Proatherogenic Role of Elevated CE Transfer From HDL to VLDL ₁ and Dense LDL in Type 2 Diabetes

Abstract

Abstract-Plasma cholesteryl ester transfer protein (CETP) facilitates intravascular lipoprotein remodeling by promoting the heteroexchange of neutral lipids. To determine whether the degree of triglyceridemia may influence the CETP-mediated redistribution of HDL CE between atherogenic plasma lipoprotein particles in type 2 diabetes, we evaluated CE mass transfer from HDL to apoB-containing lipoprotein acceptors in the plasma of type 2 diabetes subjects (nϭ38). In parallel, we investigated the potential relationship between CE transfer and the appearance of an atherogenic dense LDL profile. The diabetic population was divided into 3 subgroups according to fasting plasma triglyceride (TG) levels: group 1 (G1), TGϽ100 mg/dL; group 2 (G2), 100ϽTGϽ200 mg/dL; and group 3 (G3), TGϾ200 mg/dL. Type 2 diabetes patients displayed an asymmetrical LDL profile in which the dense LDL subfractions predominated. Plasma levels of dense LDL subfractions were strongly positively correlated with those of plasma triglyceride (TG) (rϭ0.471; Pϭ0.0003). The rate of CE mass transfer from HDL to apoB-containing lipoproteins was significantly enhanced in G3 compared with G2 or G1 (46.2Ϯ8.1, 33.6Ϯ5.3, and 28.2Ϯ2.7 g CE transferred ⅐ h Ϫ1 ⅐ mL Ϫ1 in G3, G2, and G1, respectively; PϽ0.0001 G3 versus G1, Pϭ0.0001 G2 versus G1, and Pϭ0.02 G2 versus G3). The relative capacities of VLDL and LDL to act as acceptors of CE from HDL were distinct between type 2 diabetes subgroups. LDL particles represented the preferential CE acceptor in G1 and accounted for 74% of total CE transferred from HDL. By contrast, in G2 and G3, TG-rich lipoprotein subfractions accounted for 47% and 72% of total CE transferred from HDL, respectively. Moreover, the relative proportion of CE transferred from HDL to VLDL 1 in type 2 diabetes patients increased progressively with increase in plasma TG levels. The VLDL 1 subfraction accounted for 34%, 43%, and 52% of total CE transferred from HDL to TG-rich lipoproteins in patients from G1, G2, and G3, respectively. Finally, dense LDL acquired an average of 45% of total CE transferred from HDL to LDL in type 2 diabetes patients. In conclusion, CETP contributes significantly to the formation of small dense LDL particles in type 2 diabetes by a preferential CE transfer from HDL to small dense LDL, as well as through an indirect mechanism involving an enhanced CE transfer from HDL to VLDL 1 , the specific precursors of small dense LDL particles in plasma. T he most common alterations in lipid and lipoprotein profile in type 2 diabetes involve an elevation in both postprandial and fasting plasma triglyceride (TG) and VLDL concentrations, a dense LDL phenotype, and low levels of HDL cholesterol. 1 Hypertriglyceridemia contributes significantly to the increased risk for premature cardiovascular disease in type 2 diabetes. 2 There is a strong positive correlation between plasma concentrations of TG and small dense LDL in nondiabetic subjects, suggesting that plasma TG concentrations influence LDL subclass distribution. 3 The particle si...

Cholesteryl Ester Transfer Protein TaqIB Variant, High-Density Lipoprotein Cholesterol Levels, Cardiovascular Risk, and Efficacy of Pravastatin Treatment

“…Triglycerides, which are substrates for CETP, are known to affect CETP metabolism. 39 In fact, we have recently reported an interaction between CETP plasma levels and triglycerides, such that the risk of future CAD increased with increasing CETP levels but only among individuals with high triglyceride levels. 16 However, an interaction between TaqIB genotype and triglyceride levels has never been reported, and we did not observe one in the present analysis either.…”

Plasma Levels of Cholesteryl Ester Transfer Protein and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women

“…[13][14][15][16][17] Transfer of CE out of HDL particles is determined not only by the CETP concentration but even more by the concentration of the acceptors of the transfer reaction, ie, triglyceride-rich lipoproteins such as VLDL. As triglyceride levels rise, VLDL 1 particles are the principal lipoprotein subfraction to accumulate, 18,19 which shifts the preferential net CE flux from LDL particles to VLDL 1 .…”

“…As triglyceride levels rise, VLDL 1 particles are the principal lipoprotein subfraction to accumulate, 18,19 which shifts the preferential net CE flux from LDL particles to VLDL 1 . 13,20 This shift favors the formation of CE-depleted and triglyceride-enriched LDL particles, which are precursors of small dense LDL particles, the most atherogenic LDL subfraction. 18,19 CETP further contributes to the formation of small dense LDL by preferential CE transfer from HDL to small dense LDL species and enhanced transfer to apoB-containing VLDL 1 .…”

“…18,19 CETP further contributes to the formation of small dense LDL by preferential CE transfer from HDL to small dense LDL species and enhanced transfer to apoB-containing VLDL 1 . 13,18,19 Thus, the potential detrimental effect of high CETP levels in terms of CAD risk may depend on triglyceride levels.…”

“…This analysis was predefined and was driven by the evidence that CETP-facilitated transfer of CEs to apoBcontaining particles is mediated by increased triglyceride levels in both humans [13][14][15] and mice. 16,17 As triglyceride levels rise, the principal lipoprotein subfraction to accumulate is VLDL 1 particles.…”