Cholesteryl Ester Transfer Protein Mass Research Articles

High-Density Lipoprotein and Long-Term Incidence and Progression of Aortic Valve Calcification: The Multi-Ethnic Study of Atherosclerosis.

Aortic valve calcification (AVC) shares pathological features with atherosclerosis. Lipoprotein components have been detected in aortic valve tissue, including HDL (high-density lipoprotein). HDL measures have inverse associations with cardiovascular disease, but relationships with long-term AVC progression are unclear. We investigated associations of HDL cholesterol, HDL-particle number and size, apoC3-defined HDL subtypes, and, secondarily, CETP (cholesteryl ester transfer protein) mass and activity, with long-term incidence and progression of AVC. We used linear mixed-effects models to evaluate the associations of baseline HDL indices with AVC. AVC was quantified by Agatston scoring of up to 3 serial computed tomography scans over a median of 8.9 (maximum 11.2) years of follow-up in the Multi-Ethnic Study of Atherosclerosis (n=6784). After adjustment, higher concentrations of HDL-C (high-density lipoprotein cholesterol), HDL-P (HDL particles), large HDL-P, and apoC3-lacking HDL-C were significantly associated with lower incidence/progression of AVC. Neither small or medium HDL-P nor apoC3-containing HDL-C was significantly associated with AVC incidence/progression. When included together, a significant association was observed only for HDL-C, but not for HDL-P. Secondary analyses showed an inverse relationship between CETP mass, but not activity, and AVC incidence/progression. In exploratory assessments, inverse associations for HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL with AVC incidence/progression were more pronounced for older, male, and White participants. ApoC3-containing HDL-C only showed a positive association with AVC in these subgroups. In a multiethnic population, HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL-C were inversely associated with long-term incidence and progression of AVC. Further investigation of HDL composition and mechanisms could be useful in understanding pathways that slow AVC.

Dietary stearic acid and palmitic acid do not differently affect ABCA1-mediated cholesterol efflux capacity in healthy men and postmenopausal women: A randomized controlled trial

The saturated fatty acid stearic acid (C18:0) lowers HDL cholesterol compared with palmitic acid (C16:0). However, the ability of HDL particles to promote cholesterol efflux from macrophages (cholesterol efflux capacity; CEC) may better predict coronary heart disease (CHD) risk than HDL cholesterol concentrations. We examined effects of exchanging dietary palmitic acid for stearic acid on ATP-binding cassette transporter A1 (ABCA1)-mediated CEC, and other conventional and emerging cardiometabolic risk makers. In a double-blind, randomized, crossover study with two 4-week isocaloric intervention periods, 34 healthy men and postmenopausal women (61.5±5.7 years, BMI: 25.4±2.5kg/m2) followed diets rich in palmitic acids or stearic acids. Difference in intakes was 6% of daily energy. ABCA1-mediated CEC was measured from J774 macrophages to apolipoprotein (apo)B-depleted serum. Compared with the palmitic-acid diet, the stearic-acid diet lowered serum LDL cholesterol (-0.14mmol/L; p=0.010), HDL cholesterol (-0.09mmol/L; p=<0.001), and apoA1 (-0.05g/L; p<0.001). ABCA1-mediated CEC did not differ between diets (p=0.280). Cholesteryl ester transfer protein (CETP) mass was higher on stearic acid (0.11mg/L; p=0.003), but CETP activity was comparable. ApoB100 did not differ, but triacylglycerol concentrations tended to be higher on stearic acid (p=0.100). Glucose concentrations were comparable. Effects on insulin and C-peptide were sex-dependent. In women, the stearic-acid diet increased insulin concentrations (1.57 μU/mL; p=0.002), while in men, C-peptide concentrations were lower (-0.15ng/mL; p=0.037). Interleukin 6 (0.15pg/mL; p=0.039) and tumor necrosis factor alpha (0.18pg/mL; p=0.005), but not high-sensitivity C-reactive protein, were higher on stearic acid. Soluble intracellular adhesion molecule (9ng/mL; p=0.033), but not soluble vascular cell adhesion molecule and endothelial-selectin concentrations decreased after stearic-acid consumption. As expected, stearic-acid intake lowered LDL cholesterol, HDL cholesterol, and apoA1. Insulin sensitivity in women and low-grade inflammation might be unfavorably affected by stearic-acid intake. However, palmitic-acid and stearic-acid intakes did not differently affect ABCA1-mediated CEC. This trial was registered at clinicaltrials.gov as NCT02835651.

The lipid transfer properties of CETP define the concentration and composition of plasma lipoproteins

Cholesteryl ester transfer protein (CETP) facilitates the net transfer of cholesteryl esters (CEs) and TGs between lipoproteins, impacting the metabolic fate of these lipoproteins. Previous studies have shown that a CETP antibody can alter CETP's preference for CE versus TG as transfer substrate, suggesting that CETP substrate preference can be manipulated in vivo. Hamster and human CETPs have very different preferences for CE and TG. To assess the effect of altering CETP's substrate preference on lipoproteins in vivo, here, we expressed human CETP in hamsters. Chow-fed hamsters received adenoviruses expressing no CETP, hamster CETP, or human CETP. Plasma CETP mass increased 2-fold in both the hamster and human CETP groups. Although the animals expressing human CETP still had low levels of hamster CETP, the CE versus TG preference of their plasma CETP was similar to that of the human ortholog. Hamster CETP overexpression had little impact on lipoproteins. However, expression of human CETP reduced HDL up to 50% and increased VLDL cholesterol 2.5-fold. LDL contained 20% more CE, whereas HDL CE was reduced 40%, and TG increased 6-fold. The HDL3:HDL2 ratio increased from 0.32 to 0.60. Hepatic expression of three cholesterol-related genes (LDLR, SCARB1, and CYP7A1) was reduced up to 40%. However, HDL-associated CE excretion into feces was unchanged. We conclude that expression of human CETP in hamsters humanizes their lipoprotein profile with respect to the relative concentrations of VLDL, LDL, HDL, and the HDL3:HDL2 ratio. Altering the lipid substrate preference of CETP provides a novel approach for modifying plasma lipoproteins.

CETP activity is not associated with carotid intima-media thickness in patients with poorly controlled type 2 diabetes.

The impact of cholesteryl ester transfer protein (CETP) on atherosclerotic development in humans remains unclear. Plasma cholesteryl ester transfer was shown to be associated with carotid intima-media thickness in type 2 diabetic (T2D) patients with adequate metabolic control. Since glycation of CETP may influence cholesteryl ester transfer processes, it is important to determine if plasma cholesteryl ester transfer is still a determinant of carotid intima-media thickness (IMT) in patients with poorly controlled diabetes. The aim of the present study was to determine whether CETP activity influences carotid IMT in T2D patients with poor metabolic control. In 110 individuals with T2D, we measured CETP mass concentration with ELISA, CETP activity with a radioactivity method and carotid intima-media thickness with high-resolution real-time B-mode ultrasonography. The mean HbA1C was 8.8 ± 1.7%. Carotid IMT did not correlate with CETP activity in the total population. In T2D patients with HbA1C < 8% (n = 33), mean HbA1C was 6.9% and the correlation between carotid IMT and CETP activity was not significant (p = 0.09). In a multivariable analysis that included the total population, carotid intima-media thickness was positively associated with diabetes duration (p = 0.02) but not with CETP activity or HbA1C. We observed no correlation between carotid intima-media thickness, a marker of early atherosclerosis, and CETP activity in T2D patients with poor metabolic control. Disease duration, which reflects accumulated metabolic abnormalities, may have blunted the potential effect of CETP on atherosclerosis. Metabolic control appears essential to determine the pro- or anti-atherogenic influence of CETP in patients with T2D.

Changes in lecithin: cholesterol acyltransferase, cholesteryl ester transfer protein and paraoxonase-1 activities in patients with colorectal cancer

BackgroundPrevious studies revealed decreased level of high-density lipoprotein cholesterol (HDLC) as important factor for development of colorectal cancer (CRC). Quantity and structure of HDL particles depend on activities of lipid transfer proteins lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), but this topic is largely unexplored in CRC. The main objective of this study was to investigate activities of LCAT and CETP in patients with CRC. Additionally, we analyzed activity of paraoxonase-1 (PON-1), as a main carrier of HDL-antioxidant function. Materials and methodsNinety-nine CRC patients and 101 healthy individuals were included. LCAT and CETP activities were assessed by measuring rates of formation and transfer of cholesteryl esters. PON-1 paraoxonase and arylesterase activities were measured. ResultsLower levels of HDL-C (p < .001) were observed in cohort of patients, alongside with decreased LCAT (p < .050) and increased CETP activity (p < .050). Both PON-1 activities were diminished in CRC (p < .050 and p < .001 respectively). Univariate logistic regression singled out HDL-C level (OR = 0.218, p < .001), CETP activity (OR = 1.010, p < .01) and mass (OR = 0.994, p < .001) as possible markers of elevated CRC risk. CETP mass maintained its predictive significance when adjusted for traditional risk factors and level of oxidative stress (OR = 0.993, p < .001; OR = 0.982, p < .050, respectively). ConclusionOur results demonstrated increased CETP and decreased LCAT and PON-1 activities in CRC patients. In preliminary analysis CETP mass was identified as potential significant predictor of CRC development, suggesting that alterations in HDL-C levels, alongside with changes in HDL structure might have a role in carcinogenesis.

CETP genetic variant rs1800777 (allele A) is associated with abnormally low HDL-C levels and increased risk of AKI during sepsis

High-density cholesterol (HDL-C) levels are influenced by genetic variation in several genes. Low levels of HDL-C have been associated with increased risk of acute kidney injury (AKI). We investigated whether genetic polymorphisms in ten genes known to regulate HDL-C levels are associated with both HDL-C levels and AKI development during sepsis. Two cohorts were retrospectively analyzed: Derivation Cohort (202 patients with sepsis enrolled at the Emergency Department from 2011 to 2014 in Vancouver, Canada); Validation Cohort (604 septic shock patients enrolled into the Vasopressin in Septic Shock Trial (VASST)). Associations between HDL-related genetic polymorphisms and both HDL-C levels, and risk for clinically significant sepsis-associated AKI (AKI KDIGO stages 2 and 3) were evaluated. In the Derivation Cohort, one genetic variant in the Cholesteryl Ester Transfer Protein (CETP) gene, rs1800777 (allele A), was strongly associated with lower HDL-C levels (17.4 mg/dL vs. 32.9 mg/dL, P = 0.002), greater CETP mass (3.43 µg/mL vs. 1.32 µg/mL, P = 0.034), and increased risk of clinically significant sepsis-associated AKI (OR: 8.28, p = 0.013). Moreover, the same allele was a predictor of sepsis-associated AKI in the Validation Cohort (OR: 2.38, p = 0.020). Our findings suggest that CETP modulates HDL-C levels in sepsis. CETP genotype may identify patients at high-risk of sepsis-associated AKI.

Pharmacokinetics and Pharmacodynamics of Anacetrapib in Black and White Healthy Subjects.

Anacetrapib is a cholesteryl ester transfer protein inhibitor intended for the treatment of dyslipidemia. A phase 1 study was conducted to examine the pharmacokinetics and pharmacodynamics of multiple doses of anacetrapib in black compared to white healthy subjects. Although there was no apparent race-related pharmacokinetic effect, attenuation of the lipid response was observed in black subjects. Specifically, high-density lipoprotein cholesterol percentage increased 18.1% (absolute percentage points) less in black subjects (89.9%) when compared to increases in white subjects (108.0%). Similarly, the decrease in low-density lipoprotein cholesterol was 17.8% (absolute percentage points) less in blacks (-21.2%) relative to whites (-39.0%). In contrast, there were no apparent race-related differences in cholesteryl ester transfer protein mass or activity. Anacetrapib was generally well tolerated in this study. The results of this study suggest that there may be race-related differences in pharmacodynamics of anacetrapib independent of pharmacokinetics.

Slim Body Weight Is Highly Associated With Enhanced Lipoprotein Functionality, Higher HDL-C, and Large HDL Particle Size in Young Women.

There has been no information about the correlations between body weight distribution and lipoprotein metabolism in terms of high-density lipoproteins-cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP). In this study, we analyzed the quantity and quality of HDL correlations in young women (21.5 ± 1.2-years-old) with a slim (n = 21, 46.2 ± 3.8 kg) or plump (n = 30, 54.6 ± 4.4 kg) body weight. Body weight was inversely correlated with the percentage of HDL-C in total cholesterol (TC). The plump group showed 40% higher body fat (26 ± 3 %) and 86% more visceral fat mass (VFM, 1.3 ± 0.3 kg) than the slim group, which showed 18 ± 2% body fat and 0.7 ± 0.2 kg of VFM. Additionally, the plump group showed 20% higher TC, 58% higher triglyceride (TG), and 12% lower HDL-C levels in serum. The slim group showed 34% higher apoA-I but 15% lower CETP content in serum compared to the plump group. The slim group showed a 13% increase in particle size and 1.9-fold increase in particle number with enhanced cholesterol efflux activity. Although the plump group was within a normal body mass index (BMI) range, its lipid profile and lipoprotein properties were distinctly different from those of the slim group in terms of CETP mass and activity, HDL functionality, and HDL particle size.

Duality of statin action on lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome: Quantity vs quality over time and implication of CETP

Statins impact the metabolism, concentrations, composition, and function of circulating lipoproteins. We evaluated time course relationships between statin-mediated reduction in atherogenic apolipoprotein B (ApoB)-containing particles and dynamic intravascular remodeling of ApoAI-containing lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome. Insulin-resistant, hypertriglyceridemic, hypercholesterolemic, obese males (n=12) were treated with pitavastatin (4mg/d) and response evaluated at 6, 42, and 180days. Reduction in low-density lipoprotein (LDL) cholesterol, ApoB, and triglycerides (TGs) was essentially complete at 42days (-38%, -32%, and -35%, respectively); rapid reduction equally occurred in remnant cholesterol, ApoCII, CIII, and E levels (day 6; -35%, -50%, -23%, and -26%, respectively). Small dense LDLs (LDL4 and LDL5 subpopulations) predominated at baseline and were markedly reduced on treatment (-29% vs total LDL mass). Cholesteryl ester (CE) transfer protein activity and mass decreased progressively (-18% and -16%, respectively); concomitantly, TG depletion (up to -49%) and CE enrichment occurred in all high-density lipoprotein (HDL) particle subpopulations with normalization of CE/TG mass ratio at 180days. ApoAI was redistributed from LpAI to LpAI:AII particles in HDL2a and HDL3a subpopulations; ApoCIII was preferentially depleted from LpAI:AII-rich particles on treatment. Overall, statin action exhibits duality in mixed dyslipidemia, as CE transfer protein-mediated normalization of the HDL CE/TG core lags markedly behind subacute reduction in elevated levels of atherogenic ApoB-containing lipoproteins. Normalization of the HDL neutral lipid core is consistent with enhanced atheroprotective function. The HDL CE/TG ratio constitutes a metabolomic marker of perturbed HDL metabolism in insulin-resistant states, equally allowing monitoring of statin impact on HDL metabolism, structure, and function.

CETP Gene and Its Role in Diabetes Mellitus Type II - A Review

Plasma lipoproteins are continuously remodelled through the actions of enzymes and lipid transfer proteins. In particular, the transfers of cholesteryl esters (CE) and triglycerides (TG) are facilitated by a specialized protein known as the cholesteryl ester transfer protein (CETP). Genetic polymorphisms of the enzymes and proteins involved in lipid metabolism like cholesteryl ester transfer protein CETP have been shown to affect plasma lipid concentrations. CETP modifies HDL, LDL and very low density lipoprotein (VLDL) levels. It transfers cholesterol esters (CE) from CE rich particles (HDL and LDL) to triglyceride rich particles (VLDL) in exchange of triglyceride from the latter. Several genetic polymorphisms have been reported which may be associated with alteration in CETP activity. TaqI B polymorphism has been most widely studied, which results from a silent mutation in nucleotide 277, in intron 1 of the gene. The polymorphism has been associated with decreased CETP mass and an increase in HDL-cholesterol. The TaqI polymorphism B1 allele of CETP has been shown to be an independent risk factor for development of cerebral vascular disease, in patients with T2DM.

Increased large VLDL particles confer elevated cholesteryl ester transfer in diabetes.

Plasma cholesteryl ester transfer (CET), reflecting transfer of cholesteryl esters from high density lipoproteins (HDL) towards apolipoprotein B-containing lipoproteins, may promote atherosclerosis development, and is elevated in Type 2 diabetes mellitus (T2DM). We determined the extent to which the relationship of plasma CET with very low density lipoprotein (VLDL) and low density lipoprotein (LDL) subfractions is modified in T2DM. Plasma CET, cholesteryl ester transfer protein (CETP) mass, as well as VLDL and LDL subfractions (nuclear magnetic resonance spectroscopy) were determined in 62 patients with T2DM and 53 nondiabetic subjects. Plasma CET and CETP mass were increased in T2DM, coinciding higher triglycerides and large VLDL particles (all P<0·02). Plasma CET was positively related to the VLDL and the LDL particle concentration in age-, sex- and diabetes status-adjusted analysis (both P<0·001). Multivariable linear regression analysis demonstrated an independent positive interaction between the presence of T2DM and the VLDL concentration on plasma CET (β=0·238, P=0·033). The relationship of plasma CET with the VLDL concentration was also positively modified by plasma glucose (β=0·211, P=0·004) and glycated haemoglobin (β=0·190, P=0·012). Of the individual VLDL subfractions, a positive interaction of diabetes status with large VLDL on plasma CET was observed (β=0·280, P=0·003). Neither the relationship of the LDL particle concentration nor of CETP mass with plasma CET was modified by the presence of T2DM (P>0·15). Abnormalities in the concentration and composition of large VLDL particles are likely to contribute to elevated plasma CET in T2DM.

Treatment of low HDL-C subjects with the CETP modulator dalcetrapib increases plasma campesterol only in those without ABCA1 and/or ApoA1 mutations.

We investigated the effect of dalcetrapib treatment on phytosterol levels in patients with familial combined hyperlipidemia (FCH) or familial hypoalphalipoproteinemia (FHA) due to mutations in apolipoprotein A1 (ApoA1) or ATP-binding cassette transporter A1 (ABCA1). Patients (n = 40) with FCH or FHA received dalcetrapib 600 mg or placebo in this 4-week, double-blind, crossover study. Lipids, apolipoproteins, cholesteryl ester transfer protein (CETP) activity and mass, and phytosterols were assessed. Dalcetrapib increased high-density lipoprotein cholesterol (HDL-C) and ApoA1 levels to a similar extent in FHA (+22.8, +13.9%) and FCH (+18.4, +12.1%), both p < 0.001 vs. placebo. Changes in CETP activity and mass were comparable for FHA (-31.5, +120.9%) and FCH (-26.6, +111.9%), both p < 0.0001 vs. placebo. Campesterol and lathosterol were unchanged in FHA (+3.8, +3.0%), but only campesterol was markedly increased in FCH (+25.0%, p < 0.0001 vs. placebo). Campesterol increased with dalcetrapib treatment in FCH but not in FHA, despite comparable HDL-C and ApoA1 increases, suggesting that ApoA1 and/or ABCA1 is essential for HDL lipidation by enterocytes in humans.

Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults.

ObjectivesWe investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib.MethodsHealthy volunteers received multiple daily doses of evacetrapib (10–600 mg) administered for up to 15 days in a placebo-controlled study.Key findingsMean peak plasma concentrations of evacetrapib occurred at 4–6 h and terminal half-life ranged 24–44 h. Steady state was achieved at approximately 10 days; all subjects had undetectable levels of evacetrapib 3 weeks after their last dose. The trough inhibition of cholesteryl ester transfer protein (CETP) activity was 65 and 84% at 100 and 300 mg, respectively. At the highest dose (600 mg), evacetrapib significantly inhibited CETP activity (91%), increased HDL-C (87%) and apo AI (42%), and decreased LDL-C (29%) and apo B (26%) relative to placebo. For the highest dose tested, levels of evacetrapib, CETP activity, CETP mass, HDL-C and LDL-C returned to levels at or near baseline after a 2-week washout period. Evacetrapib at the highest dose tested did not produce any significant effect on 24-h ambulatory systolic or diastolic blood pressure.ConclusionsMultiple doses of evacetrapib potently inhibited CETP activity, leading to substantial elevations in HDL-C and lowering of LDL-C. Evacetrapib was devoid of clinically relevant effects on blood pressure and mineralocorticoid levels.

Efficacy, Safety, Tolerability, and Pharmacokinetic Profile of Evacetrapib Administered as Monotherapy or in Combination With Atorvastatin in Japanese Patients With Dyslipidemia

The cholesteryl ester transfer protein (CETP) inhibitor evacetrapib has been previously shown to increase high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels, as monotherapy or in combination with statins. In this study, 165 Japanese patients with elevated LDL-C or low HDL-C levels were randomly assigned to receive placebo, evacetrapib monotherapy 30 mg, 100 mg, or 500 mg, atorvastatin 10 mg, or evacetrapib 100 mg in combination with atorvastatin 10 mg. After 12 weeks, evacetrapib monotherapy increased HDL-C levels by 74%, 115%, and 136% and decreased LDL-C levels by 15%, 23%, and 22% and CETP activity by 50%, 83%, and 95% (for the 30-mg, 100-mg, and 500-mg dose groups, respectively) versus placebo. In combination with atorvastatin 10 mg, evacetrapib 100 mg increased HDL-C levels by 103% and decreased LDL-C levels by 15% and CETP activity by 68% versus atorvastatin alone. After a 4- to 6-week washout, HDL-C, LDL-C, and CETP mass and activity returned to baseline levels in the evacetrapib-treated groups, and most patients had evacetrapib concentrations below the quantitation limit. Evacetrapib monotherapy or in combination with atorvastatin was not likely to be associated with any significant change in blood pressure and did not have any adverse effects on mineralocorticoid or glucocorticoid measures. Notably, plasma evacetrapib concentrations were mostly undetectable, and all pharmacodynamic biomarkers (HDL-C and LDL-C levels and CETP mass and activity) returned to baseline after a 4- to 6-week washout. In conclusion, evacetrapib as monotherapy or in combination with atorvastatin effectively decreased CETP activity and LDL-C levels and increased HDL-C levels after 12 weeks in Japanese patients with dyslipidemia.

Fibrates and fish oil, but not corn oil, up-regulate the expression of the cholesteryl ester transfer protein (CETP) gene

Cholesteryl ester transfer protein (CETP) is a plasma protein that reduces high density lipoprotein (HDL)-cholesterol (chol) levels and may increase atherosclerosis risk. n-3 and n-6 polyunsaturated fatty acids (PUFAs) are natural ligands, and fibrates are synthetic ligands for peroxisome proliferator activated receptor-alpha (PPARα), a transcription factor that modulates lipid metabolism. In this study, we investigated the effects of PUFA oils and fibrates on CETP expression. Hypertriglyceridemic CETP transgenic mice were treated with gemfibrozil, fenofibrate, bezafibrate or vehicle (control), and normolipidemic CETP transgenic mice were treated with fenofibrate or with fish oil (FO; n-3 PUFA rich), corn oil (CO, n-6 PUFA rich) or saline. Compared with the control treatment, only fenofibrate significantly diminished triglyceridemia (50%), whereas all fibrates decreased the HDL-chol level. Elevation of the CETP liver mRNA levels and plasma activity was observed in the fenofibrate (53%) and gemfibrozil (75%) groups. Compared with saline, FO reduced the plasma levels of nonesterified fatty acid (26%), total chol (15%) and HDL-chol (20%). Neither of the oil treatments affected the plasma triglyceride levels. Compared with saline, FO increased the plasma adiponectin level and reduced plasma leptin levels, whereas CO increased the leptin levels. FO, but not CO, significantly increased the plasma CETP mass (90%) and activity (23%) as well as increased the liver level of CETP mRNA (28%). In conclusion, fibrates and FO, but not CO, up-regulated CETP expression at both the mRNA and protein levels. We propose that these effects are mediated by the activation of PPARα, which acts on a putative PPAR response element in the CETP gene.

Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice

Cholesteryl ester transfer protein (CETP) activity results in a proatherogenic lipoprotein profile. In cholestatic conditions, farnesoid X receptor (FXR) signaling by bile acids (BA) is activated and plasma HDL cholesterol (HDL-C) levels are low. This study tested the hypothesis that FXR-mediated induction of CETP contributes to this phenotype. Patients with cholestasis and high plasma BA had lower HDL-C levels and higher plasma CETP activity and mass compared with matched controls with low plasma BA (each P < 0.01). BA feeding in APOE3*Leiden transgenic mice expressing the human CETP transgene controlled by its endogenous promoter increased cholesterol within apoB-containing lipoproteins and decreased HDL-C (each P < 0.01), while hepatic CETP mRNA expression and plasma CETP activity and mass increased (each P < 0.01). In vitro studies confirmed that FXR agonists substantially augmented CETP mRNA expression in hepatocytes and macrophages dependent on functional FXR expression (each P < 0.001). These transcriptional effects are likely mediated by an ER8 FXR response element (FXRE) in the first intron. In conclusion, using a translational approach, this study identifies CETP as novel FXR target gene. By increasing CETP expression, FXR activation leads to a proatherogenic lipoprotein profile. These results have clinical relevance, especially when considering FXR agonists as emerging treatment strategy for metabolic disease and atherosclerosis.

Skew of Plasma Low- and High-Density Lipoprotein Distributions to Less Dense Subfractions in Normotriglyceridemic Chronic Kidney Disease Patients on Maintenance Hemodialysis Treatment

Background: Plasma levels of small, dense low-density lipoprotein (LDL) were reported to increase in chronic kidney disease (CKD) patients on hemodialysis (HD), but most of these patients were hypertriglyceridemic. Plasma levels of small, dense LDL are known to increase in hypertriglyceridemic subjects. Therefore, to investigate the direct effect of CKD on the distribution of LDL subfractions, we investigated the distribution of LDL subfractions in normotriglyceridemic CKD patients on HD. Methods: The levels of plasma lipoprotein subfractions and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), which markedly influence the distributions of plasma LDL and high-density lipoprotein (HDL) subfractions, were compared between 40 HD patients and 40 normolipidemic controls. Plasma lipoproteins were subfractionated into seven subfractions by ultracentrifugation. Results: Plasma levels of cholesterol (C) in remnant-like particle, which is equivalent to the triglyceride (TG)-rich lipoprotein remnant, were twice as high in HD patients as those in controls with matched TG levels. Plasma levels of C and TG in VLDL and IDL (intermediate density lipoprotein) were slightly higher in HD patients than in controls. The C/TG ratio of VLDL was significantly higher in HD patients than in controls. In comparison with the corresponding values in controls, the C and TG levels in low-density LDL and HDL₂ in HD patients were high, whereas those in medium-density LDL, high-density LDL, and HDL₃ were low. Plasma LCAT activity and CETP mass were lower in HD patients than in controls. Conclusion: Distribution of LDL and HDL skewed toward less dense fractions in normotriglyceridemic CKD patients on HD. A decrease in reverse C transport likely played an important role in these changes in the patients.

Cholesteryl Ester Transfer Protein in Patients with Rheumatoid Arthritis

To investigate how cholesteryl ester transfer protein (CETP), one of the enzymes involved in the reverse cholesterol transfer, is expressed in patients with rheumatoid arthritis (RA) and its potential relationship with both dyslipidemia and the risk of cardiovascular mortality observed in these patients. Plasma CETP concentrations and CETP activity were measured in 101 patients with RA and 115 sex- and age-matched controls. A multivariable analysis adjusted for standard cardiovascular risk factors, including high-density lipoprotein cholesterol, was performed to evaluate the influence of CETP on dyslipidemia and cardiovascular mortality risk, as assessed by the Systematic Coronary Risk Evaluation (SCORE) risk function. Patients with RA showed lower CETP activity [beta coefficient = -10.82 (95% CI -19.56 to 2.07) pmol/3 h; p = 0.02] and an inferior CETP mass [β = -0.85 (95% CI -1.64 to 0.05) μg/ml; p = 0.03] versus controls. Divided into those taking and those not taking glucocorticoids, patients taking glucocorticoids revealed lower CETP activity and mass [β = -8.98 (95% CI -14.55 to 3.41) pmol/3 h; p = 0.00, for CETP activity; and β = -0.77 (95% CI -1.46 to 0.08) μg/ml; p = 0.03, for CETP mass]. Patients with RA not taking glucocorticoids showed no differences versus controls in either CETP activity or mass. Both current prednisone intake [β = -16.14 (95% CI -24.87 to 7.41) pmol/3 h; p = 0.00] and average daily prednisone intake during the last 3 months [β = -0.36 (95% CI -0.54 to 0.18) μg/ml; p = 0.01] were strongly and inversely correlated with CETP activity and mass, respectively. CETP activity showed an inverse trend compared to SCORE risk, demonstrating that lower levels were effective predictors of total mortality when a higher SCORE risk was found [β = -4.7 (95% CI -9.3 to 0.02) pmol/3 h; p = 0.04] in patients with RA. CETP is downregulated in patients with RA who are taking glucocorticoids. Low CETP activity is associated with an increased level of cardiovascular risk in patients with RA.

Low normal thyroid function enhances plasma cholesteryl ester transfer in Type 2 diabetes mellitus

BackgroundPlasma cholesteryl ester transfer (CET), reflecting endogenous transfer of cholesteryl esters from HDL to very low and low density lipoproteins, is elevated in Type 2 diabetes mellitus (T2DM), and may predict (subclinical) cardiovascular disease. Low normal thyroid function may adversely affect lipoprotein metabolism and atherosclerosis development. We tested whether plasma CET is related to thyroid function in euthyroid T2DM and non-diabetic subjects. Subjects and methodsPlasma CET was measured in 74 T2DM and 82 non-diabetic subjects with thyroid-stimulating hormone (TSH) and free thyroxine levels within the reference range. ResultsPlasma CET was 20% higher in T2DM (P = 0.003) coinciding higher cholesteryl ester transfer protein (CETP) mass (P = 0.009) and triglycerides (P = 0.02). In univariate analysis, plasma CET was correlated positively with TSH in T2DM only (r = 0.330, P = 0.004). Multiple linear regression analysis revealed a positive interaction between the presence of T2DM and TSH on plasma CET after controlling for age, sex, body mass index, non-HDL cholesterol, triglycerides and CETP mass (β = 0.167, P = 0.030). The relationship of plasma CET with TSH was also positively modified by plasma glucose and HbA1c (interaction terms: β = 0.119, P = 0.036, β = 0.170, P = 0.001, respectively). Additionally, plasma triglycerides interacted positively with TSH on plasma CET in T2DM (β = 0.198, P = 0.011). ConclusionsLow normal thyroid function, as inferred from higher TSH, confers increased plasma CET in the context of chronic hyperglycemia. Effects of thyroid function on plasma CET may be particularly relevant in hypertriglyceridemic T2DM. Low normal thyroid function could influence atherosclerosis susceptibility in T2DM by affecting the plasma cholesteryl ester transfer process.

Altered relationship of plasma triglycerides to HDL cholesterol in patients with HIV/HAART-associated dyslipidemia: Further evidence for a unique form of Metabolic Syndrome in HIV patients

IntroductionPlasma triglycerides (TG) and HDL-C are inversely related in Metabolic Syndrome (MetS), due to exchange of VLDL-TG for HDL-cholesteryl esters catalyzed by cholesteryl ester transfer protein (CETP). We investigated the relationship of TG to HDL-C in highly-active antiretroviral drug (HAART)-treated HIV patients. MethodsFasting plasma TG and HDL-C levels were compared in 179 hypertriglyceridemic HIV/HAART patients and 71 HIV-negative persons (31 normotriglyceridemic (NL) and 40 hypertriglyceridemic due to type IV hyperlipidemia (HTG)). CETP mass and activity were compared in 19 NL and 87 HIV/HAART subjects. ResultsAmong the three groups, a plot of HDL-C vs. TG gave similar slopes but significantly different y-intercepts (9.24±0.45, 8.16±0.54, 6.70±0.65, sqrt(HDL-C) for NL, HIV and HTG respectively; P<0.001); this difference persisted after adjusting HDL-C for TG, age, BMI, gender, glucose, CD4 count, viral load and HAART strata (7.18±0.20, 6.20±0.05 and 4.55±0.15 sqrt(HDL-C) for NL, HIV and HTG, respectively, P<0.001). CETP activity was not different between NL and HIV, but CETP mass was significantly higher in HIV (1.47±0.53 compared to 0.93±0.27μg/mL, P<0.0001), hence CETP specific activity was lower in HIV (22.67±13.46 compared to 28.46±8.24nmol/μg/h, P=0.001). ConclusionsDyslipidemic HIV/HAART patients have a distinctive HDL-C plasma concentration adjusted for TG. The weak inverse relationship between HDL-C and TG is not explained by altered total CETP activity; it could result from a non-CETP-dependent mechanism or a decrease in CETP function due to inhibitors of CETP activity in HIV patients’ plasma.