Atherogenese bei Adipositas

Zusammenfassung

Bei Adipositaspatienten finden sich abnorme Plasmalipoproteine, die in der Zirkulation persistieren und in der Gefäßwand leicht zu inflammatorisch wirksamen Partikeln modifiziert werden können. Sie tragen wahrscheinlich wesentlich zu der Entstehung und schnellen Progression der Atherosklerose bei diesen Patienten bei. Hierzu zählen VLDL und Chylomikronen-Remnant-Partikel, small dense LDL, sowie glykierte LDL. Die bei Adipositas auftretenden abnormen Lipoproteine sind leicht oxidierbar, sie zeigen eine erhöhte Affinität zu den Scavenger-Rezeptoren der Makrophagen und induzieren eine chronische Inflammation der Gefäßwand. Als Surrogatmarker für die Konzentrationsbestimmung atherogener Lipoproteine bei Adipositas und die erhöhten Triglyzeridkonzentrationen kann heute die Apolipoprotein-B-Plasmakonzentration herangezogen werden. Die klinische Wertigkeit einer isolierten Bestimmung der besonders atherogenen small dense LDL wird zurzeit mit einem neuen homogenen Messverfahren untersucht. Der klinische Nutzen einer Bestimmung glykierter LDL für die Risikoeinschätzung der Atherosklerose bleibt abzuwarten. Es bleibt abschließend festzuhalten, dass bei Adipositaspatienten eine Reihe abnormer Lipoproteine mit besonders atherogenen Eigenschaften auftreten können. Therapeutische Strategien in der Behandlung der Adipositas müssen daher immer auch eine Normalisierung der Dyslipid ämie und eine möglichst vollständige Reduktion der abnormen Lipoproteine einschließen.

Summary

Patients suffering from adiposity show hypertriglyceridemia, low HDL and abnormal plasma lipoprotein particles, which contribute to the fast progression atherosclerosis. The lipoprotein metabolism in adiposity is frequently characterized by the appearance of cholesterol enriched small dense Low Density Lipoproteins (sdLDL), glycated LDL and the persistence of VLDL and chylomicron remnant particles in the circulation. The abnormal lipoproteins show reduced resistance to oxidation. They are bound with high affinity to scavenger receptors of macrophages. They show specific atherogenic properties and enhance the inflammatory process in the arterial wall. Therefore, abnormal plasma lipoproteins associated with adiposity increase the risk for coronary heart disease, stroke and peripheral atherosclerosis. There is still a debate, which plasma lipid marker predict best the coronary risk in adiposity and metabolic syndrome. Apolipoprotein B levels may be used as a surrogate marker for all atherogenic lipoproteins. A more specific approach may be the quantification of small dense LDL cholesterol levels using novel high-throughput assays. The clinical utility of glycated LDL analysis is still unclear. In summary, abnormal lipoproteins are strongly involved in the progression of atherosclerosis in patients with adiposity. Strategies of adiposity treatment should include the normalization of lipoprotein abnormalities in this high risk patient group.

Schlüsselwörter

sdLDL - Remnants - glykierte LDL - Atherosklerose - LDL-Oxidation - Adipositas - Inflammation

Keywords

sdLDL - remnants - glycated LDL - atherosclerosis - adiposity - LDL-oxidation - inflammation

• Literatur

• 1 Tabas I. et al. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007; 116: 1832-1844.
• 2 Eckel RH. et al. The metabolic syndrome. Lancet 2005; 365: 1415-1428.
• 3 Expert panel on detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-2498.
• 4 Ginsberg H. New perspectives on atherogenesis: role of abnormal trigyceride-rich lipoprotein metabolism. Circulation 2002; 106: 2137-2142.
• 5 Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 1995; 15: 551-561.
• 6 Chait A, Heinecke JW. Lipoprotein modification: cellular mechanisms. Curr Opin Lipidol 1994; 05: 365-370.
• 7 Bhakdi S. et al. On the pathogenesis of atherosclerosis: enzymatic transformation of human low density lipoprotein to an atherogenic moiety. J Exp Med 1995; 182: 1959-1971.
• 8 Goldstein JL. et al. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U SA 1979; 76: 333-337.
• 9 Krieger M. et al. Molecular flypaper, host defense, and atherosclerosis. Structure, binding properties, and functions of macrophage scavenger receptors. J Biol Chem 1993; 268: 4569-4572.
• 10 Tirosh A. et al. Changes in triglyceride levels and risk for coronary heart disease in young men. Ann Intern Med 2007; 147: 377-385.
• 11 Chung BH. et al. Liposome-like particles isolated from human athersosclerotic plaques are structurally similar to surface remnants of triglyceride-rich lipoproteins, Arterioscler Thromb Vasc Res. 1994; 14: 622-635.
• 12 Karpe F. et al. Remnant-like particle cholesterol concentrationand progression of coronary and vein-graft atherosclerosis in response to gemfibrozil treatment. Atherosclerosis 2001; 157: 181-187.
• 13 Galeano NF. et al. Apoprotein B structure and receptor recognition of triglyceride-rich low density lipoprotein (LDL) is modified in small dense LDL but not in triglyceride-rich LDL of normal size. J Biol Chem 1994; 269: 511-519.
• 14 De Graaf J. et al. Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. Arterioscler Thromb Vasc Res 1991; 11: 298-306.
• 15 Otvos JD. et al. Low density lipoprotein and high density lipoprotein paricle subclasses predict coronary events and are favourably changed by gemfibrizil therapy in the Veterans Affaires Kigh Density Lipoprotein Intervention trial. Circulation 2006; 113: 1566-1563.
• 16 Stalenhoef AJ, de Graaf J. Association of fasting and nonfasting serum triglycerides with cardiovascular disease and the role of remnant-like lipoproteins and small dense LDL. Curr Opin Lipidology 2008; 19: 355-361.
• 17 Tames FJ. et al. Nonenzymatic glycation of apolipoprotein B in the sera of diabetic and nondiabetic subjects. Atherosclerosis 1992; 93: 237-244.
• 18 Akanji AO. et al. Determinants of glycated LDL levels in nondiabetic and diabetic hyperlipidemia patients in Kuwait. Clin Cim Acta 2002; 317: 171-176.
• 19 Younis N. et al. Glycation as an atherogenic modification of LDL. Curr Opin Lipidology 2008; 19: 378-384.
• 20 Imanaga Y. et al. In vivo and in vitro evidence for the glycoxidation of lowipoprotein in human atherosclerotic plaque. Atherosclerosis 2000; 150: 343-355.
• 21 Steinberg D. et al. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320: 915-924.
• 22 Nagy L. et al. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 1998; 93: 229-240.
• 23 Tsimikas S, Witztum JL. The role of oxidited phospholipids in mediating lipoprotein (a) atherogenecity. Curr Opin Lipidology 2008; 19: 369-377.
• 24 Krieger M. The other side of scavenger receptors: pattern recognition for host defense. Curr Opin Lipidol 1997; 08: 275-280.
• 25 Endemann G. et al. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem 1993; 268: 11811-1186.
• 26 Li AC, Glass CK. PPAR-and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res 2004; 45: 2161-2173.
• 27 Teupser D. et al. Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDL-receptor deficient mice. Arterioscler Thromb Vasc Biol 2008; 28: 2009-2015.
• 28 Teupser D. et al. Expression of vascular cell adhesion molecule-1 (VCAM-1) in the aortae of hypercholesterolemic rabbits with high (HAR) and low (LAR) atherosclerotic response. Atherosclerosis 1997; 128: 157-164.
• 29 Cushing SD. et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A 1990; 87: 5134-5138.
• 30 Terkeltaub R. et al. Chemokines and atherosclerosis. Curr Opin Lipidol 1998; 09: 397-405.
• 31 Kruth HS. The fate of lipoprotein cholesterol entering the arterial wall. Curr Opin Lipidol 1997; 08: 246-252.
• 32 Stiko-Rahm A. et al. Native and oxidized LDL enhances production of PDGF AA and the surface expression of PDGF receptors in cultured human smooth muscle cells. Arterioscler Thromb 1992; 12: 1099-1109.
• 33 Ohlsson BG. et al. Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-kappaB to DNA and the subsequent expression of tumor necrosis factor-alpha and interleukin-1beta in macrophages. J Clin Invest 1996; 98: 78-89.
• 34 Shibata N, Glass CK. Regulation of macrophage function in inflammation and atherosclerosis. J Lipid Res 2009; 50 (Suppl.): S277-S281.
• 35 Lusis AJ. et al. Genetic basis of atherosclerosis: part I: new genes and pathways. Circulation 2004; 110 (13) 1868-1873.