ATHEROGENIC LIPOPROTEIN PROFILE OF THE METABOLIC SYNDROME

BERG, GABRIELA (SIMPOSIO)

BUENOS AIRES, ARGENTINA

Congreso; 11TH WORLD CONGRESS ON THE MENOPAUSE; 2005

INTERNATIONAL MENOPAUSE SOCIETY

The risk of cardiovascular disease linked to the metabolic syndrome  appears to be especially high in women. It is estimated that half of the cardiovascular events observed in women are related to this syndrome. In addition, the postmenopausal status is associated with a 60% increased risk of metabolic syndrome (1). The metabolic syndrome is a constellation of metabolic disturbances all of which are also risk factors for cardiovascular disease. The cluster of abnormalities includes glucose intolerance (type 2 diabetes, impaired glucose tolerance, or impaired fasting glycaemia), insulin resistance, central obesity, dyslipidaemia and hypertension. However, insulin resistance is the leading cause of metabolic syndrome and it is also the main factor determining the concomitant atherogenic dyslipidaemia. In normal conditions, insulin has a lipogenic and antilipolytic action on adipose tissue, it stimulates lipoprotein lipase (LPL), enzyme hydrolysing triglyceride-rich lipoproteins in plasma, to be stored in adipose tissue. On the other hand, insulin inhibits hormone sensitive lipase, enzyme that hydrolyses triglycerides stored in adipose tissue. When insulin resistance develops, the increased lipolysis in adipose tissue determines an overabundance of free fatty acids  (FFA)  that flux to the liver, increasing in turn the production of apoB-triglyceride-rich very low-density lipoprotein (VLDL). This phenomena is enhanced when the accumulation of adipose tissue is mainly abdominal. In the postmenopause, abdominal obesity is quite frequent, this would be related in part, to estrogens decrease and aging (2). The accumulation of fat in the abdominal region, is an important factor leading to  metabolic syndrome in postmenopausal women. In parallel, insulin resistance can reduce LPL concentrations in adipose tissue, thus contributing to the lower catabolism of VLDL in plasma. Therefore, the increase in plasma triglycerides (TG) is characteristic of the insulin resistance syndrome being one of the diagnostic criterion for metabolic syndrome. In the liver, Hepatic Lipase (HL) mediates TG hydrolisis within low density lipoproteins (LDL) as well as phospholipids and TG hydrolisis within high density lipoproteins (HDL). The transcription and synthesis of this enzyme is inhibited by estrogens and stimulated by insulin, androgens and thyroid hormones. In postmenopausal women the activity of HL is increased as a consequence of the decreased levels of estrogens (3). In insulin resistant states, HL activity is also increased which can results in a modification of LDL composition, towards lower size and higher density particles. Although LDL cholesterol plasma levels are not always increased in metabolic syndrome, an increased proportion of small dense LDL is frequently observed. Small dense LDL, typical of the metabolic syndrome and the postmenopause (4,5), can filtrate through the endothelial basement membrane, in addition small dense LDL particles have an increased adherence to proteoglycans and are more prone to oxidation. It is noteworthy that the increase in small dense LDL is an independent risk factor for cardiovascular disease. Finally, another lipoprotein which can be modified in the metabolic syndrome is HDL. This lipoprotein level is frequently reduced in the metabolic syndrome, as a consequence of hypertriglyceridemia and increased HL activity. Low HDL is one of the main alterations as well as one of the diagnostic criteria for metabolic syndrome. Although estrogens increase the synthesis of apoA, the major HDL apolipoprotein, and decrease SRB-I, the receptor where HDL are catabolized, HDL levels are not always reduced in postmenopause (2,3).Nevertheless, in posmentopausal women with metabolic syndrome, HDL levels could be reduced, and it would be an additional risk factor.   1.       Carr M. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003;88:2404-2411. 2.      Berg G, Mesch V, Boero L, et al. Lipid and lipoprotein profile throughout the menopausal transition. Effects of hormones, age and central obesity. Horm Metab Res 2004,36:215-220. 3.      Berg G, Siseles N, Gonzalez A et al. Higher values of Hepatic Lipase activity in postmenopause. Menopause 2001;8(2): 51-57. 4.      Carr M, Kim K, Zambon A et al. Changes in LDL density across the menopausal transition. J Investig Med. 2000 48(4):245-50. 5.       Berg G, Muzzio ML, Wikinski R, Shreier L. A quantitative dense LDL subfraction measurement. Nutr Metab Cardiov Diseas 14(2):73-80, 2004.