nach oben

Diabetologia

Erschienen in:

01.02.2005 | Article

Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells

verfasst von: B. E. Brown, R. T. Dean, M. J. Davies

Erschienen in: Diabetologia | Ausgabe 2/2005

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

Previous studies have implicated the glycoxidative modification of low-density lipoprotein (LDL) by glucose and aldehydes (apparently comprising both glycation and oxidation), as a causative factor in the elevated levels of atherosclerosis observed in diabetic patients. Such LDL modification can result in unregulated cellular accumulation of lipids. In previous studies we have characterized the formation of glycated, but nonoxidized, LDL by glucose and aldehydes; in this study we examine whether glycation of LDL, in the absence of oxidation, gives rise to lipid accumulation in arterial wall cell types.

Methods

Glycated LDLs were incubated with macrophage, smooth muscle, or endothelial cells. Lipid loading was assessed by HPLC analysis of cholesterol and individual esters. Oxidation was assessed by cholesterol ester loss and 7-ketocholesterol formation. Cell viability was assessed by lactate dehydrogenase release and cell protein levels.

Results

Glycation of LDL by glycolaldehyde and methylglyoxal, but not glucose (in either the presence or absence of copper ions), resulted in cholesterol and cholesterol ester accumulation in macrophage cells, but not smooth muscle or endothelial cells. The extent of lipid accumulation depends on the degree of glycation, with increasing aldehyde concentration or incubation time, giving rise to greater extents of particle modification and lipid accumulation. Modification of lysine residues appears to be a key determinant of cellular uptake.

Conclusions/interpretation

These results are consistent with LDL glycation, in the absence of oxidation, being sufficient for rapid lipid accumulation by macrophage cells. Aldehyde-mediated “carbonyl-stress” may therefore facilitate the formation of lipid-laden (foam) cells in the artery wall.

Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820CrossRefPubMed

Eaton JW, Dean RT (2000) Diabetes and atherosclerosis. In: Dean RT, Kelly DT (eds) Atherosclerosis. Oxford University Press, Oxford, pp 24–45

Ross R, Glomset MD (1976) The pathogenesis of atherosclerosis. N Engl J Med 295:369–377

Steinberg D (1997) Oxidative modification of LDL and atherogenesis. Circulation 95:1062–1071PubMed

Li AC, Glass CK (2002) The macrophage foam cell as a target for therapeutic intervention. Nat Med 8:1235–1242

Goldstein JL, Ho YK, Basu SK, Brown MS (1979) Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U S A 76:333–337

Lopes-Virella MF, Klein RL, Virella G (1996) Modification of lipoproteins in diabetes. Diabetes Metab Rev 12:69–90

Tomkin GH, Owens D (2001) Abnormalities in Apo B-containing lipoproteins in diabetes and atherosclerosis. Diabetes Metab Res Rev 17:27–43

Lyons TJ, Jenkins AJ (1997) Lipoprotein glycation and its metabolic consequences. Curr Opin Lipidol 8:174–180

10.

Baynes JW, Thorpe SR (2000) Glycoxidation and lipoxidation in atherogenesis. Free Radic Biol Med 28:1708–1716CrossRefPubMed

11.

Kawamura M, Heinecke JW, Chait A (1994) Pathophysiological concentrations of glucose promote oxidative modification of low density lipoprotein by a superoxide-dependent pathway. J Clin Invest 94:771–778

12.

Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9PubMed

13.

Chisolm GM, Steinberg D (2000) The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med 28:1815–1826

14.

Nagai R, Hayashi CM, Xia L, Takeya M, Horiuchi S (2002) Identification in human atherosclerotic lesions of GA-pyridine, a novel structure derived from glycolaldehyde-modified proteins. J Biol Chem 277:48905–48912CrossRef

15.

Schleicher ED, Wagner E, Nerlich AG (1997) Increased accumulation of the glycoxidation product N^ε-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 99:457–468PubMed

16.

Sakata N, Imanaga Y, Meng J et al (1999) Increased advanced glycation end products in atherosclerotic lesions of patients with end-stage renal disease. Atherosclerosis 142:67–77

17.

Thornalley PJ, Langborg A, Minhas HS (1999) Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J 344:109–116

18.

Odani H, Shinzato T, Matsumoto Y, Usami J, Maeda K (1999) Increase in three α, β-dicarbonyl compound levels in human uremic plasma: specific in vivo determination of intermediates in advanced Maillard reaction. Biochem Biophys Res Commun 256:89–93

19.

Atkins TW, Thornally PJ (1989) Erythrocyte glyoxalase activity in genetically obese (ob/ob) and streptozotocin diabetic mice. Diabetes Res 11:125–129

20.

Glomb MA, Monnier VM (1995) Mechanism of protein modification by glyoxal and glycolaldehyde, reactive intermediates of the Maillard reaction. J Biol Chem 270:10017–10026

21.

Reddy S, Bichler J, Wells-Knecht KJ, Thorpe SR, Baynes JW (1995) N^ε-(carboxymethyl)lysine is a dominant advanced glycation end product (AGE) antigen in tissue proteins. Biochemistry 34:10872–10878

22.

Lopes-Virella MF, Klein RL, Lyons TJ, Stevenson HC, Witztum JL (1988) Glycosylation of low-density lipoprotein enhances cholesteryl ester synthesis in human monocyte-derived macrophages. Diabetes 37:550–557

23.

Knott HM, Brown BE, Davies MJ, Dean RT (2003) Glycation and glycoxidation of low-density lipoproteins by glucose and low-molecular mass aldehydes: formation of modified and oxidized particles. Eur J Biochem 270:3572–3582

24.

Jessup W, Simpson JA, Dean RT (1993) Does superoxide have a role in macrophage-mediated oxidative modification of LDL? Atherosclerosis 99:107–120

25.

Havel RJ, Hader HA, Bragdon JH (1955) The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest 34:1345–1353PubMed

26.

Knight BL, Soutar AK (1982) Degradation by cultured fibroblasts and macrophages of unmodified and 1,2-cyclohexanedione-modified low density lipoprotein from normal and homozygous familial hypercholesterolaemic subjects. Biochem J 202:145–152

27.

Basu SK, Goldstein JL, Anderson RGW, Brown MS (1976) Degradation of cationized low density lipoprotein and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts. Proc Natl Acad Sci U S A 73:3178–3182

28.

Kritharides L, Jessup W, Mander E, Dean RT (1995) Apolipoprotein A-1-mediated efflux of sterols from oxidised LDL-loaded macrophages. Arterioscler Thromb Vasc Biol 15:276–289

29.

Jessup W, Mander EL, Dean RT (1992) The intracellular storage and turnover of apolipoprotein B of oxidised LDL in macrophages. Biochim Biophys Acta 1126:167–177

30.

Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685PubMed

31.

Jaffe EA, Nachman RL, Becker CG, Minick CR (1973) Culture of human endothelial cells derived from umbilical veins: identification by morphologic and immunologic criteria. J Clin Invest 52:2745–2756PubMed

32.

Dean RT, Hylton W, Allison AC (1979) Induction of macrophage lysosomal enzyme secretion by agents acting at the plasma membrane. Exp Cell Biol 47:454–462

33.

Kritharides L, Jessup W, Gifford J, Dean RT (1993) A method for defining the stages of low-density lipoprotein oxidation by the separation of cholesterol- and cholesteryl ester-oxidation products using HPLC. Anal Biochem 213:79–89

34.

Brownlee M (1995) Advanced protein glycosylation in diabetes and aging. Annu Rev Med 46:223–234

35.

Sakata N, Uesugi N, Takebayashi S et al (2001) Glycoxidation and lipid peroxidation of low-density lipoprotein can synergistically enhance atherogenesis. Cardiovasc Res 49:466–475

36.

Haberland ME, Olch CL, Fogelman AM (1984) Role of lysines in mediating interaction of modified low density lipoproteins with the scavenger receptor of human monocyte macrophages. J Biol Chem 259:11305–11311

37.

Haberland ME, Fogelman AM, Edwards PA (1982) Specificity of receptor-mediated recognition of malondialdehyde-modified low density lipoproteins. Proc Natl Acad Sci U S A 79:1712–1716

38.

Bucala R, Mitchell R, Arnold K, Innerarity T, Vlassara H, Cerami A (1995) Identification of the major site of apolipoprotein B modification by advanced glycosylation end products blocking uptake by the low density lipoprotein receptor. J Biol Chem 270:10828–10832

39.

Wang X, Bucala R, Milne R (1998) Epitopes close to the apolipoprotein B low density lipoprotein receptor-binding site are modified by advanced glycation end products. Proc Natl Acad Sci U S A 95:7643–7647

40.

Thornalley PJ (1996) Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification—a role in pathogenesis and antiproliferative chemotherapy. Gen Pharmacol 27:565–573

41.

Sakurai T, Kimura S, Nakano M, Kimura H (1991) Oxidative modification of glycated low density lipoprotein in the presence of iron. Biochem Biophys Res Commun 177:433–439

42.

Kobayashi K, Watanabe J, Umeda F, Nawata H (1995) Glycation accelerates the oxidation of low density lipoprotein by copper ions. Endocr J 42:461–465

43.

Schalkwijk CG, Vermeer MA, Stehouwer CD, te Koppele J, Princen HM, van Hinsbergh VW (1998) Effect of methylglyoxal on the physico-chemical and biological properties of low-density lipoprotein. Biochim Biophys Acta 1394:187–198

44.

Lo TW, Westwood ME, McLellan AC, Selwood T, Thornalley PJ (1994) Binding and modification of proteins by methylglyoxal under physiological conditions: a kinetic and mechanistic study with N-alpha-acetylarginine, N-alpha-acetylcysteine, and N-alpha-acetyllysine, and bovine serum albumin. J Biol Chem 269:32299–32305

45.

Degenhardt TP, Thorpe SR, Baynes JW (1998) Chemical modification of proteins by methylglyoxal. Cell Mol Biol (Noisy-le-grand) 44:1139–1145

46.

Nagai R, Matsumoto K, Ling X, Suzuki H, Araki T, Horiuchi S (2000) Glycolaldehyde, a reactive intermediate for advanced glycation end products, plays an important role in the generation of an active ligand for the macrophage scavenger receptor. Diabetes 49:1714–1723PubMed

47.

Boscoboinik DO, Chatelain E, Bartoli G-M, Stauble B, Azzi A (1994) Inhibition of protein kinase c activity and vascular smooth muscle cell growth by d-α-tocopherol. Biochim Biophys Acta 1224:418–426

48.

Tasinato A, Boscoboinik D, Bartoli G-M, Maroni P, Azzi A (1995) d-α-Tocopherol inhibition of vascular smooth muscle cell proliferation occurs at physiological concentrations, correlates with protein kinase c inhibition, and is independent of its antioxidant properties. Proc Natl Acad Sci U S A 92:12190–12194

49.

Guyton JR, Klemp KF (1994) Development of the atherosclerotic core region: chemical and ultrastructural analysis of microdissected atherosclerotic lesions from human aorta. Arterioscler Thromb 14:1305–1314

50.

Esterbauer H, Gebicki J, Puhl H, Jurgens G (1992) The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med 13:341–390

51.

Tabas I (1999) Non-oxidative modifications of lipoproteins in atherogenesis. Annu Rev Nutr 19:123–139

52.

Steinbrecher UP, Witztum JL (1984) Glucosylation of low-density lipoproteins to an extent comparable to that seen in diabetes slows their catabolism. Diabetes 33:130–134

53.

Lyons TJ, Klein RL, Baynes JW, Stevenson HC, Lopes-Virella MF (1987) Stimulation of cholesteryl ester synthesis in human monocyte-derived macrophages by low-density lipoproteins from type 1 (insulin-dependent) diabetic patients: the influence of non-enzymatic glycosylation of low-density lipoproteins. Diabetologia 30:916–923

Titel: Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells
verfasst von: B. E. Brown
R. T. Dean
M. J. Davies
Publikationsdatum: 01.02.2005
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 2/2005
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-004-1648-4

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

„Überwältigende“ Evidenz für Tripeltherapie beim metastasierten Prostata-Ca.

22.05.2024 Prostatakarzinom Nachrichten

Patienten mit metastasiertem hormonsensitivem Prostatakarzinom sollten nicht mehr mit einer alleinigen Androgendeprivationstherapie (ADT) behandelt werden, mahnt ein US-Team nach Sichtung der aktuellen Datenlage. Mit einer Tripeltherapie haben die Betroffenen offenbar die besten Überlebenschancen.

So sicher sind Tattoos: Neue Daten zur Risikobewertung

22.05.2024 Melanom Nachrichten

Das größte medizinische Problem bei Tattoos bleiben allergische Reaktionen. Melanome werden dadurch offensichtlich nicht gefördert, die Farbpigmente könnten aber andere Tumoren begünstigen.

CAR-M-Zellen: Warten auf das große Fressen

22.05.2024 Onkologische Immuntherapie Nachrichten

Auch myeloide Immunzellen lassen sich mit chimären Antigenrezeptoren gegen Tumoren ausstatten. Solche CAR-Fresszell-Therapien werden jetzt für solide Tumoren entwickelt. Künftig soll dieser Prozess nicht mehr ex vivo, sondern per mRNA im Körper der Betroffenen erfolgen.

Frühzeitige HbA1c-Kontrolle macht sich lebenslang bemerkbar

22.05.2024 Typ-2-Diabetes Nachrichten

Menschen mit Typ-2-Diabetes von Anfang an intensiv BZ-senkend zu behandeln, wirkt sich positiv auf Komplikationen und Mortalität aus – und das offenbar lebenslang, wie eine weitere Nachfolgeuntersuchung der UKPD-Studie nahelegt.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2005

Determinants of subclinical diabetic heart disease

Genetic testing for maturity onset diabetes of the young: uptake, attitudes and comparison with hereditary non-polyposis colorectal cancer

To the Editor

Low subcutaneous thigh fat is a risk factor for unfavourable glucose and lipid levels, independently of high abdominal fat. The Health ABC Study

mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes