#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Atherogenic Dyslipidemia and the Metabolic Syndrome: Pathophysiological Mechanisms


Authors: A. Žák;  A. Slabý
Authors‘ workplace: IV. interní klinika 1. LF UK a VFN, Praha
Published in: Čas. Lék. čes. 2008; 147: 459-470
Category: Review Article

Overview

Atherogenic dyslipidemia (ADL), a frequent metabolic derangement found in patients with manifest atherosclerosis, is characterized by hypertriglyceridemia, low plasma HDL cholesterol and prevalence of small dense LDL particles. The key pathogenetic mechanisms of ADL are closely linked to insulin resistance, the lack of appropriate responses to insulin in peripheral cells, especially in adipose tissue, skeletal muscles and liver. Impaired insulin signalling leads to a decreased suppression of lipolysis, defective fat storage in adipocytes, and increased flux of free fatty acids to the liver, which together with posttranslational stabilization of apolipoprotein B enhances the assembly and secretion of VLDL particles. Decreased activity of lipoprotein lipase contributes to slow clearance of triglyceride-rich particles, with negative consequences in LDL metabolism. Impaired HDL synthesis, intravascular remodelling, and catabolism decreases reverse cholesterol transport from peripheral tissues, hepatocytes and macrophages. Small dense LDL particles are considered to be highly atherogenic, due to increased penetration of arterial intima, and decreased antioxidant capacity. Better understanding of pathophysiological mechanisms involved in ADL could promote new therapeutic methods, as well as increase the compliance with essential lifestyle interventions.

Key words:
atherogenic dyslipidemia, insulin resistance, hypertriglyceridemia, reverse cholesterol transport, low-density lipoprotein size.


Sources

1. Superko, H. R.: Beyond LDL cholesterol reduction. Circulation, 1996, 94, s. 2351–2354.

2. Petersen, K. F., Shulman, G. I.: Etiology of insulin resistance. Am. J. Med, 2006, 119 (Suppl. 5A), s. 10S–16S.

3. Laakso, M.: Gene variants, insulin resistance, and dyslipidaemia. Curr. Opin. Lipidol., 2004, 15, s. 115–120.

4. Miranda, P. J., DeFronzo, R. A., Califf, R. M. et al.: Metabolic syndrome: Definition, pathophysiology, and mechanisms. Am. Heart J., 2005, 149, s. 33–45.

5. Le Roith, D., Zick, Y.: Recent advances in our understanding of insulin action and insulin resistance. Diabetes Care, 2001, 24, s. 588–597.

6. Cusi, K., Maezono, K., Osman, A. et al.: Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J. Clin. Invest., 2000, 105, s. 311–320.

7. Avramoglu, R. K., Basciano, H., Adeli, K.: Lipid and lipoprotein dysregulation in insulin resistant states. Clin. Chim. Acta, 2006, 368, s. 1–19.

8. Lewis, G. F., Carpentier, A., Adeli, K. et al.: Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr. Rev, 2002, 23, s. 201–229.

9. Gregor, M. F., Hotamisligil, G. S.: Thematic review series: Adipocyte biology: The endoplasmic reticulum and metabolic disease. J. Lipid Res., 2007, 48, s. 1905–1914.

10. Sharma, A. M.: The obese patient with diabetes mellitus: From research targets to treatment options. Am. J. Med., 2006, 119 (Suppl. 5A), s. 17S–23S.

11. Fisler, J. S., Warden, C. H.: Uncoupling proteins, dietary fat and the metabolic syndrome. Nutr. Metab., 2006, 3, 38, doi:10.1186/1743-7075-3-38.

12. Lara-Castro, C., Luo, N., Wallace, P. et al.: Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes, 2006, 55, s. 249–259.

13. Bouloumié, A., Curat, C. A., Sengenés, C. et al.: Role of macrophage tissue infiltration in metabolic diseases. Curr. Opin. Clin. Nutr. Metab. Care, 2005, 8, s. 347–354.

14. Sonnenberg, G. E., Krakower, G. R., Kissebah, A. H.: A novel pathway to the manifestations of metabolic syndome. Obes. Res., 2004, 12, s. 180–186.

15. Hokanson, J. E., Austin, M. A.: Plasma triglyceride level is a risk factor for cardiovascular disease independent of high density lipoprotein cholesterol level: A meta-analysis of population-based prospective studies. J. Cardiovasc. Risk, 1996, 3, s. 213–219.

16. Adeli, K., Taghibiglou, C., Van Iderstine, S. C. et al.: Mechanisms of hepatic very low-density lipoprotein overproduction. Trends Cardiovasc. Med., 2001, 11, s. 170–176.

17. Chan, D. C., Barrett, P. H., Watts, G. F.: Recent studies of lipoprotein kinetics in the metabolic syndrome and related disorders. Curr. Opin. Lipidol., 2006, 17, s. 28–36.

18. Krauss, R. M., Siri, P. W.: Metabolic abnormalities: Triglyceride and low-density lipoprotein. Endocrinol. Metab. Clin. North Am., 2004, 33, s. 405–415.

19. Ginsberg, H. N., Zhang, Y.-L., Hernandez-Ono, A.: Metabolic syndrome: Focus on dyslipidemia. Obesity, 2006, 14 (Suppl.), s. 41S–49S.

20. Rangan, V. S., Smith, S.: Fatty acid synthesis in eukaryotes. In: Biochemistry of lipids, lipoproteins and membrane. Vance, D. E. Vance, J. E. (eds.), 4th ed. Amsterdam, Elsevier Science B. V., 2002, s. 151–179.

21. Olivecrona, T., Bergo, M., Hultin, M. et al.: Nutritional regulation of lipoprotein lipase. Can. J. Cardiol., 1995, 11 (Suppl.), s. 73G–78G.

22. Chan, D. C., Barrett, P. H., Watts, G. F.: Lipoprotein transport in the metabolic syndrome: Pathophysiological and interventional studies employing stable isotopy and modelling metods. Clin. Sci., 2004, 107, s. 233–249.

23. Deeb, S. S., Zambon, A., Carr, M. C. et al.: Hepatic lipase and dyslipidemia: Interactions among genetic variants, obesity, gender, and diet. J. Lipid Res., 2003, 44, s. 1279–1286.

24. Lewis, G. F., Rader, D. J.: New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ. Res., 2005, 96, s. 1221–1232.

25. Després, J. P., Lemieux, I., Dagenais, G. R. et al.: HDL-cholesterol as a marker of coronary heart disease risk: The Quebec Cardiovascular Study. Atherosclerosis, 2000, 153, s. 263–272.

26. Gotto, A. M., Pownall, H. J.: Manual of Lipid Disorders. 3rd ed. Philadelphia, Lippincott, Williams & Wilkins, 2003.

27. Malik, S.: Transcriptional regulation of the apolipoprotein AI gene. Front. Biosci., 2003, 8, s. d360–d368.

28. Horowitz, B. S., Goldberg, I. J., Merab, J. et al.: Increased plasma and renal clearance of an exchangeable pool of apolipoprotein A-I in subjects with low levels of high density lipoprotein cholesterol. J. Clin. Invest., 1993, 91, s. 1743–1752.

29. Rye, K. A., Bright, R., Psaltis, M. et al.: Regulation of reconstituted high density lipoprotein structure and remodeling by apolipoprotein E. J. Lipid Res., 2006, 47, s. 1025–1036.

30. Jahangiri, A., Rader, D. J., Marchadier, D. et al.: Evidence that endothelial lipase remodels high density lipoproteins without mediating the dissociation of apolipoprotein A-I. J. Lipid Res., 2005, 46, s. 896–903.

31. Murakami, M., Kudo, I.: New phospholipase A(2) isozymes with a potential role in atherosclerosis. Curr. Opin. Lipidol., 2003, 14, s. 431–436.

32. Hammad, S.M., Barth, J. L., Knaak, C. et al.: Megalin acts in concert with cubilin to mediate endocytosis of high density lipoproteins. J. Biol. Chem., 2000, 275, s. 12003–12008.

33. Rothblat, G. H., Llera-Moya, M., Atger, V. et al.: Cell cholesterol efflux: Integration of old and new observations provides new insights. J. Lipid. Res., 1999, 40, s. 781–796.

34. Schwartz, C. C., VandenBroek, J. M., Cooper, P. S.: Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J. Lipid. Res., 2004, 45, s. 1594–1607.

35. Wadham, C., Albanese, N., Roberts, J. et al.: High-density lipoproteins neutralize C-reactive protein proinflammatory activity. Circulation, 2004, 109, s. 2116–2122.

36. Barter, P. J., Puranik, R., Rye, K. A.: New insights into the role of HDL as an anti-inflammatory agent in the prevention of cardiovascular disease. Curr. Cardiol. Rep., 2007, 9, s. 493–498.

37. Lamarche, B. A., St-Pierre, A. C., Ruel, I. L. et al.: A prospective, population-based study of low density lipoprotein particle size as a risk factor for ischemic heart disease in men. Can. J. Cardiol., 2001, 17, s. 859–865.

38. Sevanian, A., Hwang, J., Hodis, H. et al.: Contribution of an in vivo oxidized LDL to LDL oxidation and its association with dense LDL subpopulations. Arteioscler. Thromb. Vasc. Biol., 1996, 16, s. 784–793.

39. Davidsson, P., Hulthe, J., Fagerberg, B. et al.: A proteomic study of the apolipoproteins in LDL subclasses in patients with the metabolic syndrome and type 2 diabetes. J. Lipid Res., 2005, 46, s. 1999–2006.

40. Berneis, K. K., Krauss, R. M.: Metabolic origins and clinical significance of LDL heterogeneity. J. Lipid Res., 2002, 43, s. 1363–1379.

41. Vessby, B.: Dietary fat, fatty acid composition in plasma and the metabolic syndrome. Curr. Opin. Lipidol., 2003, 14, s. 15–19.

42. Warensjö, E., Sundström, J., Lind, L. et al.: Factor analysis of fatty acids in serum lipids as a measure of dietary fat quality in relation to the metabolic syndrome in men. Am. J. Clin. Nutr., 2006, 84, s. 442–448.

43. Žák, A., Vecka, M., Tvrzická, E. et al.: Složení esterifikovaných mastných kyselin a lipoperoxidace u metabolického syndromu. Čas. Lék. čes., 2007, 146, s. 484–491.

44. Evans, J. L., Goldfine, I. D., Maddux, B. A. et al.: Oxidative stress and stress-activated signaling pathways: A unifying hypothesis of type 2 diabetes. Endocrine Rev., 2002, 23, s. 599–622.

45. Laaksonen, D. E., Lakka, T. A., Lakka, H.-M. et al.: Serum fatty acid composition predicts development of impaired fasting glycaemia and diabetes in middle-aged men. Diabet. Med., 2002, 19, s. 456–464.

46. Leskinen, M. H., Solakivi, T., Kunnas, T. et al.: Serum fatty acids in postinfarction middle-aged men. Scand. J. Clin. Lab. Med., 2005, 65, s. 485–490.

47. Decsi, T., Csábi, G., Török, K. et al.: Polyunsaturated fatty acids in plasma lipids of obese children with and without metabolic cardiovascular syndrome. Lipids, 2000, 35, s. 1179–1184.

48. Klein-Platat, C., Drai, J., Oujaa, M. et al.: Plasma fatty acid composition is associated with the metabolic syndrome and low grade inflammation in overweight adolescents. Am. J. Clin. Nutr., 2005, 82, s. 1178–1184.

49. Simonen, P. P., Gylling, H., Miettinen, T. A.: Introducing a new component of the metabolic syndrome: low cholesterol absorption. Am. J. Clin. Nutr., 2000, 72, s. 82–88.

50. Simonen, P. P., Gylling, H., Miettinen, T. A.: Body weight modulates cholesterol metabolism in non-insulin dependent type 2 diabetics. Obesity Res., 2002, 5, s. 328–335.

51. Gylling, H., Tuominen, J. A., Koivisto, V. A. et al.: Cholesterol metabolism in type 1 diabetes. Diabetes, 2004, 53, s. 2217–2222.

52. Haffner, S. M.: Risk constellations in patients with the metabolic syndrome: Epidemiology, diagnosis, and treatment patterns. Am. J. Med., 2006, 119 (Suppl. 5A), s. 3S–9S.

53. Richardi, G., Giacco, R., Rivellese, A. A.: Dietary fat, insulin sensitivity and the metabolic syndrome. Clin. Nutr., 2004, 23, s. 447–456.

54. Chong, M. F., Fielding, B. A., Frayn, K. N.: Mechanisms for the acute effect of fructose on postprandial lipemia. Am. J. Clin. Nutr., 2007, 85, s. 1511–1520.

55. Berglund, L., Lefevre, M., Ginsberg, H. N. et al.: Comparison of monounsaturated fat with carbohydrates as a replacement for saturated fat in subjects with a high metabolic risk profile: studies in the fasting and postprandial states. Am. J. Clin. Nutr., 2007, 86, s. 1611–1620.

56. Lombardo, Y. B., Chicco, A. G.: Effects of dietary polyunsaturated n-3 fatty acids on dyslipidemia and insulin resistance in rodents and humans. A review. J. Nutr. Biochem., 2006, 17, s. 1–13.

57. Žák, A., Tvrzická, E., Zeman, M. et al.: Patofyziologie a klinický význam vícenenasycených mastných kyselin řady n‑3. Čas. Lék. čes., 2005, 144 (Suppl. 1), s. 6–18.

58. Watts, G. F., Barrett, P. H., Ji, J. et al.: Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome. Diabetes, 2003, 52, s. 803–811.

59. Shepherd, J., Betteridge, J., Van Gaal, L. et al.: Nicotinic acid in the management of dyslipidaemia associated with diabetes and metabolic syndrome: A position paper developed by a European Consensus Panel. Curr. Med. Res. Opin., 2005, 21, s. 665–682.

60. Nagashima, K., Lopez, C., Donovan, D. et al.: Effects of the PPARgamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus. J. Clin. Invest., 2005, 115, s. 1323–1332.

61. Lefebvre, F., Chinetti, C., Fruchart, J.-C. et al.: Sorting out the role of PPARalpha in energy metabolism and vascular homeostasis. J. Clin. Incest., 2006, 116, s. 571–580.

62. Štulc, T., Češka, R.: Duální blokáda receptorů PPAR. Farmakoterapie, 2006, 2, s. 13–16.

63. Nissen, S. E., Wolski, K., Topol, E. J.: Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA, 2005, 294, s. 2581–2586.

64. Bensaid, M., Gary-Bobo, M., Esclangon, A. et al.: The cannabinoid CB1 receptor antagonist SR 141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol. Pharmacol., 2003, 63, s. 908–914.

Labels
Addictology Allergology and clinical immunology Angiology Audiology Clinical biochemistry Dermatology & STDs Paediatric gastroenterology Paediatric surgery Paediatric cardiology Paediatric neurology Paediatric ENT Paediatric psychiatry Paediatric rheumatology Diabetology Pharmacy Vascular surgery Pain management Dental Hygienist
Topics Journals
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#