Increased LCAT activity and hyperglycaemia decrease the antioxidative functionality of HDL
Paul J. W. H. Kappelle
Department of Endocrinology
These authors contributed equally to this study.
Search for more papers by this authorJan Freark de Boer
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases
These authors contributed equally to this study.
Search for more papers by this authorFrank G. Perton
Laboratory Center, University Medical Center Groningen, University of Groningen, Groningen
Search for more papers by this authorWijtske Annema
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases
TI Food and Nutrition, Wageningen, The Netherlands
Search for more papers by this authorRobin P. F. Dullaart
Department of Endocrinology
These authors contributed equally to this study.
Search for more papers by this authorUwe J. F. Tietge
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases
TI Food and Nutrition, Wageningen, The Netherlands
These authors contributed equally to this study.
Search for more papers by this authorPaul J. W. H. Kappelle
Department of Endocrinology
These authors contributed equally to this study.
Search for more papers by this authorJan Freark de Boer
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases
These authors contributed equally to this study.
Search for more papers by this authorFrank G. Perton
Laboratory Center, University Medical Center Groningen, University of Groningen, Groningen
Search for more papers by this authorWijtske Annema
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases
TI Food and Nutrition, Wageningen, The Netherlands
Search for more papers by this authorRobin P. F. Dullaart
Department of Endocrinology
These authors contributed equally to this study.
Search for more papers by this authorUwe J. F. Tietge
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases
TI Food and Nutrition, Wageningen, The Netherlands
These authors contributed equally to this study.
Search for more papers by this authorAbstract
Eur J Clin Invest 2012; 42 (5): 487–495
Background Type 2 diabetes mellitus increases the risk of atherosclerotic cardiovascular disease. Antioxidative properties of high density lipoprotein (HDL) are important for atheroprotection. This study investigated whether the antioxidative functionality of HDL is altered in type 2 diabetes mellitus and aimed to identify potential determinants of this parameter.
Materials and methods In a cross-sectional study, we investigated 74 patients with type 2 diabetes and 75 control subjects. Antioxidative properties of HDL were measured and expressed as either (i) HDL antioxidative capacity or (ii) HDL antioxidation index after multiplying HDL antioxidative capacity results with individual plasma HDL cholesterol concentrations. Lecithin:cholesterol acyltransferase (LCAT) and paraoxonase-1 (PON-1) activities were determined.
Results HDL antioxidative capacity was similar in patients with diabetes and controls, while the HDL antioxidation index was decreased in patients with diabetes (P = 0·005) owing to lower plasma HDL cholesterol (P < 0·001). LCAT activity was higher and PON-1 activity lower in type 2 diabetes mellitus (each P < 0·001). In the combined subjects, HDL antioxidative capacity was inversely related to LCAT activity (P < 0·01). The HDL antioxidation index correlated negatively with blood glucose (P < 0·001), HbA1c and LCAT activity (each P < 0·01), and positively with PON-1 activity (P < 0·01). Multiple linear regression analysis demonstrated that high LCAT activity was associated with both decreased HDL antioxidation capacity (P < 0·05) and index (P < 0·001) independent of diabetes status, glycaemic control and PON-1.
Conclusions Overall, the antioxidative functionality of HDL is impaired in type 2 diabetes mellitus mostly because of lower HDL cholesterol. Hyperglycaemia, increased LCAT activity and lower PON-1 activity likely contribute to impaired antioxidative functionality of HDL.
References
- 1 Assmann G, Gotto AM Jr. HDL cholesterol and protective factors in atherosclerosis. Circulation 2004; 109: III8–14.
- 2 Linsel-Nitschke P, Tall AR. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov 2005; 4: 193–205.
- 3 deGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Coll Cardiol 2008; 51: 2199–211.
- 4 Corsetti JP, Zareba W, Moss AJ, Rainwater DL, Sparks CE. Elevated HDL is a risk factor for recurrent coronary events in a subgroup of non-diabetic postinfarction patients with hypercholesterolemia and inflammation. Atherosclerosis 2006; 187: 191–7.
- 5 Corsetti JP, Gansevoort RT, Sparks CE, Dullaart RP. Inflammation reduces HDL protection against primary cardiac risk. Eur J Clin Invest 2010; 40: 483–9.
- 6 Ansell BJ, Fonarow GC, Fogelman AM. The paradox of dysfunctional high-density lipoprotein. Curr Opin Lipidol 2007; 18: 427–34.
- 7 Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev 2006; 58: 342–74.
- 8 Dixon JB. The effect of obesity on health outcomes. Mol Cell Endocrinol 2010; 316: 104–8.
- 9 Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 2008; 371: 1800–9.
- 10 Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375: 2215–22.
- 11 Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002; 287: 2570–81.
- 12 Njajou OT, Kanaya AM, Holvoet P, Connelly S, Strotmeyer ES, Harris TB et al. Association between oxidized LDL, obesity and type 2 diabetes in a population-based cohort, the Health, Aging and Body Composition Study. Diabetes Metab Res Rev 2009; 25: 733–9.
- 13 Scanu AM, Edelstein C. HDL: bridging past and present with a look at the future. FASEB J 2008; 22: 4044–54.
- 14 Mackness M, Durrington P, Mackness B. Paraoxonase 1 activity, concentration and genotype in cardiovascular disease. Curr Opin Lipidol 2004; 15: 399–404.
- 15 Borggreve SE, De Vries R, Dullaart RP. Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins. Eur J Clin Invest 2003; 33: 1051–69.
- 16 Navab M, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Fogelman AM. HDL as a biomarker, potential therapeutic target, and therapy. Diabetes 2009; 58: 2711–7.
- 17 Kontush A, Chapman MJ. Why is HDL functionally deficient in type 2 diabetes? Curr Diab Rep 2008; 8: 51–9.
- 18 Simera I, Moher D, Hoey J, Schulz KF, Altman DG. A catalogue of reporting guidelines for health research. Eur J Clin Invest 2010; 40: 35–53.
- 19 WHO. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia. http://www.who.int/diabetes/publications/en/ 2006.
- 20 Tietge UJF, Pratico D, Ding T, Funk CD, Hildebrand RB, Van Berkel T et al. Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress. J Lipid Res 2005; 46: 1604–14.
- 21 Nijstad N, de Boer JF, Lagor WR, Toelle M, Usher D, Annema W et al. Overexpression of apolipoprotein O does not impact on plasma HDL levels or functionality in human apolipoprotein A-I transgenic mice. Biochim Biophys Acta 2011; 1811: 294–9.
- 22 Dullaart RP, Perton F, Sluiter WJ, de Vries R, van Tol A. Plasma lecithin: cholesterol acyltransferase activity is elevated in metabolic syndrome and is an independent marker of increased carotid artery intima media thickness. J Clin Endocrinol Metab 2008; 93: 4860–6.
- 23 Dullaart RP, Perton F, van der Klauw MM, Hillege HL, Sluiter WJ. High plasma lecithin:cholesterol acyltransferase activity does not predict low incidence of cardiovascular events: possible attenuation of cardioprotection associated with high HDL cholesterol. Atherosclerosis 2010; 208: 537–42.
- 24 Albers JJ, Chen CH, Adolphson JL. Lecithin:cholesterol acyltransferase (LCAT) mass; its relationship to LCAT activity and cholesterol esterification rate. J Lipid Res 1981; 22: 1206–13.
- 25 Dullaart RP, de Vries R, Sluiter WJ, Voorbij HA. High plasma C-reactive protein (CRP) is related to low paraoxonase-I (PON-I) activity independently of high leptin and low adiponectin in type 2 diabetes mellitus. Clin Endocrinol (Oxf) 2009; 70: 221–6.
- 26 Nobecourt E, Jacqueminet S, Hansel B, Chantepie S, Grimaldi A, Chapman MJ et al. Defective antioxidative activity of small dense HDL3 particles in type 2 diabetes: relationship to elevated oxidative stress and hyperglycaemia. Diabetologia 2005; 48: 529–38.
- 27 Gowri MS, Van der Westhuyzen DR, Bridges SR, Anderson JW. Decreased protection by HDL from poorly controlled type 2 diabetic subjects against LDL oxidation may be due to the abnormal composition of HDL. Arterioscler Thromb Vasc Biol 1999; 19: 2226–33.
- 28 Hoang A, Murphy AJ, Coughlan MT, Thomas MC, Forbes JM, O’Brien R et al. Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties. Diabetologia 2007; 50: 1770–9.
- 29 Nobecourt E, Tabet F, Lambert G, Puranik R, Bao S, Yan L et al. Nonenzymatic glycation impairs the antiinflammatory properties of apolipoprotein A-I. Arterioscler Thromb Vasc Biol 2010; 30: 766–72.
- 30 Lambert G, Sakai N, Vaisman BL, Neufeld EB, Marteyn B, Chan CC et al. Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice. J Biol Chem 2001; 276: 15090–8.
- 31 Ng DS, Maguire GF, Wylie J, Ravandi A, Xuan W, Ahmed Z et al. Oxidative stress is markedly elevated in lecithin:cholesterol acyltransferase-deficient mice and is paradoxically reversed in the apolipoprotein E knockout background in association with a reduction in atherosclerosis. J Biol Chem 2002; 277: 11715–20.
- 32 Berard AM, Foger B, Remaley A, Shamburek R, Vaisman BL, Talley G et al. High plasma HDL concentrations associated with enhanced atherosclerosis in transgenic mice overexpressing lecithin-cholesteryl acyltransferase. Nat Med 1997; 3: 744–9.
- 33 Furbee JW Jr, Parks JS. Transgenic overexpression of human lecithin: cholesterol acyltransferase (LCAT) in mice does not increase aortic cholesterol deposition. Atherosclerosis 2002; 165: 89–100.
- 34 Mehlum A, Gjernes E, Solberg LA, Hagve TA, Prydz H. Overexpression of human lecithin:cholesterol acyltransferase in mice offers no protection against diet-induced atherosclerosis. Apmis 2000; 108: 336–42.
- 35 Mehlum A, Muri M, Hagve TA, Solberg LA, Prydz H. Mice overexpressing human lecithin: cholesterol acyltransferase are not protected against diet-induced atherosclerosis. Apmis 1997; 105: 861–8.
- 36 Brousseau ME, Santamarina-Fojo S, Vaisman BL, Applebaum-Bowden D, Berard AM, Talley GD et al. Overexpression of human lecithin:cholesterol acyltransferase in cholesterol-fed rabbits: LDL metabolism and HDL metabolism are affected in a gene dose-dependent manner. J Lipid Res 1997; 38: 2537–47.
- 37 Furbee JW Jr, Sawyer JK, Parks JS. Lecithin:cholesterol acyltransferase deficiency increases atherosclerosis in the low density lipoprotein receptor and apolipoprotein E knockout mice. J Biol Chem 2002; 277: 3511–9.
- 38 Calabresi L, Pisciotta L, Costantin A, Frigerio I, Eberini I, Alessandrini P et al. The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families. Arterioscler Thromb Vasc Biol 2005; 25: 1972–8.
- 39 Kuivenhoven JA, Pritchard H, Hill J, Frohlich J, Assmann G, Kastelein J. The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res 1997; 38: 191–205.
- 40 Hovingh GK, Hutten BA, Holleboom AG, Petersen W, Rol P, Stalenhoef A et al. Compromised LCAT function is associated with increased atherosclerosis. Circulation 2005; 112: 879–84.
- 41 Calabresi L, Baldassarre D, Castelnuovo S, Conca P, Bocchi L, Candini C et al. Functional lecithin: cholesterol acyltransferase is not required for efficient atheroprotection in humans. Circulation 2009; 120: 628–35.
- 42 Holleboom AG, Kuivenhoven JA, Vergeer M, Hovingh GK, van Miert JN, Wareham NJ et al. Plasma levels of lecithin:cholesterol acyltransferase and risk of future coronary artery disease in apparently healthy men and women: a prospective case-control analysis nested in the EPIC-Norfolk population study. J Lipid Res 2010; 51: 416–21.
- 43 Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation 2003; 108: 2034–40.
- 44 Vohl MC, Neville TA, Kumarathasan R, Braschi S, Sparks DL. A novel lecithin-cholesterol acyltransferase antioxidant activity prevents the formation of oxidized lipids during lipoprotein oxidation. Biochemistry 1999; 38: 5976–81.
- 45 Podrez EA. Anti-oxidant properties of high-density lipoprotein and atherosclerosis. Clin Exp Pharmacol Physiol 2010; 37: 719–25.