Plasma concentrations of cholesteryl ester transfer protein in hyperlipoproteinemia. Relation to cholesteryl ester transfer protein activity and other lipoprotein variables.

Abstract

Cholesteryl ester transfer protein (CETP) mediates an important pathway for reverse cholesterol transport. Concentrations of CETP in fasting plasma were measured by radioimmunoassay in two different groups of hyperlipoproteinemic subjects. Plasma CETP concentrations measured by radioimmunoassay correlated closely with cholesterol ester transfer activity in normal plasma (r=0.86). In the first group of 58 patients, plasma CETP concentrations were significantly increased, as compared with those in 79 normal subjects and in hypercholesterolemic (+26%) and combined hyperlipoproteinemic (+25%) subjects but were not altered in moderately hypertriglyceridemic subjects. Marked elevations in plasma CETP levels were documented in patients with dysbetalipoproteinemia (+68%) and severe chylomicronemia (+85%). Similar results were obtained in a second population of 50 hyperlipoproteinemic subjects. Significant correlations were found between plasma CETP levels and total cholesterol (r=0.52), very low density lipoprotein (VLDL) cholesterol (r=0.63), and apolipoprotein E concentration (r=0.40). Correction of the lipoprotein phenotype by dietary means resulted in significant reductions in plasma CETP concentrations in patients with chylomicronemia and dysbetalipoproteinemia. In these subjects, plasma high density lipoprotein cholesterol concentrations increased as CETP decreased. These studies indicate that CETP levels increase in association with enhanced peripheral cholesterol transport via low density lipoprotein, /3-VLDL, or chylomicron remnants. (Arteriosclerosis and Thrombosis 1991;ll:797-804) E arly studies by Rehnborg and Nichols 1 and Nichols and Smith 2 demonstrated that on incubation of normolipemic plasma, cholesteryl ester (CE) increased in very low density lipoprotein (VLDL), whereas triglyceride (TG) concentration decreased in VLDL but increased in high density lipoprotein (HDL) and low density lipoprotein (LDL). These experiments were the first to document CE transfer between lipoproteins, a phenomenon that was further clarified by the demonstra- tion by Zilversmit et al 3 that the d>1.21 g/ml fraction contained a protein that catalyzed CE transfer between lipoproteins, a protein that is now identified as cholesteryl ester transfer protein (CETP). More recently, two research groups have purified and characterized CETP, which is a very hydrophobic protein with a molecular size of M r 74,000, 45 in agreement with the data derived from the cloning and sequencing of the cDNA encoding for CETP. 6 While CETP mediates only the exchange of CEs between HDL and LDL, 7 it does promote net transfer of CEs from HDL to VLDL and chylomicrons. 8 This specificity of the transfer reaction makes it a major pathway for reverse cholesterol transport in many mammalian species. However, the significance of plasma levels of CETP in atherosclerosis must be considered in terms of the two facets of the CETPmediated system -factors facilitating the accumulation of HDL CE (secretion of nascent HDL, its interaction with peripheral cells...

Cholesteryl Ester Transfer Protein Biosynthesis and Cellular Cholesterol Homeostasis Are Tightly Interconnected

“…Similarly, plasma CETP concentrations are increased in certain hyperlipoproteinemic conditions such as chylomicronemia and dysbetalipoproteinemia (49). The increase in plasma CETP associated with these conditions may reflect enhanced delivery of lipoprotein-derived cholesterol to responsive tissues, such as adipose, where CETP gene expression is up-regulated (22,40,49). In the present study we examined the responsiveness of CETP synthesis by cultured adipocytic cells to cholesterol.…”

“…High cholesterol diets increase plasma CETP levels in humans and hamsters, which are associated with an increase in CETP mRNA in liver, spleen, heart, and adipose tissue (4,40,48). Similarly, plasma CETP concentrations are increased in certain hyperlipoproteinemic conditions such as chylomicronemia and dysbetalipoproteinemia (49). The increase in plasma CETP associated with these conditions may reflect enhanced delivery of lipoprotein-derived cholesterol to responsive tissues, such as adipose, where CETP gene expression is up-regulated (22,40,49).…”

Influence of plasma cholesteryl ester transfer activity on the LDL and HDL distribution profiles in normolipidemic subjects.

“…For example, CETP showed no relation to HDL in hyperlipoproteinemic patients. 42 Moreover, in monkeys fed high-fat, high-cholesterol diets, plasma CETP concentration had a strong inverse correlation with HDL-C concentration but was positively correlated with LDL-C concentration. 4 In fact, similar results were observed in humans.…”

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

“…Second, we have studied CETP under physiological conditions in which CETP activity and CETP concentration are assumed to be strongly correlated. 32 This contrasts with the reduced CETP activity on pharmacological inhibition that is accompanied by an increase in CETP plasma concentration, probably because the interaction of the small molecules with the CETP protein disturbs CETP clearance from the circulation. 10,11 When these considerations are taken into account, care is warranted when extrapolating our finding that low CETP concentrations are associated with a moderately reduced risk for CAD in healthy individuals to the putative effects of CETP inhibition on CAD risk in patients.…”