2nd International Symposium on Triglycerides and HDL

Lipoprotein subclasses Robert S. Rosenson (Chicago IL) discussed lipoprotein subclasses, inflammation, and cardiovascular disease (CVD) risk in the metabolic syndrome. Insulin resistance impairs VLDL particle clearance, leading to greater interchange of core triglyceride from VLDL with LDL and HDL, with LDL and HDL triglyceride enrichment leading both to become substrates for hepatic lipase, resulting in smaller, denser particles. Insulin resistance also is associated with decreased levels of apolipoprotein (apo)A1, and elevated free fatty acid (FFA) levels downregulate the ABCA1 transporter, which is involved in reverse cholesterol transport. Insulin resistance then is associated with smaller HDL and LDL and with largersized VLDL. As the number of metabolic syndrome components increases, LDL particle number increases with increased small, dense LDL and decreased large LDL particle numbers. Persons with LDL 100, therefore, may or may not have low particle number, so that only onequarter of persons with the metabolic syndrome in the Framingham Offspring Study who had LDL 100 had optimal LDL particle distribution (1). In the Women’s Health Study, LDL particle number was associated with risk, particularly if small and large particle numbers were included; the only additional lipid variable adding to risk in this analysis is HDL cholesterol. In the AFCAPS/ TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study), low HDL was an important risk marker, with risk particularly related to apoB level. Rosenson noted that this again supports the “need to pay attention to atherogenic lipoproteins.” Lipoprotein subclasses are related to inflammation, with smaller, usually negatively charged, particles more likely to pass through the extracellular matrix, enter the vascular wall, and interact with monocyte receptors, initiating an inflammatory cascade. Lipoprotein-associated phospholipase A2 is associated with increased LDL oxidation and with inflammatory response and may be important as an additional nontraditional marker independent of C-reactive protein (CRP). HDL particles have antioxidant effects, including prevention of LDL oxidation and reduction in vascular inflammation. A number of adipokines are involved in vascular inflammation, with protective effect of adiponectin, as well as proinflammatory effects of factors such as interleukin (IL)-6 and tumor necrosis factor (TNF). Persons with metabolic syndrome “are in a chronic inflammatory state,” with inflammatory proteins such as serum amyloid A changing the composition of HDL, reducing protection against oxidative modification of LDL. Adipocyte serum amyloid A increases as a function of BMI, with decreasing calorie intake lowering plasma serum amyloid A (2). Anatol Kontush (Paris, France) further discussed the heterogeneity of HDL particles, ranging from lipid-poor apoA1containing particles and preHDL particles to larger HDL2 particles. Cholesteryl ester transfer protein (CETP), phospholipase transfer protein, and hepatic and endothelial lipases are involved in HDL metabolism. Various HDL subfractions have varying degrees of antioxidative activity, with evidence that changes in HDL in the metabolic syndrome reduce this protective effect. Kontush showed studies of the antioxidative activity of HDL in decreasing LDL oxidation, with the smaller and denser HDL3 particles more effectively decreasing LDL oxidation. Systemic oxidative stress was increased in persons with metabolic syndrome to an extent similar to that in persons with type 2 diabetes, as shown by increased plasma 8-isoprostane levels. The major difference between fractions of persons with and without metabolic syndrome is in the HDL3 fraction, particularly in the most dense subfraction, with strong correlation between the LDL oxidation rate in the presence of the most dense HDL3 fraction and the plasma 8-isoprostane level. Small dense HDLs are depleted of cholesterol esters and enriched in triglycerides in metabolic syndrome, suggesting a prooxidative effect of triglyceride, with dysfunction of small dense HDL3 particles in metabolic syndrome reflecting increased CETP activity with accelerated VLDL triglyceride incorporation in HDL and transfer of HDL cholesterol to VLDL. Kontush suggested that this represents a mechanism underlying the relationship between triglycerides and atherosclerosis, so that CETP inhibitors and perhaps niacin may have particular benefit in metabolic syndrome and type 2 diabetes.