Cholesteryl Ester Transfer Research Articles

Cholesteryl ester transfer is associated with HDL size and coronary artery calcification in type 1 diabetic and non-diabetic subjects

Cholesteryl ester transfer is associated with HDL size and coronary artery calcification in type 1 diabetic and non-diabetic subjects

Effect of growth hormone replacement therapy on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone-deficient adults

The effects of growth hormone (GH) replacement on plasma lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP), factors involved in high density lipoprotein (HDL) metabolism, are unknown. We carried out a 6 months study in 24 GH-deficient adults who were randomized to placebo (n = 8), low dose GH (1 U daily, n = 8), and high dose GH (2 U daily, n = 8), followed by a 6 months open extension study with high dose GH (1 dropout). No significant changes in plasma lipoproteins, LCAT, CETP, and PLTP activities, cholesterol esterification (EST) and cholesteryl ester transfer (CET) were observed after placebo. After 6 months of GH (combined data, n = 24), very low + low density lipoprotein (VLDL + LDL) cholesterol (P < 0.05) and apolipoprotein B (P < 0.05) decreased, whereas HDL cholesterol and HDL cholesteryl ester increased (P < 0.05). Prolonged treatment showed comparable effects. Plasma apolipoprotein A-I and Lp[a] remained unchanged. Plasma LCAT (P < 0.01) and CETP activities (P < 0.01), as well as EST (P < 0.01) and CET decreased (P < 0.01) after 12 months of GH (n = 15), but PLTP activity did not significantly change. Changes in EST and CET after 12 months of treatment were independently related to changes in plasma LCAT (P = 0.001 and CETP activity (P = 0.01).In conclusion, GH replacement therapy improves the lipoprotein profile in GH-deficient adults. Chronic GH replacement lowers plasma LCAT and CETP activities, contributing to a decrease in cholesterol esterification and cholesteryl ester transfer. These effects may have consequences for HDL metabolism and reverse cholesterol transport.

Decreased plasma cholesterol esterification and cholesteryl ester transfer in hypopituitary patients on glucocorticoid replacement therapy

Cardiovascular risk is increased in hypopituitary patients. No data are available with respect to the effect of glucocorticoid replacement therapy on high density lipoproteins (HDL) metabolism in such patients. Plasma lecithin:cholesterol acyl transferase (LCAT), cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are important determinants of HDL remodelling. The possible influence of conventional glucocorticoid replacement on plasma lipids, plasma LCAT, CETP and PLTP activity levels, as well as on plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) was evaluated in 24 consecutive hypopituitary patients (12 men and 12 women) with untreated growth hormone deficiency of whom 17 had adrenal insufficiency and were treated with cortisone acetate, 25 to 37.5 mg daily. Twenty-three patients were on stable levothyroxin therapy and 22 patients used sex steroids. Urinary excretion of cortisol and cortisone metabolites was higher (p<0.12) were not significantly different in patients receiving and not receiving glucocorticoids. Fasting blood glucose, plasma insulin and insulin resistance were similar in the groups. Plasma total (p<0.05) and very low+low density lipoprotein cholesterol (p<0.01) were lower in patients receiving glucocorticoids, whereas HDL cholesterol and plasma triglycerides were not different between patients treated and not treated with glucocorticoids. Plasma LCAT activity was 45% lower (p<0.02) and CETP activity was 34% lower (p<0.05) in patients on glucocorticoid treatment. Multiple regression analysis showed that these effects were independent of gender and fat mass. In glucocorticoid-receiving patients, plasma EST and CET were decreased by 80% (p<0.01) and by 58% (p<0.05), respectively. These changes were at least partly attributable to lower LCAT and CETP activity levels. In contrast, plasma PLTP activity was not different between patients with and without glucocorticoid treatment, suggesting that exogenous glucocorticoids exert a different regulatory effect on plasma CETP compared to PLTP. In conclusion, this preliminary study suggests that conventional glucocorticoid replacement in hypopituitary patients is associated with a decrease in plasma cholesterol esterification and cholesteryl ester transfer, indicating that these steps in HDL metabolism are impaired. Such abnormalities in HDL metabolism could be involved in increased cardiovascular risk in glucocorticoid-treated hypopituitary patients, despite a lack of deterioration in plasma lipids.

Roles of Scavenger Receptor Bi and APO A-I in Selective Uptake of Hdl Cholesterol by Adrenal Cells

Adrenal cells obtain cholesterol for steroid production via the selective uptake of cholesteryl ester (CE) from HDL particles, a process in which CE is transferred to the plasma membrane without degradation of the HDL particle. Although this process has been studied for two decades, only recently have the receptor and the HDL ligand been identified. Scavenger class B, type I, (SR-BI) is regulated by ACTH in adrenocortical cells in parallel with steroid production. Antibody to SR-BI blocks the uptake and utilization of HDL CE for steroid production in Y1-BS1 adrenal cells. The adrenal glands of SR-BI knockout mice are depleted in cholesterol providing complementary evidence that SR-BI is responsible for HDL CE accumulation in adrenal cells. SR-BI-mediated HDL CE selective uptake is a two-step process in which SR-BI first interacts with multiple sites in apoA-I with the amphipathic helical repeat units of apoA-I serving as recognition motifs. This is followed by efficient CE transfer down its concentration gradient to the plasma membrane, a process requiring the extracellular domain of SR-BI. Other scavenger receptors bind HDL but do not afford the CE transfer step. Adrenal glands from apoA-I knockout mice lack CE stores, indicating that apoAI is essential for HDL selective uptake in vivo ApoA-I knockout HDL particles bind normally to SR-BI but do not permit efficient CE transfer to the cell. These findings suggest that apoA-I has an important role in the transfer of HDL CE that goes beyond its function as a ligand for interaction with SR-BI.

VLDL-bound lipoprotein lipase facilitates the cholesteryl ester transfer protein-mediated transfer of cholesteryl esters from HDL to VLDL

In recent years, it has been established that lipoprotein lipase (LPL) is partly associated with circulating lipoproteins. This report describes the effects of physiological amounts of very low density lipoprotein (VLDL)-bound LPL on the cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester transfer (CET) from high density lipoprotein (HDL) to VLDL. Three patients with severe LPL deficiency exhibited a strong decrease in net mass CET that was more than 80% lower than that of common hypertriglyceridemic subjects. Recombination experiments showed that this was due to an abnormal behavior of the VLDL fraction. Replacement of the latter by normal VLDL totally normalized net mass CET. We therefore prepared VLDL containing controlled amounts of bound LPL that we used as CE acceptors in experiments involving unidirectional radioisotopic CET measurements. These were carried out either in the absence or in the presence of inhibitors of LPL lipolytic activity. When LPL-induced lipolysis was totally blocked, the stimulating effect of the enzyme on the CETP-dependent CET was only reduced by about 50%, showing that it did not entirely result from its lipolytic action. These data were dependent upon neither the type of LPL inhibitor (E600 or THL) nor the source of CETP (delipidated plasma or partially purified CETP).▪ Thus, in addition to the well-known stimulating effect of LPL-dependent lipolysis on CET, our work demonstrates that physiological amounts of VLDL-bound LPL may facilitate CET through a mechanism partially independent of its lipolytic activity.—Pruneta, V., T. Pulcini, F. Lalanne, C. Marçais, F. Berthezène, G. Ponsin, and P. Moulin. VLDL-bound lipoprotein lipase facilitates the cholesteryl ester transfer protein-mediated transfer of cholesteryl esters from HDL to VLDL.

Epitope mapping for the anti-rabbit cholesteryl ester transfer protein monoclonal antibody that selectively inhibits triglyceride transfer

Among the monoclonal antibodies (Mab) against rabbit plasma cholesteryl ester transfer protein (CETP), Mab 14-8F cross-reacted with human CETP and selectively inhibited triglyceride transfer but not cholesteryl ester transfer (Ko, K. W. S., T. Ohnishi, and S. Yokoyama. 1994. J. Biol. Chem. 269: 28206;-28213). The epitope of this antibody was studied by using synthetic fragment peptides of rabbit and human CETP. Mab 14-8F reacted with the peptide R451-Q473 of human CETP near the carboxyl-terminal and not with the peptides representing any other regions, and inhibited the binding of human CETP to the goat antibody against its carboxyl-terminal peptide R451-S476. The experiments with a series of the fragment peptides in this region revealed that the epitope requires the segment 465-473 (EHLLVDFLQ) of human CETP or 485-493 (KHLLVDFLQ) of rabbit CETP (core epitope) though neither peptide by itself binds to the antibody. Both peptides needed extension at least by one residue beyond either amino- or carboxyl-end in order to show the reactivity to the antibody, but the effect was not highly residue-specific at least at the amino-end. Circular dichroism analysis demonstrated the increase of helical conformation by the extension of the "core epitope" peptides to either direction. Thus, the epitope is dependent on conformation of the core epitope induced by the presence of an additional residue(s) in either end. The core epitope occupies the central 64% of the reported linear epitope of Mab TP2, a widely used anti-human CETP monoclonal antibody that inhibits both cholesteryl ester and triglyceride transfer.Therefore, we conclude that the limited interaction of Mab with a common lipid interaction site causes selective inhibition of the transfer of triglyceride that has presumably lower priority than cholesteryl ester for the CETP reaction.

Hypocholesterolemic effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the guinea pig: Atorvastatin versus simvastatin

Male Hartley guinea pigs were fed a hypercholesterolemic diet rich in lauric and myristic acids with 0, 10, or 20 mg/kg of simvastatin or atorvastatin for 21 days. Atorvastatin and simvastatin resulted in a lowering of plasma low-density lipoprotein (LDL) cholesterol in a dose-dependent manner by an average of 48 and 61% with 10 and 20 mg/kg, respectively. Both statins were equally effective in lowering plasma LDL cholesterol and apolipoprotein B (apo-B) levels. Atorvastatin and simvastatin treatments yielded LDL particles that differed in composition from the control. Due to the relevance of LDL oxidation and cholesteryl ester transfer in plasma to the progression of atherosclerosis, these parameters were analyzed after statin treatment. Atorvastatin and simvastatin treatment decreased the susceptibility of LDL particles to oxidation by 95% as determined by the formation of thiobarbituric acid reactive substances. An 80% decrease in the transfer of cholesteryl ester between high-density lipoprotein (HDL) and the apo-B-containing lipoproteins was observed after simvastatin and atorvastatin treatment. In addition, statin effects on plasma LDL transport were studied. Simvastatin- and atorvastatin-treated guinea pigs exhibited 125 and 175% faster LDL fractional catabolic rates, respectively, compared with control animals. No change in LDL apo-B flux was induced by either treatment; however, LDL apo-B pool size was reduced after statin treatment. Hepatic microsomal free cholesterol was lower in the atorvastatin and simvastatin groups. However, only atorvastatin treatment resulted in an 80% decrease of acyl-CoA:cholesterol acyltransferase activity ( P < 0.001). In summary, atorvastatin and simvastatin had similar LDL cholesterol lowering properties, but these drugs modified LDL transport and hepatic cholesterol metabolism differently.

Insulin decreases plasma cholesteryl ester transfer but not cholesterol esterification in healthy subjects as well as in normotriglyceridaemic patients with type 2 diabetes.

Plasma cholesterol esterification (EST) and subsequent cholesteryl ester transfer (CET) from high-density lipoproteins (HDLs) towards apolipoprotein (apo) B-containing lipoproteins are key steps in HDL metabolism. The effects of exogenous hyperinsulinaemia on plasma CET and EST, measured with isotope methods, were evaluated in 10 male normotriglyceridaemic (plasma triglycerides <2.0 mmol L-1) patients with type 2 diabetes and 10 individually matched healthy subjects during a two-step hyperinsulinaemic euglycaemic clamp over 6-7 h. No between-group differences in baseline plasma lipid parameters were observed, but the HDL cholesteryl ester content was lower (P < 0.02) and the HDL triglyceride content was higher (P < 0.05) in diabetic patients. Baseline CET and EST were similar in the groups. In both groups, hyperinsulinaemia decreased plasma triglycerides (P < 0.01) and the HDL triglyceride content (P < 0.01) compared with saline infusion in healthy subjects, whereas the HDL cholesteryl ester content increased (P < 0.05 vs. saline infusion) in diabetic patients. CET was similarly decreased by hyperinsulinaemia in both groups (P < 0.01 vs. saline infusion). In contrast, the change in EST in either group was not different from that during saline administration. In the combined group, baseline CET was positively correlated with plasma triglycerides (Rs = 0.68, P < 0.01). The HDL cholesteryl ester content was negatively (Rs = -0.48, P < 0.05) and the HDL triglyceride content was positively (Rs = 0.64, P < 0.01) correlated with CET. Insulin infusion decreases plasma CET in conjunction with a fall in triglycerides but does not decrease cholesterol esterification in healthy and type 2 diabetic subjects, indicating that acute hyperinsulinaemia has a different effect on these processes involved in HDL metabolism. Despite unaltered fasting plasma CET, HDL core lipid composition was abnormal in diabetic patients, suggesting that additional mechanisms may contribute to changes in HDL metabolism in diabetes mellitus.

LDL particle size: an important drug target?

Low density lipoprotein (LDL) is the main carrier of plasma cholesterol and a major component of atherosclerotic plaque [1]. Lowering LDL cholesterol reduces coronary events and mortality from coronary artery disease (CAD) [2–4], however, the relation between LDL cholesterol concentration and (CAD) is complex. Many patients with CAD have plasma LDL cholesterol concentrations in the normal rangefor the general population [5]. Thus, it could be that coronary risk goes beyond LDL cholesterol concentration to the characteristics of the LDL particles themselves. The purpose of this communication is to address the issue of whether LDL particle size and density influences its atherogenecity and how this might be modified by drug therapy.

Differences in the lipoprotein distribution of halofantrine are regulated by lipoprotein apolar lipid and protein concentration and lipid transfer protein I activity: In vitro studies in normolipidemic and dyslipidemic human plasmas

The purpose of these studies was to determine the distribution of a lipophilic antimalarial agent, halofantrine hydrochloride (Hf), in fasted plasma from hypo‐, normo‐, and hyperlipidemic patients that displayed differences in lipoprotein concentration and lipid transfer protein I (LTP I) activity. To assess the influence of modified lipoprotein concentrations and LTP I activity on the plasma distribution of Hf, Hf at a concentration of 1000 ng/mL was incubated in either hypo‐, normo‐, or hyperlipidemic human plasma for 1 h at 37 °C. Following incubation, the plasma samples were separated into their lipoprotein and lipoprotein‐deficient plasma (LPDP) fractions by density gradient ultracentrifugation and assayed for Hf by high‐pressure liquid chromatography. The activity of LTP I in the dyslipidemic plasma samples was determined in terms of its ability to transfer cholesteryl ester from low‐density lipoproteins (LDL) to high‐density lipoproteins (HDL). Total plasma and lipoprotein cholesterol (esterified and unesterified), triglyceride, and protein levels in the dyslipidemic plasma samples were determined by enzymatic assays. When Hf was incubated in normolipidemic plasma for 1 h at 37 °, the majority of drug was found in the LPDP fraction. When Hf was incubated in human plasma of varying total lipid, lipoprotein lipid, and protein concentrations and LTP I activity, the following relationships were observed. As the triglyceride‐rich lipoprotein (TRL) lipid and protein concentration increased from hypolipidemia through to hyperlipidemia, the proportion of Hf associated with TRL increased (r > 0.90). As the HDL lipid and protein concentration increased, the proportion of Hf associated with HDL decreased (r > 0.70). As the total and lipoprotein lipid levels increased, the LTP I activity of the plasma also proportionally increased (r > 0.85). Furthermore, with the increase in LTP I activity, the proportion of Hf associated with the TRL fraction increased (r > 0.70) and the proportion of Hf associated with the HDL fraction decreased (r > 0.80). In addition, a positive correlation between the proportion of apolar lipid and Hf recovered within each lipoprotein fraction was observed within hypo‐ (r > 0.80), normo‐ (r = 0.70), and hyperlipidemic (r > 0.90) plasmas. These findings suggest that changes in the HDL and TRL lipid and protein concentrations, LTP I activity, and the proportion of apolar lipid within each lipoprotein fraction may influence the plasma lipoprotein distribution of Hf in dyslipidemia.

Comparison of Class B Scavenger Receptors, CD36 and Scavenger Receptor BI (SR-BI), Shows That Both Receptors Mediate High Density Lipoprotein-Cholesteryl Ester Selective Uptake but SR-BI Exhibits a Unique Enhancement of Cholesteryl Ester Uptake

Scavenger receptor BI (SR-BI) mediates the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE), a process by which HDL CE is taken into the cell without internalization and degradation of the HDL particle. The biochemical mechanism by which SR-BI mediates the selective uptake of HDL CE is poorly understood. Given that CE transfer will occur to some extent from HDL to protein-free synthetic membranes, one hypothesis is that the role of SR-BI is primarily to tether HDL close to the cell surface to facilitate CE transfer from the particle to the plasma membrane. In the present study, this hypothesis was tested by comparing the selective uptake of HDL CE mediated by mouse SR-BI (mSR-BI) with that mediated by rat CD36 (rCD36), a closely related class B scavenger receptor. Both mSR-BI and rCD36 bind HDL with high affinity, and both receptors mediate HDL CE selective uptake. However, SR-BI mediates selective uptake of HDL CE with a 7-fold greater efficiency than rCD36. HDL CE selective uptake mediated by rCD36 is dependent on HDL binding to the receptor, since a mutation that blocks HDL binding also blocks HDL CE selective uptake. These data lead us to hypothesize that one component of HDL CE selective uptake is the tethering of HDL particles to the cell surface. To explore the molecular domains responsible for the greater efficiency of selective uptake by mSR-BI, we compared binding and selective uptake among mSR-BI, scavenger receptor BII, and various chimeric receptors formed from mSR-BI and rCD36. The results show that the extracellular domain of mSR-BI is essential for efficient HDL CE uptake, but the C-terminal cytoplasmic tail also has a major influence on the selective uptake process.

Immunochemical evidence that cholesteryl ester transfer protein and bactericidal/permeability-increasing protein share a similar tertiary structure.

Cholesteryl ester transfer protein (CETP) plays an important role in plasma lipoprotein metabolism through its ability to transfer cholesteryl ester, triglyceride, and phospholipid between lipoproteins. CETP is a member of a gene family that also includes bactericidal/permeability-increasing protein (BPI). The crystal structure of BPI shows it to be composed of two domains that share a similar structural fold that includes an apolar ligand-binding pocket. As structurally important residues are conserved between BPI and CETP, it is thought that CETP and BPI may have a similar overall conformation. We have previously proposed a model of CETP structure based on the binding characteristics of anti-CETP monoclonal antibodies (mAbs). We now present a refined epitope map of CETP that has been adapted to a structural model of CETP that uses the atomic coordinates of BPI. Four epitopes composed of CETP residues 215-219, 219-223, 223-227, and 444-450, respectively, are predicted to be situated on the external surface of the central beta-sheet and a fifth epitope (residues 225-258) on an extended linker that connects the two domains of the molecule. Three other epitopes, residues 317-331, 360-366, and 393-410, would form part of the putative carboxy-terminal beta-barrel. The ability of the corresponding mAbs to compete for binding to CETP is consistent with the proximity of the respective epitopes in the model. These results thus provide experimental evidence that is consistent with CETP and BPI having similar surface topologies.

Cholesteryl ester transfer in hypercholesterolaemia: fasting and postprandial studies with and without pravastatin

Subjects with hypercholesterolaemia (HC) have increased fasting cholesteryl ester transfer protein (CETP) activity and accelerated cholesteryl ester transfer (CET) from HDL to apo B-containing lipoproteins. The aim of this study was to examine the effects of postprandial lipaemia and pravastatin treatment on plasma triglycerides (TG) and CETP activity and and CET and LDL Stokes’ diameter in primary HC ( n=19, total cholesterol ≥6.5, LDL-cholesterol ≥4.5, TG<4.0 mmol/l). Samples were collected fasting and 6 h after an oral fat load (0.88 g/kg body weight) after 6 weeks therapy with placebo or pravastatin 40 mg nocte according to a double-blind randomized cross-over study. Apart from significant reductions in plasma total cholesterol, LDL-cholesterol apo B and TG, pravastatin significantly reduced CETP activity in both the fasting (mean±SD, 37.9±12.2 to 32.0±10.3 nmol/ml plasma per h) and postprandial state (35.5±11.3 to 31.3±9.5 nmol/ml plasma per h) compared to equivalent placebo phases. CETP activity did not change during postprandial lipaemia despite a significant 45–55% increase in CET to triglyceride-rich lipoproteins (TRL) of d<1.006 g/ml. LDL Stokes’ diameter was unchanged postprandially or by pravastatin. The mass of TRL was the strongest contributor to variation in CET in both fasting and postprandial plasma, accounting for at least 77% of the variance of CET. Postprandial TRL-TG was the strongest contributor to variation in fasting LDL Stokes’ diameter in untreated HC (54%) whilst HDL-cholesterol was the strongest fasting contributor to variation (45%) for placebo- and pravastatin-treated HC. We conclude that pravastatin may reduce the atherogenicity of the lipoprotein profile in HC by reducing CETP activity. Furthermore, CET is strongly influenced by postprandial lipaemia which may have a cumulative effect on LDL size.

Elevated plasma cholesteryl ester transfer in NIDDM: relationships with apolipoprotein B-containing lipoproteins and phospholipid transfer protein

Lecithin:cholesteryl acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of cholesterol and the subsequent transfer of cholesteryl ester from high density lipoproteins (HDL) towards very low and low density lipoproteins (VLDL+LDL). Phospholipid transfer protein (PLTP), lipoprotein lipase (LPL) and hepatic lipase (HL) are involved in plasma phospholipid and triglyceride metabolism and also affect HDL. Equivocal changes in plasma cholesteryl ester transfer have been reported in non-insulin-dependent diabetes mellitus (NIDDM). In 16 NIDDM men with plasma triglycerides ≤4.5 mmol/l and cholesterol ≤8.0 mmol/l, plasma cholesteryl ester transfer (CET), cholesterol esterification rate, LCAT and PLTP activity levels were higher ( P<0.05 to P<0.02) in conjunction with higher plasma triglycerides ( P<0.01) and lower HDL cholesterol and cholesteryl ester levels ( P<0.05) compared to 16 matched healthy men. Multiple stepwise regression analysis demonstrated that CET was positively related to VLDL+LDL cholesterol ( P<0.001), triglycerides ( P=0.001), PLTP activity ( P=0.007) and CETP activity ( P=0.008, multiple r=0.94). NIDDM had no effect on CET, independently from these parameters. HDL cholesteryl ester was negatively related to CET ( P=0.017), HL activity ( P=0.033) and NIDDM ( P=0.047) and positively to LCAT activity levels ( P=0.034, multiple r=0.68). It is concluded that the elevated CET in plasma from NIDDM patients is associated with higher plasma triglycerides and PLTP activity levels. Furthermore, our data suggest that in normo- and moderately dyslipidaemic subjects PLTP and CETP activity levels per se may influence the rate of cholesteryl ester transfer in plasma. Plasma cholesteryl ester transfer appears to be a determinant of HDL cholesteryl ester, but other factors are likely to contribute to lower HDL cholesteryl ester levels in NIDDM.

Accelerated cholesteryl ester transfer in patients with essential hypertension and the effect of ramipril treatment

Although the transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to the apolipoprotein B-containing lipoproteins (very-low-density lipoproteins+low-density lipoproteins) has been shown to be abnormally increased in a number of conditions associated with increased cardiovascular risk, it has not been studied in patients with essential hypertension (EH). To determine whether subjects with EH have increased CE transport, CE transfer (CET) was estimated isotopically and lipoprotein lipid and phospholipid composition determined in a group of 14 untreated normolipidemic (triglycerides 116±46, cholesterol 185±30, HDL 38±10 mg/dl) otherwise healthy ethnically diverse EH subjects. CET was significantly increased in EH subjects compared to a similar group of normotensive controls (EH: k=0.27±0.09 vs. control k=0.11±0.02; P<0.01). Lipoprotein concentration and composition were comparable in the two groups and closely resembled that of an age- and sex-matched reference group. The abnormal increase in CET persisted ( k=0.25±0.12) after 3 months of treatment with the angiotensin converting enzyme (ACE) inhibitor ramipril without a change in either plasma or lipoprotein lipids. Thus, CET is increased in normolipidemic subjects with EH and is not affected by the ACE inhibitor ramipril.

Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia

Plasma triglyceride (TG) levels are inversely related to HDL-cholesterol levels and subjects with high TG and low HDL cholesterol have increased coronary heart disease (CHD) risk. Plasma cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from HDL to TG-rich lipoproteins. In this study we determined the relationship between a common CETP amino acid polymorphism (I405V) and CETP and HDL levels and CHD prevalence in 576 men of Japanese ancestry in the Honolulu Heart Program cohort. This conservative substitution was associated with altered plasma CETP concentration (1.95 +/- 0.54, 1.91 +/- 0.57, and 1.77 +/- 0.57 microg/ml for the II, IV and VV genotypes, respectively). The distribution of plasma CETP concentrations among the VV, but not II, men appeared bimodal (P < 0.01), suggesting the presence of a functionally significant CETP gene mutation(s) in a subset of V alleles. HDL-C levels were higher in VV than IV for II men (55.4 +/- 17.4, 51.3 +/- 16.6, 51.1 +/- 17.0 mg/dl, P < 0.04). However, the increase in HDL was only significant in VV men with plasma TG > 165 mg/dl. Although CHD prevalence was not significantly different among the three genotypes in this population, in the subpopulation with high plasma TG, CHD prevalence appeared higher among VV than IV or II subjects (38% vs. 27% vs. 18%, P < 0.05 for an interaction of genotype and plasma TG levels). In fresh plasma from a separate group of normolipidemic subjects, the V/I polymorphism was not associated with any change in plasma CETP specific activity. The data suggest that a widespread and common CETP gene mutation(s) in linkage disequilibrium with 405V causes low CETP. Among hypertriglyceridemic men this is associated with higher HDL and possibly with increased CHD.

Prebeta-1 HDL in plasma of normolipidemic individuals: influences of plasma lipoproteins, age, and gender

Prebeta-1 HDL is a molecular species of plasma HDL of approximately 67 kDa mass that contains apolipoprotein A-I, phospholipids, and unesterified cholesterol. It participates in a cyclic process involved in the retrieval of cholesterol from peripheral tissues. In this cycle, unesterified cholesterol from cells is incorporated into prebeta-1 HDL, providing a substrate for esterification of cholesterol by lecithin:cholesterol acyltransferase. Prebeta-1 HDL then becomes incorporated into larger HDL species of alpha mobility as esterification proceeds and is regenerated during the transfer of cholesteryl esters from alpha HDL particles to acceptor lipoproteins. Thus the steady state level of prebeta-1 HDL in plasma reflects the relative efficiencies of the major metabolic processes involved in its generation and removal. We have used an isotope dilution technique to measure prebeta-1 HDL levels in the plasmas of 136 normolipidemic individuals (46 M, 90 F). The mean absolute concentration of prebeta-1 HDL as apolipoprotein A-I was 68 ± 40 μg/ml for women, and 84 ± 49 m/ml for men. Prebeta-1 HDL represented 5.5 ± 3.3% of total apolipoprotein A-I in women, and 7.2 ± 4.0% in men. The distributions of both absolute and percent prebeta-1 HDL are highly asymmetric, with skew toward higher values. However, the skew appears not to be attributable to either plasma cholesterol or triglyceride levels which are also skewed in population samples. The percent prebeta-1 HDL was negatively correlated with HDL cholesterol levels (P < 0.0001), whereas absolute levels of prebeta-1 HDL were positively correlated with apolipoprotein A-I and negatively correlated with HDL cholesterol (P, for both, < 0.0001). Multiple linear regression analysis revealed effects of age and gender, but no association with lipoprotein fractions other than HDL. Lower levels of prebeta-1 HDL were associated with female gender in all models.—O'Connor, P. M., B. R. Zysow, S. A. Schoenhaus, B. Y. Ishida, S. T. Kunitake, J. M. Naya-Vigne, P. N. Duchateau, R. F. Redberg, S. J. Spencer, S. Mark, M. Mazur, D. C. Heilbron, R. B. Jaffe, M. J. Malloy, and J. P. Kane. Prebeta-1 HDL in plasma of normolipidemic individuals: influences of plasma, age, and gender.

Alterations in cholesteryl ester transfer, lipoprotein lipase, and lipoprotein composition after combined pancreas-kidney transplantation.

IDDM patients treated with conventional subcutaneous insulin have an abnormal increase in cholesteryl ester transfer (CET), the proatherogenic step in reverse-cholesterol transport that results in the enrichment of the apolipoprotein (apo) B-containing lipoproteins (VLDL, LDL) with cholesteryl ester (CE). This disturbance is closely linked to iatrogenic hyperinsulinemia and the nonphysiologic stimulation of lipoprotein lipase (LpL), a physiologic activator of CET, because lowering systemic insulin levels by administering insulin through the intraperitoneal insulin route normalizes LpL and CET. Hyperinsulinemia persists in IDDM patients who undergo successful pancreas-kidney transplantation (PKT) when their allografts are placed in the pelvis and drain into the iliac vein. Therefore, to determine whether hyperinsulinemia promotes CET in this setting, we studied CET, LpL, and insulin levels in 14 euglycemic normolipidemic IDDM PKT patients with near-normal kidney function (creatinine 1.5 +/- 0.4 mg/dl). Consistent with our prediction, the net mass of CE transferred from HDL to VLDL + LDL was significantly increased in the PKT group (P < 0.001) compared with nondiabetic renal transplant patients receiving the same immunosuppressive drugs and healthy control subjects. Both basal and arginine-stimulated insulin levels were increased above the kidney transplant group's levels and correlated with the mass of CE transferred at 2 h (r = 0.71, P < 0.05; r = 0.66, P < 0.05, respectively). Total basal LpL activities, LpL and hepatic triacylglycerol lipase activities, and LpL mass all tended to be higher than levels in healthy control subjects. Consistent with these changes in lipase activity, VLDL particle size was significantly reduced (P < 0.025) compared with that of control subjects. These findings indicate that PKT patients with systemically draining allografts have a persisting profile of potentially atherogenic disturbances in insulin levels, LpL, and CET that resemble IDDM patients treated with conventional subcutaneous insulin injections.

Preferential cholesteryl ester acceptors among triglyceride-rich lipoproteins during alimentary lipemia in normolipidemic subjects.

Triglyceride-rich lipoproteins (TRLs), namely chylomicrons (CMs), VLDL, and their remnants, are implicated in the atherogenic features of postprandial lipemia. In human plasma, cholesteryl ester transfer protein (CETP) mediates the heteroexchange of neutral lipids, ie, triglycerides (TG) and cholesteryl esters (CE), between distinct subpopulations of apoB- and of apoAI-containing lipoproteins. In fasting normolipidemic plasma, CETP plays an antiatherogenic role by promoting preferential CE redistribution from HDL to LDL particles of intermediate subclass with optimal binding affinity for the cellular LDL receptor. While the relative proportions and chemical compositions of donor and acceptor lipoproteins are known to influence CETP activity, elevated levels of TRL present during alimentary lipemia have been proposed to be associated with enhanced CETP activity. To identify the preferential CE acceptor particles among postprandial TRL subfractions, we investigated the effects of a typical Western meal (1200 kcal, 14% protein; 38% carbohydrate; and 48% fat, monounsaturated/polyunsaturated ratio 4:1) on the rates of postprandial CE transfer from HDL to apoB-containing lipoproteins in normolipidemic subjects (n=13). Two hours postprandially, plasma levels of TRL were significantly elevated (140 versus 51 mg/dL at baseline, P=.0001). Total rates of CE transferred (88 +/- 7 microg x h[-1] x mL[-1]) from HDL to apoB-containing lipoproteins were not significantly modified by alimentary lipemia over a period of 8 hours. Quantitatively, LDL accepted 64+/-5 microg CE per hour per milliliter plasma from HDL, whereas CM (Sf>400), VLDL1 (Sf 60 to 400), VLDL2 (Sf 20 to 60), and IDL (Sf 12 to 20) accepted 5+/-3, 16+/-3, 1.4+/-0.3, and 1.5+/-0.2, respectively. Quantitatively, VLDL1 was the major CE acceptor among TRLs (P=.0001); thus, VLDL1, but not CMs, represented the major CE acceptor among TRLs. Qualitatively however, VLDL2 and IDL displayed a higher capacity to accept CE from HDL (51.6+/-4.1 and 46.3+/-2.8 microg CE transferred per hour per milligram lipoprotein, respectively; P<.005) compared with CM, VLDL1, and LDL (12.6+/-2.8, 34.7+/-4.2, and 22.7+/-2.0 microg CE transferred per hour per milligram lipoprotein, respectively). In conclusion, elevated postprandial TRL levels are not associated with enhanced total CE transfer to these particles. Furthermore, the qualitative features of postprandial CE transfer from HDL to CM and VLDL1 were not related to the relative TG content of these particles. The CETP-facilitated enrichment of VLDL1 in CE therefore identifies them as potentially atherogenic particles during the postprandial phase.

Alterations in cholesteryl ester transfer, lipoprotein lipase, and lipoprotein composition after combined pancreas-kidney transplantation

Alterations in cholesteryl ester transfer, lipoprotein lipase, and lipoprotein composition after combined pancreas-kidney transplantation