Cholesterol Ester Transfer Protein Activity Research Articles

Association Between Lipids, Lipoproteins Composition of HDL Particles and Triglyceride-Rich Lipoproteins, and LCAT and CETP Activity in Post-renal Transplant Patients

High-density lipoprotein (HDL) remodeling within the plasma compartment and the association between lecithin-cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) activity, and lipid, lipoprotein concentrations and composition were investigated. The aim was to examine the high sensitivity of C-reactive protein (hsCRP), lipid, apolipoprotein B (apoB), apoAI, total apoAII, apoAIInonB, apoB-containing apoAII (apoB:AII), total apoCIII, apoCIIInonB, apoB-containing apoCIII (apoB:CIII) concentration and LCAT and CETP activity to gain an insight into the association between them and LCAT and CETP, 57 post-renal transplant (Tx) patients with and without statin therapy and in 15 healthy subjects. Tx patients had moderate hypertriglyceridemia, hypercholesterolemia, and dyslipoproteinemia, disturbed triglyceride-rich lipoproteins (TRLs) and HDL composition, decreased LCAT, and slightly increased hsCRP but no CETP activity. Spearman’s correlation test showed the association between lipids and lipoproteins and LCAT or CETP, and multiple ridge stepwise forward regression showed that immunosuppressive therapy in Tx patients can disturb HDL and TRLs composition. The results suggest that inhibition or activation of LCAT is due, in part, to HDL-associated lipoprotein. Lipoprotein composition of apoAI, apoAIInonB, and apoCIIInonB in HDL particle and apoB:AII TRLs can contribute to decrease LCAT mass in Tx patients. Tx patients without statin and with lower triglycerides but higher HDL cholesterol concentration and disturbed lipoprotein composition of ApoAI and apoAII in HDL particle can decrease LCAT, increase LDL cholesterol, aggravate renal graft, and accelerate atherosclerosis and chronic heart diseases.

Distinct regulation of plasma LDL cholesterol by eicosapentaenoic acid and docosahexaenoic acid in high fat diet-fed hamsters: Participation of cholesterol ester transfer protein and LDL receptor

Despite established anti-atherogenic action, previous reports have shown that fish oils or n-3 poly-unsaturated fatty acid (PUFA) increase plasma LDL-C in animals and humans. However, which component of n-3 PUFAs and what mechanisms contribute to this increase are unclear. We investigated the effects of the major components of n-3 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on plasma LDL-C in high fat diet-fed hamsters. While LDL-C increased significantly with n-3 PUFA oil and DHA, EPA had no effect on LDL-C. Interestingly, a positive correlation was found between plasma cholesterol ester transfer protein (CETP) activity and LDL-C. Only DHA increased plasma CETP activity and significantly decreased LDL receptor expression in the liver. Our data suggest that DHA, not EPA, is a major factor in the LDL-C increasing effect of n-3 PUFA oil. These differential effects on LDL-C may arise from differences in plasma CETP activity and LDL receptor expression.

Abstract 19: Single-Dose Extended-Release Niacin Acutely Attenuates HDL Reduction in the Setting of Experimental Oral Fat Challenge: A Possible Role of ANGPTL-3 and CETP Modulation

Background: High density lipoprotein (HDL-c) levels are inversely correlated with the development of atherosclerosis and are reduced postprandially. Niacin is the most potent elevator of fasting HDL-c but the mechanisms are not fully elucidated, and its effects on postprandial HDL-c are largely unknown. Aim: Our aim was to determine whether a single dose ER niacin before a fat challenge acutely attenuates the postprandial drop in HDL-c compared to placebo, and to determine whether angiopoeitin like protein 3 (ANGPTL3) and cholesterol ester transfer protein (CETP) contribute to increased postprandial HDL-c by niacin. Method: We conducted 2 postprandial studies in healthy volunteers: 1. a double-blinded, placebo-controlled, random-order crossover experiment comparing 2 grams of ER niacin to matching placebo, and 2. open-label administration of 1 gram of ER niacin compared to a fat load without niacin. Study drug was administered 1 hour prior to an oral fat load of heavy cream followed by serial plasma sampling for triglyceride (TG), apolipoprotein A-1 (Apo A-1), ANGPTL3, and CETP mass and activity, and HDL-c over 12 hours. Data are expressed as means (95% CI) for incremental (iAUC) or total (tAUC) area under the curve. Results: Study 1 involved 304 fat challenges in 152 subjects. As expected HDL-c dropped after the fat load alone, with an iAUC of -71.9 mg/dL*h (-65.1 to -78.6),whereas 1 gram ER niacin reduced the drop to -32.5 mg/dL*h (-25.6 to -39.3) a 55% difference (p<0.00001). In Study 2, 2 grams ER-Niacin mitigated the drop in HDLc more effectively: the iAUC was -19.0 (-35.7 to -2.3) on placebo vs. -2.1 (-18.8 to +14.6) mg/dL*h on niacin, an 89% difference ( p=0.047). ANGPTL3 iAUC was +2206 ng/mL*h (+1811 to +2602) on placebo vs. +2560 ng/mL*h (+2165 to +2955) on ER-niacin, a 16% rise (p=0.001). CETP activity decreased from an iAUC of +118.2 nmol/L*h (95%CI +90.5 to +146) to -15.7 nmol/L*h (95%CI -36.4 to +5.1) on niacin, so that the usual postprandial increase in CETP activity was abolished by niacin (p<0.00001). Postprandial TG tAUC was strongly inversely correlated with HDL tAUC (Spearman’s rho -0.62, p<0.00005). Conclusions: HDL-c decreases significantly in the setting of an experimental oral fat load. We found that one-time dosing with either 1 or 2 grams of ER-Niacin mitigated this decline in drug-naive subjects. Acute pharmacodynamic effects of ER-niacin including TG lowering, ANGPTL3 elevation and CETP suppression may play a mechanistic role in this process.

Apolipoprotein C-I Binds More Strongly to Phospholipid/Triolein/Water than Triolein/Water Interfaces: A Possible Model for Inhibiting Cholesterol Ester Transfer Protein Activity and Triacylglycerol-Rich Lipoprotein Uptake

Apolipoprotein C-I (apoC-I) is an important constituent of high-density lipoprotein (HDL) and is involved in the accumulation of cholesterol ester in nascent HDL via inhibition of cholesterol ester transfer protein and potential activation of lecithin:cholesterol acyltransferase (LCAT). As the smallest exchangeable apolipoprotein (57 residues), apoC-I transfers between lipoproteins via a lipid-binding motif of two amphipathic α-helices (AαHs), spanning residues 7-29 and 38-52. To understand apoC-I's behavior at hydrophobic lipoprotein surfaces, oil drop tensiometry was used to compare the binding to triolein/water (TO/W) and palmitoyloleoylphosphatidylcholine/triolein/water (POPC/TO/W) interfaces. When apoC-I binds to either interface, the surface tension (γ) decreases by ~16-18 mN/m. ApoC-I can be exchanged at both interfaces, desorbing upon compression and readsorbing on expansion. The maximal surface pressures at which apoC-I begins to desorb (Π(max)) were 16.8 and 20.7 mN/m at TO/W and POPC/TO/W interfaces, respectively. This suggests that apoC-I interacts with POPC to increase its affinity for the interface. ApoC-I is more elastic on POPC/TO/W than TO/W interfaces, marked by higher values of the elasticity modulus (ε) on oscillations. At POPC/TO/W interfaces containing an increasing POPC:TO ratio, the pressure at which apoC-I begins to be ejected increases as the phospholipid surface concentration increases. The observed increase in apoC-I interface affinity due to higher degrees of apoC-I-POPC interactions may explain how apoC-I can displace larger apolipoproteins, such as apoE, from lipoproteins. These interactions allow apoC-I to remain bound to the interface at higher Π values, offering insight into apoC-I's rearrangement on triacylglycerol-rich lipoproteins as they undergo Π changes during lipoprotein maturation by plasma factors such as lipoprotein lipase.

Abstract 8817: Niacin Promotes Macrophage Reverse Cholesterol Transport in Hypercholesterolemic Mice In a CETP-Dependent Manner

Background- Niacin is the most effective drug currently available to increase HDL-cholesterol. The aim of the present study was to examine the effect of niacin on macrophage reverse cholesterol transport (RCT), a primary atheroprotective property of HDL, and to determine the mechanisms by which this occurs. Methods and Results- Niacin increased HDL-cholesterol in homozygous LDL receptor-deficient ( Ldlr -/- ) mice expressing human cholesterol ester transfer protein (CETP) ( Ldlr -/- . CETP ), but not in the mice without CETP. Niacin promoted macrophage RCT in the mice in a CETP-dependent manner. Treatment of Ldlr -/- . CETP mice with niacin decreased plasma CETP activity ex vivo , without the alteration of hepatic CETP expression or plasma CETP mass. Niacin also promoted macrophage RCT by reducing CETP activity even in the setting of partial lack of LDL receptor with CETP expression ( Ldlr +/- . CETP mice). Ldlr -/- . CETP mice and Ldlr +/- . CETP mice with niacin had the enhanced plasma capacity to promote macrophage cholesterol efflux. Moreover, niacin attenuated the transfer of cholesteryl esters from HDL to VLDL/LDL fractions in vivo , consistent with its inhibitory effect on CETP activity. Kinetic studies showed that niacin increased fecal excretion of HDL-derived cholesteryl esters in Ldlr -/- . CETP , but not in Ldlr -/- mice. Conclusions- Our observations demonstrate that niacin promotes macrophage RCT in vivo by decreasing plasma CETP activity in the setting of both complete and partial lack of LDL receptor. Niacin-mediated reduction in CETP activity leads to the enhanced direct pathway of RCT from HDL fractions into feces with the promotion of plasma efflux capacity from macrophages in the mice.

Post-menopausal hormone therapy reduces autoantibodies to oxidized apolipoprotein B100

The aim of the study was to verify whether post-menopausal hormone replacement therapy (HRT) modifies autoantibody titers against oxidized low-density lipoprotein (LDL) (anti-LDLoxi), against epitopes of oxidized apolipoprotein B100 and common carotid intima-media thickness (IMT) in these women. Sixty-eight women in pre-menopause (PMW) and 216 in post-menopause (POMW) were recruited; eighty-three had undergone HRT for at least 12 months, where 48 received conjugated estrogens alone (EHRT) and 35 received conjugated estrogen and medroxyprogesterone acetate (CHRT). ELISA was used to determine autoantibodies. Lipoprotein lipase (LPL), hepatic lipase (HL), cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP) activities were assayed by radiometric methods. IMT was measured using Doppler ultrasound. Anti-oxidized LDL and anti-D antibodies increased by 40% (p ≤ 0.003) and 42% (p ≤ 0.006), respectively, with menopause. There was a surprising and significant 7% reduction in anti-D2 antibody titers with HRT (p ≤ 0.050), indicating a positive effect of treatment on the immune response to oxidized LDL. Combined HRT decreased activities of HL and LPL. HRT did not change common carotid IMT, which was increased by 32% as expected after menopause (p ≤ 0.030). This study describes, for the first time, the protective effect of HRT on decreasing autoantibody titers against oxidized apolipoprotein B in LDL.

Continuous and intermittent walking alters HDL2-C and LCATa

PurposeThe purpose of this study was to determine if exercise, whether continuous (CE: completed all in one session) or intermittent (completed in either two (IE 2) or three (IE 3) exercise sessions) expending the same number of calories alters reverse cholesterol transport or low density lipoprotein (LDL) particle size. MethodsSixteen healthy (22±2.1 year old) men (VO2 max=37.0±3.3mL/kg/min) randomly completed three exercise trials, CE, IE 2 and IE 3, expending 450 calories. Blood samples were drawn immediately post-exercise (IPE) and 24 and 48h following exercise and analyzed for total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) and subfractions (HDL2-C, HDL3-C). Samples were also analyzed to determine LDL-C particle size, lecithin cholesterol acyl transferase activity (LCATa) and cholesterol ester transfer protein activity (CETPa). ResultsHDL2-C increased significantly 48h post-exercise in the CE and IE 2 groups. Additionally, the IE 3 group had significant increases in HDL2-C at 24 (39%) and 48h post-exercise by 66%. This change in HDL2-C was significantly and positively correlated (r=0.62; p<0.05) to the changes in LCATa which increased compared to baseline at 48h post-exercise in the CE and IE 3 groups. No significant changes in LDL particle size or alterations in CETPa were seen. ConclusionsThe results of this study indicate that whether the exercise is continuous or intermittent, keeping calorie expenditure the same, causes significant changes in the HDL2-C subfraction, which was augmented by an increase in LCATa.

An in vivo method for the measurement of cholesterol ester transfer protein (CETP) activity in humans

Low HDLc concentrations in the metabolic syndrome are driven by elevated TG-rich lipoproteins (TRL) through the enzyme CETP. The goal of this study was to determine the quantitative transfer of postprandial TG into HDL in vivo. Obese patients (5M, 4F, 44±10 y) were chronically infused (13C1-acetate) and fed (d31-TG) stable isotopes for 4 days to track de novo and dietary fatty acids (FA) in TRL and HDL. As expected, fasting HDLc concentrations (mean ± SD, 21±2 mg/dL) correlated negatively with TRL-TG (R2=0.49, P=0.03). From fasting to feeding, the TG concentration increased in both TRL (from 165.5±57.0 to 184.2±53.7 mg/dL) and HDL (8.0±3.0 to 13.1±2.6 mg/dL, P< 0.03 for both). The fractional contribution of de novo FA in TRL and HDL-TG were nearly identical during the fasting state (10.9±1.2 vs 9.3±1.0%). However, after a meal, de novo FA rose first in TRL, followed by a rise in HDL, to achieve peak values of 20.2±1.0 and 11.8±1.1%, respectively. The peak fed-state de novo FA in both lipoproteins correlated positively (R2=0.914, P=0.0002). Furthermore, the dietary label peaked in HDL-TG within 1h after feeding, and the contribution of dietary FA to TRL-TG positively correlated to those in HDL-TG (R2=0.958, P=0.02). Using a multiple stable isotope approach, these are the first data in humans to document the direct transfer of TG from TRL to HDL in vivo. This work was funded by a UW-Stout Faculty Research Initiative Award.

Effect of Bariatric Surgery-Induced Weight Loss on SR-BI-, ABCG1-, and ABCA1-Mediated Cellular Cholesterol Efflux in Obese Women

We tested the hypothesis that quantitative changes in high-density lipoprotein (HDL) particles weight loss induced by Roux-en-Y bypass (RYGBP) in morbidly obese subjects might be associated with improved functionality of these particles in the reverse cholesterol transport pathway. Thirty-four morbidly obese women were recruited and followed up before and 6 months after RYGBP. After surgery, along with a major weight loss (-20%; P < 0.0001), we observed a significant increase in HDL mass concentration (+14%; P < 0.04), reflecting a specific increase in large HDL2 subfraction levels (+42%; P < 0.01), whereas those of HDL3 remained unchanged. Cholesterol ester transfer protein activity decreased significantly (-15%; P < 0.0001). Efflux capacity of total plasma increased significantly via both scavenger receptor class B type I (SR-BI) (+58%; P < 0.0001) and ATP binding cassette G1 (ABCG1) (+26%; P < 0.0001) pathways. Such enhanced capacity resulted from increased capacity of HDL2 particles to mediate cholesterol efflux through the SR-BI pathway (+56%, P < 0.001) and from the increase plasma level of cholesteryl ester-rich HDL2 particles for the ABCG1 pathway. RYGBP-induced weight loss results in improvement in atherogenic lipid profile including a shift toward a more cardioprotective HDL subfraction profile. In addition, our in vitro studies demonstrated an increased in plasma efflux capacity via both SR-BI and ABCG1 after surgery.

Effect of increasing doses of Rosuvastatin and Atorvastatin on apolipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and inflammatory parameters

This paper contains detailed results of a sub-population of the prospective randomized RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study.Objective:Statin treatment results in substantially decreased incidence of cardiovascular events but the exact pathophysiological mechanism of their beneficial effect is yet unclear. We aimed to examine the effects of up-titrated doses of two widely used statins (atorvastatin (ATOR) and rosuvastatin (ROSU)) on parameters involved in lipoprotein metabolism, in patients with low high density lipoprotein cholesterol values (HDL-C).Research design and methods:In this RADAR substudy, 80 patients, aged 40–80 years, with known cardiovascular disease and low HDL-C (<1.0 mmol/l), were randomized to receive, after an initial 6 week dietary run-in phase, either ATOR 20 mg (n = 41) or ROSU 10 mg (n = 39). The doses were up-titrated (in 6 week intervals) to 80 mg of ATOR or 40 mg of ROSU at 12 weeks. Serum lipoproteins and lipoprotein metabolism parameters were measured at baseline and at 6 and 18 weeks of follow up.Results:Both statins significantly reduced total cholesterol (TChol) and non-HDL-C values with ROSU being more effective for the doses studied (p < 0.05). No statistically significant effect on HDL-C was observed for either statin. Apolipoproteins (apo) B, CI, CIII, AV and E were significantly reduced in both groups (p < 0.05), while the ratio of HDL particles containing both apoAI and apoAII (LpAI-AII) over HDL containing apoAI alone (LpAI) was changed for both statins with the decrease of LpAI being more prominent in the ATOR group (p = 0.028). Cholesterol ester transfer protein (CETP) mass and activity, phospholipid transfer protein (PLTP) activity and lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity were all significantly reduced in both treatment groups over the follow-up period (p < 0.001). ATOR displayed a more prominent decrease of PLTP activity compared to ROSU (p = 0.043), while ROSU displayed a more prominent decrease of Lp-PLA2 activity compared to ATOR (p = 0.04). Both statins effectively reduced, in a dose-dependent way, high sensitivity C-reactive protein values over time, while no effect on the levels of circulating inter cellular adhesion molecule 1 (cICAM-1) was observed.Conclusions:The effects of statin treatment extend further and beyond a mere TChol and LDL cholesterol reduction, as demonstrated by the aforementioned alterations of lipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and pro-atherogenic and inflammatory molecules. ROSU and ATOR displayed a similar pattern of effect on lipid metabolism with discrete differences in the magnitude of this effect in certain variables. Despite the limitations of small population size and lack of clinical end points, reported data provide an insight for the possible pathophysiological mechanisms implicated in the effect of increasing dosages of different statin treatments.

Hepatic Lipase Deficiency in a Middle-Eastern/Arabic Male∗

Summary Hepatic lipase (HL) defi ciency is a rare genetic disorder that has been associated with premature atherosclerosis despite high plasma highdensity lipoprotein (HDL) cholesterol concentrations in the affected individuals. The authors describe the clinical and biochemical features of HL defi ciency in a young male of Middle-Eastern-Arabic origin. This is the fi rst report of cholesterol ester transfer protein (CETP) activity and mass in HL defi ciency in a patient from this ethnic group. While the CETP mass was high, its activity was low, a discrepancy likely due to the abnormal composition of patient’s HDL particles.

Persistence of an atherogenic lipid profile after treatment of acute infection with brucella

Serum lipid changes during infection may be associated with atherogenesis. No data are available on the effect of Brucellosis on lipids. Lipid parameters were determined in 28 patients with Brucellosis on admission and 4 months following treatment and were compared with 24 matched controls. Fasting levels of total cholesterol (TC), HDL-cholesterol (HDL-C), triglycerides, apolipoproteins (Apo) A, B, E CII, and CIII, and oxidized LDL (oxLDL) were measured. Activities of serum cholesterol ester transfer protein (CETP), paraoxonase 1 (PON1), and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and levels of cytokines [interleukins (IL)-1beta, IL-6, and tumor necrosis factor (TNFa)] were also determined. On admission, patients compared with controls had 1) lower levels of TC, HDL-C, LDL-cholesterol (LDL-C), ApoB, ApoAI, and ApoCIII and higher LDL-C/HDL-C and ApoB/ApoAI ratios; 2) higher levels of IL-1b, IL-6, and TNFa; 3) similar ApoCII and oxLDL levels and Lp-PLA(2) activity, lower PON1, and higher CETP activity; and 4) higher small dense LDL-C concentration. Four months later, increases in TC, HDL-C, LDL-C, ApoB, ApoAI, and ApoCIII levels, ApoB/ApoAI ratio, and PON1 activity were noticed compared with baseline, whereas CETP activity decreased. LDL-C/HDL-C ratio, ApoCII, and oxLDL levels, Lp-PLA(2) activity, and small dense LDL-C concentration were not altered. Brucella infection is associated with an atherogenic lipid profile that is not fully restored 4 months following treatment.

Hypertriglyceridemia in Watanabe Heritable Hyperlipidemic Rabbits Was Associated with Increased Production and Reduced Catabolism of Very-Low-Density Lipoproteins

Watanabe heritable hyperlipidemic (WHHL) rabbit is an animal model for human familial hypercholesterolemia. Recently, we segregated a new mutant of WHHL rabbits with plasma levels of triglycerides (TG) >500 mg/dl (designated as TGH-WHHL). To investigate the underlying mechanisms for hypertriglyceridemia, we compared TGH-WHHL with WHHL rabbits with lower plasma TG levels (<250 mg/dl, designated as TGL-WHHL). A Triton WR-1339 injection experiment revealed that TGH-WHHL rabbits had increased secretion and decreased clearance of TG-rich lipoproteins. Furthermore, TGH-WHHL rabbits had lower a post-heparin activity of lipoprotein lipase and a higher cholesterol ester transfer protein activity than TGL-WHHL rabbits. Cultured hepatocytes isolated from TGH-WHHL rabbits showed a higher secretion rate of TG and cholesterol than those of TGL-WHHL rabbits. In addition, TGH-WHHL rabbits exhibited marked insulin resistance. These data suggest that hypertriglyceridemia exhibited by WHHL rabbits is caused by both increased production and impaired catabolism of TG-rich lipoproteins and associated with insulin resistance.

Cholesterol Ester Transfer Protein (CETP), Postprandial Lipemia and Hypolipidemic Drugs

Cholesterol ester transfer protein (CETP) plays a significant role in high density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT). A reduction in CETP activity leads to an increase in HDL-cholesterol levels. However, the relationship between reduced CETP function and atherosclerosis is complex and confusing. In the hypertriglyceridemic state, CETP is highly expressed and RCT leads to the formation of small dense low density lipoprotein (LDL) and small dense HDL, both of which are involved in the progression of atherosclerosis. Significant associations of the B1B1 genotype with higher plasma CETP concentration and/or CETP activity and lower HDL cholesterol were reported in several, but not all, studies. The magnitude of postprandial lipemia is also associated with plasma CETP concentration and lipoprotein content and size. Several conditions such as metabolic syndrome, hypertension, insulin resistance, obesity and familial hypercholesterolaemia are characterized by a more pronounced postprandial hypertriglyceridemia and delayed TG clearance than normal states. Thus, CETP is considered as a candidate target for drug therapy. A number of synthetic CETP inhibitors (CGS25159 and JTT-705) were evaluated in animals with satisfactory results. In humans, two CETP inhibitors were evaluated, JTT-705 and torcetrapib, leading to HDL increase. However, torcetrapib administration was associated with an increase in blood pressure and other "off-target" effects. It is also not clear whether the HDL produced during treatment with torcetrapib is bioactive (i.e. an "on target" undesirable action). In the current review, CETP function regarding lipid metabolism (in fasting and fed states) from human and animal studies as well as the current knowledge on CETP inhibitors are discussed. We also discuss gender influence on the action of hypolipidemic drugs and their effect on CETP mass and activity, as well as on the lipid profile.

Tacrolimus-Induced Elevation in Plasma Triglyceride Concentrations After Administration to Renal Transplant Patients Is Partially Due to a Decrease in Lipoprotein Lipase Activity and Plasma Concentrations

Hyperlipidemia is a frequent and persistent complication in solid organ transplant recipients, leading to the high occurrence of cardiovascular disease in this patient population. Lipid abnormalities including increased total cholesterol, triglycerides (TG), and low-density lipoprotein-cholesterol have been reported frequently in transplantation patients and a variety of immunosuppressive therapies seem to be one of the main factors that influence posttransplant lipidemic profiles. For many years, tacrolimus (TAC) has been used as an immunosuppressive drug in transplantation. The aim of our investigation was to determine the effect of TAC administration on the plasma lipid profile and some key regulatory proteins of plasma lipid metabolism including cholesterol ester transfer protein, hepatic lipase and lipoprotein lipase (LPL) within renal transplant patients. Twenty-five renal transplant patients were recruited and received TAC therapy, of which nine of these patients were treated with statin therapy for dyslipidemia. The effects of TAC on plasma total cholesterol, TG, HDL-C, low-density lipoprotein-cholesterol, cholesterol ester transfer protein, hepatic lipase and LPL concentration and activity were determined from patients plasma samples collected before the transplant surgery (baseline), and weekly for four consecutive weeks after surgery and TAC administration. We observed that TAC significantly increases plasma TG concentrations and reduces LPL plasma concentration and activity in renal transplant patients, independent of any lipid lowering drug treatment patients received. Taken together, these findings suggest that the reduction in LPL activity, partly due to the decrease of plasma LPL concentration after TAC administration may be an explanation for hypertriglyceridemia observed in patients administered TAC.

Hypercholesterolaemia in anorexia nervosa: Frequency and changes during refeeding

High total cholesterol (TC) is common in patients with anorexia nervosa (AN), but its mechanisms remain unclear. Patients and methods We prospectively studied plasma lipoprotein (LP), haptoglobin, free (f) T3, fT4, TSH, transthyretin and albumin in 120 malnourished adult AN patients (BMI: 13.5 ± 1.5 kg/m 2), 116 non-AN malnourished patients and 119 healthy subjects, matched for age and gender. Results In 18% of our AN patients, TC was higher than 270 mg/100 mL (in non-AN: 5%; P < 0.01). TC, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and HDL2 levels were higher in AN patients than in non-AN patients ( P < 0.001). Low TC (<150 mg/100 mL) and LP levels were observed in 8% of AN patients, but only when BMI was less than 13 kg/m 2. Cholesterol ester transfer protein (CETP) activity was higher in AN patients than in healthy subjects. LP was positively correlated with BMI, albumin, fT3 and haptoglobin levels. In AN patients, there was a biphasic LP profile (low values when BMI was very low, normal values in an intermediate state, and high values when BMI was highest and where bulimia was also present). Conclusion In AN, both high and low cholesterol-rich LP levels were observed. Low T3 and low catabolism allow LP to be maintained, while CETP activity increases cholesterol turnover as an adaptation to its low intake. In severely malnourished AN patients, this fails and LP drops. On the other hand, LP values were higher in the bingeing–purging type of AN than in the restrictive type. Recovery from AN results in the normalization of the LP profile.

Raisins and walking alter appetite hormones and plasma lipids by modifications in lipoprotein metabolism and up-regulation of the low-density lipoprotein receptor

The purpose of this study was to determine the effects of consuming raisins, increasing steps walked, or a combination of these interventions on lipoprotein metabolism and appetite hormones by assessing plasma apolipoprotein concentrations, cholesterol ester transfer protein activity, low-density lipoprotein (LDL) receptor messenger RNA (mRNA) abundance, and plasma ghrelin and leptin concentrations. Thirty-four subjects (17 men and 17 postmenopausal women) were matched for weight and sex and randomly assigned to consume 1 cup raisins per day (RAISIN), increase the amount of steps walked per day (WALK), or a combination of both interventions (RAISIN + WALK). The subjects completed a 2-week run-in period, followed by a 6-week intervention. Ribonucleic acid was extracted from mononuclear cells, and LDL receptor mRNA abundance was quantified by use of reverse transcriptase polymerase chain reaction. Plasma apolipoproteins were measured by Luminex (Austin, TX) technology. Apoproteins A-1, B, C-II, and E and cholesterol ester transfer protein activity were not altered for any of the groups. In contrast, apolipoprotein C-III was significantly decreased by 12.3% only in the WALK group ( P < .05). Low-density lipoprotein receptor mRNA abundance was increased for all groups after the intervention ( P < .001). There was a significant group effect for plasma leptin ( P = .026). Plasma concentrations increased for RAISIN and RAISIN + WALK. Similarly, plasma ghrelin concentrations were elevated postintervention for both groups consuming raisins ( P < .05). These data suggest that walking and raisin consumption decrease plasma LDL cholesterol by up-regulating the LDL receptor and that raisin consumption may reduce hunger and affect dietary intake by altering hormones influencing satiety.

Carbohydrate restriction and dietary cholesterol distinctly affect plasma lipids and lipoprotein subfractions in adult guinea pigs

To evaluate the effects of carbohydrate restriction (CR) and dietary cholesterol on lipoprotein metabolism, adult male guinea pigs (10 guinea pigs/diet) were fed either low (0.04 g/100 g) or high (0.25 g/100 g) amounts of dietary cholesterol, in combination with either low (10% total energy) or high (54.2% total energy) dietary carbohydrate (control groups) for a total of four groups: high carbohydrate–low cholesterol (control-L), high carbohydrate–high cholesterol (control-H), low carbohydrate–low cholesterol (CR-L) and low carbohydrate–high cholesterol (CR-H). Plasma triglyceride concentrations were lower ( P<.01%), while high-density lipoprotein cholesterol concentrations were higher ( P<.05) in the CR groups compared to the control groups. In contrast, high dietary cholesterol (CR-H and control-H) resulted in higher concentrations of total and low-density lipoprotein (LDL) cholesterol compared to those guinea pigs fed the low-cholesterol diets ( P<.01). Dietary cholesterol significantly increased the total number of LDL particles ( P<.001) and the number of small LDL ( P<.001), as determined by nuclear magnetic resonance. In contrast, carbohydrate restriction (CR-L and CR-H) resulted in lower concentrations of medium very-low-density lipoprotein and small LDL particles compared to the high-carbohydrate groups. Plasma lecithin:cholesterol acyltransferase (LCAT) activity was decreased and cholesterol ester transfer protein activity was increased by dietary cholesterol, whereas carbohydrate restriction increased LCAT activity ( P<.05). These findings are similar to those observed in humans, thus validating the use of adult guinea pigs to study lipid responses to carbohydrate restriction. The results also indicate that the atherogenicity of lipoproteins induced by high dietary cholesterol is attenuated by carbohydrate restriction in guinea pigs.

Peroxisome Proliferator‐Activated Receptor α Agonists Regulate Cholesterol Ester Transfer Protein

Peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the nuclear receptor superfamily that regulates multiple target genes involved in lipid metabolism. Cholesterol ester transfer protein (CETP) is a secreted glycoprotein that modifies high-density lipoprotein (HDL) particles. In humans, plasma CETP activity is inversely correlated with HDL cholesterol levels. We report here that PPARalpha agonists increase CETP mRNA, protein and accordingly its activity. In a human CETP transgenic animal model harboring the natural flanking regions (Jiang et al. in J Clin Investigat 90:1290-1295, 1992), both fenofibrate and a specific synthetic PPARalpha agonist LY970 elevated human CETP mRNA in liver, serum protein and CETP activity. In hamsters, the endogenous liver CETP mRNA level and the serum CETP activity were dose-dependently upregulated by fenofibrate. In addition Wy14643, a PPARalpha agonist, also significantly elevated CETP mRNA and activity. In a carcinoma cell line of hepatic origin, HepG2 cells, overexpression of PPARalpha resulted in increased CETP mRNA and agonist treatment further elevated CETP mRNA levels. We conclude that PPARalpha agonists upregulate CETP expression and activity and may play an important role in PPARalpha (agonist mediated HDL cholesterol homeostasis in humans.

Cholesterol provided by eggs and carbohydrate restriction distinctly modulate lipoprotein metabolism in adult men

Twenty eight men (BMI 26‐37 kg/m2) between 40‐70 y were recruited to evaluate the effects of carbohydrate restriction (CR, ~10% energy from carbohydrates) and dietary cholesterol (CHOL) on lipoprotein metabolism. Subjects were randomly allocated to the EGG group (640 additional mg CHOL/d) or the SUB group (0 mg additional CHOL/d) for 12 wk. Lipoprotein size and subclasses determined by use of NMR, apolipoproteins (apo) A‐I, A‐II, B, C‐II, C‐III, and E measured by antibody‐immobilized beads and Luminex MAP technology and lecithin cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein activities were measured both at baseline and post‐intervention. We observed a 45% decrease in plasma triglycerides for all subjects, which was associated with decreases in the large and medium VLDL subclasses (P &lt; 0.001). In agreement with these observations, a decrease in apo B (P &lt; 0.01) was also observed. In addition, CR resulted in a 133% increase in apo C‐II [lipoprotein lipase (LPL) activator] and a 65% decrease in apo C‐III, (LPL inhibitor) (P &lt; 0.0001). The smaller HDL subclasses and apo A‐II levels were also decreased at 12 wk (P &lt; 0.001). CHOL effects were mainly on LDL and HDL metabolism. Although an increase of the larger LDL subclass was observed for all subjects, the EGG group had a greater increase (P &lt; 0.05). The EGG group also presented increases in HDL‐C, higher number of large HDL particles (P &lt; 0.01) and an increased LCAT activity (P &lt; 0.05) compared to the SUB group. These results indicate that CR favorably alters VLDL metabolism while CHOL provided by eggs favors the formation of less atherogenic lipoproteins, larger LDL and HDL.