT: Apolipoprotein A-I-mediated efflux of sterols from oxidized LDL-loaded macrophage. Arterioscler Thromb Vasc Biol 1995, 15:276.
• [16]Gelissen IC, Brown AJ, Mander EL, Kritharides L, Dean RT, Jessup W: Sterol efflux is impaired from macrophage foam cells selectively enriched with 7-ketocholesterol. J Biol Chem 1996, 271(30):17852.
• [17]Jessup W, Kritharides L: Metabolism of oxidized LDL by macrophages. Curr Opin Lipidol 2000, 11(5):473-81.
• [18]Lin CY, Morel DW: Esterification of oxysterols in human serum: effects on distribution and cellular uptake. J Lipid Res 1996, 37(1):168-78.
• [19]Machado-Lima A, Iborra RT, Pinto RS, Sartori CH, Oliveira ER, Stefano JT, Nakandakare ER, Giannella-Neto D, Corrêa-Giannella L, Passarelli M: AGE-albumin induces intracellular lipid accumulation by modifying the expression of genes involved in macrophage reverse cholesterol transport and cholesterol homeostasis. Atherosclerosis 2011, 12(suppl 1):35-36-P.
• [20]Passarelli M, Tang C, McDonald TO, O'Brien KD, Gerrity RG, Heinecke JW, Oram JF: Advanced glycation end product precursors impair ABCA1-dependent cholesterol removal from cells. Diabetes 2005, 54(7):2198.
• [21]Pinto RS, Paim BA, Vercesi AE, Castilho G, Nakandakare ER, Quintão EC, Passarelli M: The reduction in hdl receptor levels in macrophages is related to ros generation induced by advanced glycated albumin. Atherosclerosys 2011, 12(suppl 1):35-P.
• [22]Valencia JV, Mone M, Koehne C, Rediske J, Hughes TE: Binding of receptor for advanced glycation end products (RAGE) ligants is not sufficient to induce inflammatory signals: lack of activity of endotoxin-free albumin-derived advanced glycation end products. Diabetologia 2004, 47(5):844.
• [23]Yehuda H, Szuchman-Sapir A, Khatib S, Musa R, Tamir S: Human atherosclerotic plaque lipid extract promotes expression of proinflammatory factors in human monocytes and macrophage-like cells. Atherosclerosis, in press.