Cholesterol Ester Transfer Protein Activity Research Articles

The safety and immunogenicity of a CETP vaccine in healthy adults

A cholesterol ester transfer protein (CETP) vaccine (CETi-1) that induces auto-antibodies that specifically bind and inhibit activity of endogenous CETP has been demonstrated in rabbits to significantly increase HDL-C and reduce the development of atherosclerosis. In a Phase I human trial with CETi-1, one patient at the highest dose (250 mg) out of a total of 36 patients who received a single injection developed anti-CETP antibodies. In an extension study of 23 patients, 53% (8/15) who received a second injection of the active vaccine developed anti-CETP antibodies compared with 0% (0/8) in the placebo group. The vaccine was well tolerated and no significant laboratory abnormalities occurred. CETi-1 is a feasible therapy in humans to induce CETP auto-antibodies. Future research will determine if repeat inoculations will induce a sufficient anti-CETP antibody response to inhibit CETP and increase HDL levels.

EFFECT OF EXERCISE AND OMEGA-3 FATTY ACID SUPPLEMENTATION ON REVERSE CHOLESTEROL TRANSPORT VARIABLES

PURPOSE The purpose of this investigation was to examine the interaction of a session of aerobic exercise with omega-3 fatty acids (n-3 FA) supplementation on reverse cholesterol transport (RCT) variables. METHODS Subjects were 10 recreationally active males, aged 25 ± .5 y (M ± SE), VO2max 53.1 ± 1.7, who supplemented n-3 FA (60% EPA, 40% DHA) at 4 g/d for 3–5 wk. Before and after supplementation, subjects completed a 60 min session of treadmill exercise at 60% VO2max. Following a 24 h diet and activity control period, blood was drawn immediately before and after the exercise session to assess RCT variables: high-density lipoprotein cholesterol (HDL-C) and subfractions, lecithin: cholesterol acyltransferase activity (LCATa), and cholesterol ester transfer protein activity (CETPa). RESULTS Nutrient and kcal intake did not change over the supplementation period. ANOVA with repeated measures indicated that post n-3 FA supplementation concentrations were higher than pre supplementation for total HDL-C concentrations (50.0 ± 2.9 vs 52.8 ± 3.2 mg/dl) and HDL2-C (13.9 ± 1.3 vs 18.1 ± 2.4). But HDL3-C (36.1 ± 1.9 vs 34.7 ± 2.0), LCATa (1.7 ± .06 vs 1.6 ± .05 % esterification), or CETP (22.7 ± 1.4 vs 23.4 ± 2.2 % fluorescence) were not affected by supplementation. Post exercise plus supplementation concentrations were higher than supplementation alone only for total HDL3-C (34.7 ± 2.0 vs 37.4 ± 2.4) but not for HDL-C (52.8 ± 3.2 vs 56.2 ± 4.0 or HDL2-C (18.1 ± .4 vs 18.7 ± .0). Post exercise plus supplementation concentrations were different from exercise alone for HDL-C (50.4 ± 2.8 vs 56.2 ± 4.0) and HDL2-C (13.5 ± 1.1 vs 18.7 ± 2.0). The combined treatments had no additional effects on LCATa or CETPa. CONCLUSIONS In general, n-3 FA supplementation or an exercise session positively affected HDL-C and subfractions but did not affect the enzymes associated with RCT. The combination of n-3 FA and exercise may have additional effects on HDL-C and subfractions than either treatment alone in active young men. Supported by UMC Research Council and Hegarty Foundation

1P-0227 Apolipoprotein A-1 interaction with plasma membrane lipid rafts controls cholesterol export from macrophages

During reverse cholesterol transport plasma phospholipid transfer protein (PLTP) converts high density lipoprotein3 (HDL3) into two new subpopulations, HDL2-like particles and pre-β-HDL. The acute-phase response is accompanied with dramatic changes in lipid metabolism including alterations in HDL concentration, composition, and thereby its function as a substrate for HDL remodeling proteins in circulation. To evaluate how acute-phase HDL (AP-HDL) functions in PLTP-mediated HDL conversion, we collected plasma samples from patients with severe acute-phase response (n=17), and from healthy controls (n=30). Subsequently, total HDL (1.063<d<1.21 g/ml) was isolated from patients and controls and incubated in the absence and presence of purified PLTP. The results show that HDL isolated from the acute-phase patients is converted by PLTP in vitro in a corresponding manner as normal HDL. In the combined population, C-reactive protein correlated significantly with lecithin-cholesterol acyltransferase (LCAT) activity (r=−0.53), cholesterol ester transfer protein activity (r=−0.80), PLTP activity (r=0.44), and PLTP mass (r=−0.66). When compared to the controls, the patients had 31% higher PLTP activity, but 52% lower PLTP mass leading to a 165% higher PLTP specific activity in the patients. The present data indicate that during the acute-phase response, plasma PLTP activity and mass are strongly affected by the lipoprotein distribution as well as lipid composition. We suggest that the decrease of HDL during the acute phase is caused by reduced LCAT and increased PLTP activities both increasing the plasma levels of lipid-poor apoA-I particles.

Changes in LPLa and reverse cholesterol transport variables during 24-h postexercise period

We investigated the time course of exercise-induced lipoprotein lipase activity (LPLa) and reverse cholesterol transport (RCT) during the 24-h postexercise period. Subjects were 10 sedentary normolipidemic males [NTG; fasting triglyceride (TG) = 89.1 +/- 8.6 mg/dl] and 6 hyperlipidemic males (HTG; fasting TG = 296.8 +/- 64.0 mg/dl). Each subject performed a control trial (no exercise) and 4 exercise trials. In the exercise trials, a subject jogged on a treadmill at 60% of his maximal O(2) consumption for 1 h. Pre- and postheparin blood samples were taken before exercise (baseline) and at 4, 8, 12, and 24 h after exercise. There was no group difference in LPLa (P > 0.05) over the time points. When the LPLa data from the two groups were combined, LPLa at 24 h after exercise was higher than baseline or at 4, 8, 12 h after exercise (P < 0.05). Plasma TG and lecithin-cholesterol acyltransferase activity (LCATa) were higher in HTG than in NTG, and the total high-density lipoprotein-cholesterol (HDL(tot)-Chol) was lower in HTG than in NTG (P < 0.05). HDL(2)-Chol, LCATa, and cholesterol ester transfer protein activity did not differ during the 24-h postexercise period (P > 0.05). These results suggest that LPLa is still increasing 24 h after an acute aerobic exercise and that the magnitude of the increase in exercise-induced LPLa in HTG was similar to that in NTG. Furthermore, in the sedentary population with or without HTG, the variables related to RCT do not change during the 24-h period after exercise.

The Seeds from Plantago ovata Lower Plasma Lipids by Altering Hepatic and Bile Acid Metabolism in Guinea Pigs

Psyllium, the husks from Plantago ovata (PO), is recognized as a potent agent in lowering plasma cholesterol. In this study, we tested the potential hypolipidemic effects of the seeds from PO and the mechanisms associated with the lowering of plasma lipids. Male Hartley guinea pigs (n = 30; 10 per group) were fed either a control diet or diets containing 7.5 or 10 g/100 g PO for 4 wk. Diets were identical in composition except for the fiber source. The control diet contained 10 g/100 g cellulose and 2.5 g/100 g guar gum, whereas the PO diets were adjusted to a total of 12.5 g/100 g fiber with cellulose. Although a dose response was not observed, plasma triglycerides and LDL cholesterol were 34 and 23% lower in the PO groups compared with the control (P < 0.01). Lecithin cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) activities were significantly affected by the PO diets. The control group had 100 and 36% higher LCAT and CETP (P < 0.01) activities, respectively, compared with the PO groups. Hepatic total and free cholesterol concentrations were not affected by PO, but cholesteryl ester concentrations were 50% (P < 0.01) lower in the PO groups compared with the control. The activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol synthesis was up-regulated in the PO groups by 37%. Similarly, the activity of cholesterol 7alpha-hydroxylase, the regulatory enzyme of cholesterol catabolism to bile acids was 33% higher in the PO groups (P < 0.02). Fecal bile acids were 3 times higher in the PO groups than in the control group. These results suggest that PO exerts its hypolipidemic effect by affecting bile acid absorption and altering hepatic cholesterol metabolism.

Pre-Menopausal Women, Classified as Hypo- or Hyper-Responders, do not Alter their LDL/HDL Ratio Following a High Dietary Cholesterol Challenge

Background: Cholesterol is the dietary component that has elicited the most public interest in conjunction with coronary heart disease. However, the impact of excess dietary cholesterol intake on plasma cholesterol levels cannot be accurately predicted; therefore, its role in disease progression is not straightforward. Individual response variation can be due to factors such as ethnicity, hormonal status, obesity and genetic predisposition.Objective: The purpose of this study was to evaluate the differences that occur within the plasma compartment of normolipidemic pre-menopausal women, classified based on their response to a high dietary cholesterol challenge.Design: We recruited 51 pre-menopausal women (29 Caucasian and 22 of Hispanic origin) aged 18 to 49 years with initial plasma cholesterol concentrations ranging from 3.62 to 5.17 mmol/L. Using a cross-over research design, women were randomly allocated to an egg (640 mg additional dietary cholesterol per day) or placebo group (0 mg additional dietary cholesterol per day) initially, and the two 30 day periods were separated by a three-week washout.Results: An initial evaluation of the ethnicity effects revealed elevations in both plasma LDL-C (p < 0.0001) and HDL-C (p < 0.001) concentrations in both Hispanics and Caucasians during the high dietary cholesterol period. However, these increases were not accompanied by a change in the LDL/HDL ratio. Subjects were then classified as hypo- (< 0.05 mmol/L increase in total plasma cholesterol per each additional 100 mg of dietary cholesterol consumed per day) or hyper-responders (≥0.06 mmol/L increase in total blood cholesterol per each additional 100 mg of dietary cholesterol consumed per day), based on their reaction to the additional dietary cholesterol provided. Hypo-responders did not experience an increase in LDL-C or HDL-C during the egg period, while both lipoproteins were elevated in hyper-responders. However, the LDL/HDL ratio, an important parameter of coronary heart disease risk, was maintained for all subjects during the egg period independent of response. Furthermore, hyper-responders had higher concentrations of apo C-III (p < 0.001), apo B (p < 0.001) and cholesterol ester transfer protein (CETP) (p < 0.05) during this period.Conclusion: These data revealed that excess dietary cholesterol does not increase the risk of developing an atherogenic lipoprotein profile in pre-menopausal women, regardless of their response classification. Although the addition of 640 mg of cholesterol to the diet did result in an increase in plasma cholesterol in hyper-responders, the LDL/HDL ratio was maintained. This result, accompanied by increases in CETP activity, leads to the speculation that hyper-responders may process the excess cholesterol in the plasma compartment through an enhancement of the reverse cholesterol transport pathway. With this mechanism identified, further measurement of additional parameters is needed to verify this conclusion.

Association between HDL-cholesterol and the Taq1B polymorphism in the cholesterol ester transfer protein gene in obese women

Cholesterol ester transfer protein (CETP) facilitates reverse cholesterol transport via HDL-C and this activity may be increased in obese subjects. In normal weight subjects the Taq1B variant of the CETP gene is associated with lower CETP activity and higher HDL-C. The aim of this study was to examine the relationship between the Taq1B polymorphism and HDL-C in obese women before and after weight loss. A total of 245 women (41 with type 2 diabetes) were genotyped for the Taq1B variant. Plasma lipids, insulin, glucose and oral glucose tolerance were also measured before and after weight loss. When all subjects were examined together the Taq1B genotype was not associated with HDL-C. However, when non-diabetic subjects were divided by median fasting insulin, a strong linear association was observed between Taq1B genotype and HDL-C in subjects below median for fasting insulin (B1B1 1.19±0.07 mmol/l, B1B2 1.35±0.06, B2B2 1.71±0.09, P<0.000). This association was not observed in subjects with fasting insulin above median or subjects with type 2 diabetes, either before or after weight loss. Therefore, the B2B2 genotype is associated with elevated HDL-C in obese women with low fasting insulin only. Improved insulin sensitivity during weight loss did not change this relationship in women with high fasting insulin or type 2 diabetes.

Efficacy of a Therapeutic Lifestyle Change/Step 2 diet in moderately hypercholesterolemic middle-aged and elderly female and male subjects

Lifestyle modification to decrease cardiovascular disease (CVD) risk has recently been reaffirmed by both the National Cholesterol Education Program and American Heart Association (AHA). Using a randomized crossover design, the Therapeutic Lifestyle Change (TLC)/Step 2 diet relative to a typical Western diet was assessed in 36 moderately hypercholesterolemic subjects in a clinical setting under iso-weight conditions. Mean lipoprotein and apolipoprotein levels (fasting and non-fasting), fatty acid profiles, parameters of HDL metabolism, and glucose homeostasis were determined. Relative to the Western diet, the TLC/Step 2 diet resulted in 11% and 7% lower LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C), respectively, with no significant change in TG levels or total cholesterol-HDL-C ratio. Similar responses were observed in the non-fasting state. Linoleic (18:2n-6c) and α-linolenic (18:3n-3) acids increased at the expense of oleic acid (18:1n-9c) in the cholesteryl ester, TG, and phospholipid subfractions. The dietary changes had no significant effect on fractional esterification rate of HDL, phospholipid transfer protein (PLTP), or cholesterol ester transfer protein activities, or glucose and insulin levels. Female and male subjects responded similarly. The TLC/Step 2 diet resulted in a decrease in some CVD risk factors and no apparent adverse effects in others.—Lichtenstein, A. H., L. M. Ausman, S. M. Jalbert, M. Vilella-Bach, M. Jauhiainen, S. McGladdery, A. T. Erkkilä, C. Ehnholm, J. Frohlich, and E. J. Schaefer. Efficacy of a Therapeutic Lifestyle Change/Step 2 diet in moderately hypercholesterolemic middle-aged and elderly female and male subjects.

Effect of HMG-CoA reductase inhibitor on plasma cholesteryl ester transfer protein activity in primary hypercholesterolemia: comparison among CETP/TaqIB genotype subgroups.

We investigated the effects of HMG-CoA reductase inhibitors (statins) on the activity and concentration of plasma cholesterol ester transfer protein (CETP) in 30 hypercholesterolemic patients. Patients were divided into three groups according to TaqIB polymorphism of the CETP gene. The activity (158 +/- 23% control, mean +/- SEM) and concentration (4.1 +/- 1.0 mg/l) of plasma CETP were significantly (p < 0.005) higher in the subjects with the B1B1 genotype than B2B2 genotype (106 +/- 25% and 2.5 +/- 1.1 mg/l, respectively). Plasma CETP activity and concentration levels in the B1B2 group were intermediate between those of the B1B1 and B2B2 groups, and significantly (p < 0.05) low compared with the B1B1 group.Both the activity and concentration of plasma CETP were positively correlated with the LDL-cholesterol concentration (r = 0.608, p < 0.0005 and r = 0.552, p < 0.005, respectively). The administration of statins significantly reduced not only the activity (p < 0.01) but also the concentration (p < 0.05) of plasma CETP in hypercholesterolemic patients. Taken together, we confirmed that statins would be effective in increasing HDL levels in Japanese B1B1 carriers, because of a lower concentration of HDL cholesterol and higher level of plasma CETP compared to the other genotypes. The genetic variation in the CETP gene may be one important factor in designing better treatments.

The role of plasma phospholipid transfer protein (PLTP) in HDL remodeling in acute-phase patients

During reverse cholesterol transport plasma phospholipid transfer protein (PLTP) converts high density lipoprotein 3 (HDL 3) into two new subpopulations, HDL 2-like particles and pre-β-HDL. The acute-phase response is accompanied with dramatic changes in lipid metabolism including alterations in HDL concentration, composition, and thereby its function as a substrate for HDL remodeling proteins in circulation. To evaluate how acute-phase HDL (AP-HDL) functions in PLTP-mediated HDL conversion, we collected plasma samples from patients with severe acute-phase response ( n=17), and from healthy controls ( n=30). Subsequently, total HDL (1.063< d<1.21 g/ml) was isolated from patients and controls and incubated in the absence and presence of purified PLTP. The results show that HDL isolated from the acute-phase patients is converted by PLTP in vitro in a corresponding manner as normal HDL. In the combined population, C-reactive protein correlated significantly with lecithin-cholesterol acyltransferase (LCAT) activity ( r=−0.53), cholesterol ester transfer protein activity ( r=−0.80), PLTP activity ( r=0.44), and PLTP mass ( r=−0.66). When compared to the controls, the patients had 31% higher PLTP activity, but 52% lower PLTP mass leading to a 165% higher PLTP specific activity in the patients. The present data indicate that during the acute-phase response, plasma PLTP activity and mass are strongly affected by the lipoprotein distribution as well as lipid composition. We suggest that the decrease of HDL during the acute phase is caused by reduced LCAT and increased PLTP activities both increasing the plasma levels of lipid-poor apoA-I particles.

Impact of hydrogenated fat on high density lipoprotein subfractions and metabolism

Relative to saturated fatty acids, trans-fatty acids/hydrogenated fat-enriched diets have been reported to increase low density lipoprotein (LDL) cholesterol levels and either decrease or have no effect on high density lipoprotein (HDL) cholesterol levels. To better understand the effect of trans-fatty acids/hydrogenated fat on HDL cholesterol levels and metabolism, 36 subjects (female, n = 18; male, n = 18) were provided with each of three diets containing, as the major sources of fat, vegetable oil-based semiliquid margarine, traditional stick margarine, or butter for 35-day periods. LDL cholesterol levels were 155 +/- 27, 168 +/- 30, and 177 +/- 32 mg/dl after subjects followed the semiliquid margarine, stick margarine, and butter-enriched diets, respectively. HDL cholesterol levels were 43 +/- 10, 42 +/- 9, and 45 +/- 10 mg/dl, respectively. Dietary response in apolipoprotein (apo) A-I levels was similar to that in HDL cholesterol levels. HDL(2) cholesterol levels were 12 +/- 7, 11 +/- 6, and 14 +/- 7 mg/dl, respectively. There was virtually no effect of dietary fat on HDL3 cholesterol levels. The dietary perturbations had a larger effect on particles containing apoA-I only (Lp A-I) than apoA-I and A-II (Lp A-I/A-II). Cholesterol ester transfer protein (CETP) activity was 13.28 +/- 5.76, 15.74 +/- 5.41, and 14.35 +/- 4.77 mmol x h(-1) x ml(-1), respectively. Differences in CETP, phospholipid transfer protein activity, or the fractional esterification rate of cholesterol in HDL did not account for the differences observed in HDL cholesterol levels. These data suggest that the saturated fatty acid component, rather than the trans- or polyunsaturated fatty acid component, of the diets was the putative factor in modulating HDL cholesterol response.

Cholesteryl ester transfer and cholesterol esterification in type 1 diabetes: relationships with plasma glucose

The activities of two crucial enzymes of reverse cholesterol transport, cholesterol ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), and their relationships with lipid profile and fasting plasma glucose were examined in 35 type 1 diabetic children. The CETP and LCAT activities were significantly lower (p<0.05) in the 4 subjects with normal fasting plasma glucose levels (<6.39 mmol/l) than in the 28 with high plasma glucose levels (CEPT activity, 10.63+/-3.81 vs. 32.18+/-13.94 nmol/ml h; LCAT activity, 25.52+/-4.53 vs. 39.52+/-12.52 nmol/ml h; both p<0.05). The subjects with high plasma glucose levels also had higher total and LDL-cholesterol than those with normal glucose levels. CETP activity was positively correlated with fasting plasma glucose, CETP concentration, LCAT activity, total cholesterol, free cholesterol, LDL-C, and LDL-cholesteryl ester, while negatively correlated with cholesteryl ester to free cholesterol ratio, LDL triglyceride to protein ratio, and LDL triglyceride to cholesteryl ester ratio. LCAT activity was found to positively correlate with CETP activity, total cholesterol, free cholesterol, LDL-C, CETP concentration, and LDL-cholesteryl ester, while it negatively correlated with cholesteryl ester to free cholesterol ratio. The results observed in type 1 diabetic subjects suggest that (1) accelerated LCAT and CETP activities may result in the accumulation of LDL-cholesteryl ester; and (2) fasting plasma glucose may be a major determinant of CETP activity.

Effect of 6 dietary fatty acids on the postprandial lipid profile, plasma fatty acids, lipoprotein lipase, and cholesterol ester transfer activities in healthy young men

There is increasing evidence that postprandial triacylglycerol-rich lipoproteins may be related to atherogenic risk. The objective was to investigate the effect of individual fatty acid intakes on postprandial plasma lipoprotein triacylglycerol and cholesterol concentrations, plasma fatty acids, and preheparin lipoprotein lipase and cholesterol ester transfer protein (CETP) activities. Six test fats high (approximately 43% by wt) in stearic acid, palmitic acid, palmitic + myristic acid, oleic acid, elaidic acid (trans 18:1), and linoleic acid were produced by interesterification. After having fasted for 12 h, 16 healthy young men were served the individual test fats incorporated into meals (1 g fat/kg body wt) in random order on different days separated by washout periods. Blood samples were drawn before and 2, 4, 6, and 8 h after the meals. Different responses to the test-fat meals were observed for plasma lipoprotein triacylglycerol and cholesterol concentrations, plasma fatty acid concentrations, and lipoprotein lipase and CETP activities (diet x time interaction: 0.001 < P < 0.05). Intake of the long-chain saturated fatty acids stearic and palmitic acids resulted in a relatively lower lipemic response than did intake of the unsaturated fatty acids, probably because the saturated fatty acids were absorbed less and at a lower rate; therefore, the lipemic response took longer to return to postabsorptive values. Fatty acid chain length and degree of saturation appear to affect the extent and duration of lipemia and affect hepatic output indirectly. These effects may not be mediated via effects on lipoprotein lipase and CETP activities.

Effect of the nonenzymatic glycosylation of high density lipoprotein-3 on the cholesterol ester transfer protein activity.

This study examines the relationship between high density lipoprotein-3 (HDL-3) glycation and cholesteryl ester transfer mediated by cholesteryl ester transfer protein (CETP). HDL-3 were glycated with various glucose concentrations (0-200 mM) for 3 d at 37 degrees C with sodium cyanoborohydride as reducing agent and antioxidants. About 47% of the lysine residues were glycated in the presence of 200 mM glucose, resulting in an increase in the cholesterol ester (CE) transfer of about 30%. Apparent kinetic parameters [expressed as maximal transfer (appT(max)) and CE concentration at half of T(max)(appK(H))] of CETP activity with glycated HDL-3 showed conflicting and paradoxical data: an increase in CETP activity associated with a decrease of CETP affinity. These alterations were not due to a change in HDL-3 lipid and protein composition nor to a peroxidative process but were associated with an increase in HDL-3 electronegativity and a decrease of HDL-3 fluidity. This study suggests that glycation modifies the apolipoprotein's conformation and solvation which are major determinants of interfacial properties of HDL-3. These modifications in turn affect CETP reactivity.

Comparison of the effects of diet and simvastatin on serum high-density lipoprotein cholesterol and cholesteryl ester transfer protein activity in outpatients with hypercholesterolemia

We compared the effects of diet alone with those of diet plus simvastatin on serum lipids and lipoproteins, especially serum highdensity lipoprotein cholesterol (HDL-C) and plasma cholesteryl ester transfer protein (CETP) activity, to determine whether these treatments affect the metabolism of HDL-C by CETP. A total of 27 outpatients (17 women and 10 men) with hypercholesterolemia (total cholesterol [TC] ≥220 mg/dL) were randomly assigned to treatment with diet (group D) or diet plus simvastatin 5 mg/d (group S). Serum TC and low-density lipoprotein cholesterol (LDL-C) decreased significantly in response to both diet and diet plus simvastatin treatment, although the reductions were significantly greater in group S than in group D (TC: 20% vs 13% [ P < 0.05], LDL-C: 28% vs 18% [ P < 0.01], respectively). Neither serum triglyceride (TG) levels nor percentage changes in TG differed significantly between the 2 groups. Serum HDL-C levels decreased in group D ( P < 0.01) but increased in group S ( P < 0.05). The serum TC:HDL-C and apolipoprotein B:A-I ratios decreased significantly in both groups ( P < 0.05 and P < 0.01 in group D, and P < 0.0001 and P < 0.0001 in group S, respectively); the magnitude of the changes was greater in group S than in group D ( P < 0.001, both ratios). Serum HDL 2-C levels increased significantly only in group S ( P < 0.05); HDL 3-C, the HDL 2-C:HDL 3-C ratio, and CETP activity did not change significantly in either group. An inverse correlation between ΔCETP and ΔHDL 2-C was found in group D ( r = −.550, P < 0.05); however, this correlation was not significant in group S. Simvastatin administration, which caused a significant reduction in both TC and LDL-C levels, did not produce a significant change in serum CETP activity. This is probably caused by the inadequate decrease in TG levels or the maintenance of increased levels of CETP, during which TG-rich lipoproteins such as very-low-density lipoprotein and LDL act as acceptors for cholesteryl esters transferred from HDL-C by CETP activity.

Increased cholesterol ester transfer protein (CETP) activity modulates composition and metabolic clearance of HDL in insulin resistant states

Increased cholesterol ester transfer protein (CETP) activity modulates composition and metabolic clearance of HDL in insulin resistant states

正常TG血症者におけるCETP活性とリポ蛋自リパーゼ, HDL-およびLDL-コレステロールとの関係

There has been conflicting data as to the role of cholesterol ester transfer protein (CETP), which show that it is atherogenic or anti-atherogenic by the HDLcholesterol catabolism. Accordingly, further investigations are necessary as to the role of CETP. This study was conducted to determine the role of CETP for lipid metabolism in normotriglyceridemia. Methods Plasma lipid levels, apolipoprotein concentration and CETP activities were measured in 31 male and 19 female subjects (aged 30 to 80 years). Further more, their relationships to coronary heart disease (CHD) prevalence was analyzed. Patients with hepatic and thyroidal dysfunction and diabetes mellitus were excluded from this study. CETP activities were measured by the method of Katoh et al Results: A positive correlation between LDL-cholesterol and CETP activity (r=0.46, p<0.01) was found, but no correlation was found between HDL-cholesterol and CETP activity. There was no relationship between the incidence of CHD and CETP activity. Conclusion: It is suggested that CETP also plays an important role in the metabolism of LDL-cholesterol, in addition to in the transfer of HDLcholesterol. However, it remains unknown whether CETP is atherogenic or anti-atherogenic.

In vivo evidence for increased apolipoprotein A-I catabolism in subjects with impaired glucose tolerance.

The in vivo kinetics of the HDL apolipoproteins (apo) A-I and A-II were studied in six subjects with impaired glucose tolerance (IGT) and six control subjects with normal glucose tolerance (NGT), using a stable isotope approach. During a 12-h primed constant infusion of L-[ring-13C6]-phenylalanine, tracer enrichment was determined in apoA-I and apoA-II from ultracentrifugally isolated HDL. The rates of HDL apoA-I and apoA-II production and catabolism were estimated using a one-compartment model-based analysis. Triglycerides were higher in IGT subjects (1.33 +/- 0.21 vs. 0.84 +/- 0.27 mmol/l, P < 0.05), but were within the normal range. HDL cholesterol and apoA-I levels were significantly lower in subjects with IGT (1.07 +/- 0.15 vs. 1.36 +/- 0.14 mmol/l, P < 0.05; 0.94 +/- 0.10 vs. 1.34 +/- 0.07 g/l, P < 0.01). In IGT subjects, HDL composition was significantly altered, characterized by an increase in HDL triglycerides (4.9 +/- 1.9 vs. 3.2 +/- 1.0%, P < 0.05) and HDL phospholipids (34.7 +/- 2.6 vs. 27.5 +/- 5.8%, P < 0.05) and a decrease in HDL cholesteryl esters (10.1 +/- 2.0 vs. 12.7 +/- 2.9%, P < 0.05) and HDL apoA-I (31.5 +/- 4.4 vs. 43.2 +/- 2.4%, P < 0.05). The mean fractional catabolic rate (FCR) of HDL apoA-I was significantly higher in IGT subjects (0.34 +/- 0.05 vs. 0.26 +/- 0.03 day(-1), P < 0.01), while the HDL apoA-I production rate (PR), as well as the PR and FCR of HDL apoA-II, showed no differences between the two groups. There were significant correlations between HDL apoA-I FCR and the following parameters: HDL apoA-I (r = -0.902, P < 0.001), HDL cholesterol (r = -0.797, P = 0.001), plasma triglycerides (r = 0.743, P < 0.01), HDL triglycerides (r = 0.696, P < 0.01), and cholesterol ester transfer protein activity (r = 0.646, P < 0.01). We observed a strong positive association between increased apoA-I catabolism and insulin (r = 0.765, P < 0.01) and proinsulin (r = 0.797, P < 0.01) concentrations. These data support the hypothesis that the decrease in HDL cholesterol and apoA-I levels in IGT is principally the result of an enhanced apoA-I catabolism. The latter seems to be an early metabolic finding in IGT even when other lipid parameters, especially plasma triglycerides, still appear to be not or only weakly affected.

Compositional and functional changes of low-density lipoprotein during hemodialysis in patients with ESRD

This study focused on the effects of hemodialysis on the atherogenic properties of low density lipoprotein (LDL) in patients with end-stage renal disease (ESRD). The impact of cholesterol ester transfer protein (CETP) activity and lipolysis on LDL composition, particularly the changes during hemodialysis, was investigated. Blood was drawn from 15 normotriglyceridemic (NTG) and 15 hypertriglyceridemic patients [HTG; triglycerides (TG) < 2.2 mmol/liter] before hemodialysis, during (1.5 hr after the beginning of anticoagulation) and at the end of treatment. In each sample, lipid values and CETP activity were measured. LDL was prepared and characterized by its components and diameters (2 to 16% PAGGE). To investigate the functional properties of LDL, fractions obtained from NTG and HTG patients were incubated with human skin fibroblasts and a cell line of murine macrophages (P388), and cholesterol ester formation rates were measured. In comparison to LDL from NTG patients at baseline, HTG-LDL were enriched in triglycerides (P < 0.02), depleted in cholesterol proportion (P < 0.01) and small in size (P < 0.001). These LDL induced the cholesterol esterification rates (50 micrograms/mL LDL-protein) in a twofold greater unsaturation in macrophages when compared to LDL from NTG patients (P < 0.04). The rates in fibroblasts were reduced by approximately half (P < 0.05). During hemodialysis, LDL were decreased in size (P < 0.001) and depleted in TG (P < 0.01), particularly in the hypertriglyceridemic state. Although CETP activity increased during hemodialysis (P < 0.001), the cholesterol content remained unchanged. When HTG-LDL obtained during hemodialysis were incubated with cells, esterification rates particularly in macrophages were markedly accelerated in comparison to the unmodified lipoprotein at baseline (P < 0.05). LDL from HTG patients with ESRD was TG-enriched, CH-depleted and smaller in size. As the intracellular esterification rates induced by LDL were related to the cellular uptake, these LDL were a superior substrate for murine macrophages with the tendency of intracellular accumulation, and an inferior substrate for fibroblasts suggesting a decreased uptake by the specific receptor pathway. TG-depletion of LDL during hemodialysis, particularly in HTG patients due to a lipase-mediated TG-hydrolysis, increased these effects in macrophages. We suggest that the alterations of LDL that occur during repeated hemodialysis in vivo could contribute to the high prevalence of premature atherosclerosis found in HTG patients with ESRD.

Effect of 20 days' bed rest on the reverse cholesterol transport system in healthy young subjects.

To study the effects of 20 days of bed rest on HDL cholesterol, lipoprotein lipase, hepatic triglyceride lipase, cholesterol ester transfer protein and lecithin-cholesterol acyltransferase. A 20-day intervention study. Makita general hospital. Five male and five female healthy participants, mean age 20.4 years, range 19-24 years. Twenty days of bed rest. Lipid, lipoprotein, lipoprotein lipase, hepatic triglyceride lipase, cholesterol ester transfer protein and lecithin-cholesterol acyltransferase. Fasting HDL, HDL2 and HDL3 cholesterol levels decreased from 1.748 to 1.404 mmol L(-1) (P < 0.01), from 0.807 to 0.628 mmol L(-1) (P < 0.01) and from 0.939 to 0.784 mmol L(-1) (P < 0.05), respectively, while VLDL triglyceride levels increased from 0.365 to 0.754 mmol L(-1) (P < 0.05). Plasma post-heparin lipoprotein lipase activity decreased from 0.494 to 0.418 micromol mL(-1) h(-1) (P < 0.01), but plasma post-heparin hepatic triglyceride lipase activity and cholesterol ester transfer protein activity did not change during bed rest. Lecithin-cholesterol acyltransferase activity increased from 72.5 to 84.8 nmol mL(-1) h(-1) (P < 0.001). Twenty days of bed rest induced a decline in HDL cholesterol levels and an increase in VLDL triglyceride levels. When considering lipoprotein lipase, hepatic triglyceride lipase, cholesterol ester transfer protein and lecithin-cholesterol acyltransferase as factors in the decreased HDL cholesterol, the contribution of lipoprotein lipase is suggested.