Plasma Cholesteryl Ester Transfer Protein Research Articles

Assessing lipid-lowering and plasma cholesteryl ester transfer protein activity of Centranthus longiflorus and β-Sitosterol following administration to triton WR1339- treated rats.

The aim of this study was to evaluate the lipid-lowering and plasma cholesteryl ester transfer protein(CETP) activity of Centranthus longiflorus(CL) and β-Sitosterol(βS) following intraperitoneal administration of Triton-WR 1339 (=Tyloxapol) (TWR) to male Wistar rats. Hyperlipidemia(HL) was developed by intraperitoneal injection of TWR. The animals were divided into main eight groups of six rats each. Rats were housed in separate cages and fed a standard diet for 7 days. After 7 days, ethanol extraction of CL plant, aqueous suspension of βS and anacetrapib was given to rats by oral gavage 1 h before the triton injection. Blood samples were collected and used for the biochemical parameters analysis. Histopathological studies were also performed on liver tissue. In hyperlipidemic rats(HR), CL extract and βS reduced total cholesterol similarly. βS lowered low-density lipoprotein(LDL-C) more than CL extract. Both CL extract and βS approximated impaired Alanine transaminase(ALT) and Aspartate transaminase(AST) levels in HR's to the level of control. CL extract provided better protection than βS against deterioration in liver tissue samples seen in hyperlipidemic rats. Finally, CL extract and βS inhibited CETP, at which point βS was more effective. These findings showed that CL extract and βS reduce plasma lipid concentration and may have a hypolipidemic effect due to their anti-CETP properties.

A Randomized, Parallel, Open-Label, Single-Dose and Multiple-Dose Clinical Trial to Investigate the Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Obicetrapib in Healthy Participants in China.

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Previous research has demonstrated similar pharmacokinetic (PK) responses to single doses of obicetrapib between Japanese and White males, but the PK responses have not been established in Chinese individuals. The purpose of this randomized, parallel, open-label trial was to characterize the PK and pharmacodynamic (PD; CETP activity and plasma lipids) responses and safety of single doses (5, 10, or 25 mg; N = 36) and multiple doses (10 mg for 14 days; N = 12) of obicetrapib in healthy Chinese individuals. The maximum concentration and area under the drug concentration-time curve of obicetrapib from 0 h to infinity increased with dose after all single doses of obicetrapib. After 7 consecutive days of dosing, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol reached their minimum and maximum changes of 42% reduction and 108% increase, respectively. Primary PK and PD parameters after single- and multiple-dose administration of obicetrapib were similar to those in healthy white participants in previous studies. One participant in the 5 mg dose group experienced a treatment-emergent adverse event of decreased white blood cell and neutrophil counts, which resolved without intervention. In conclusion, these findings support the inclusion of Chinese individuals in the ongoing phase 3 clinical development program of obicetrapib.

Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): New Amterdam Pharma Background Elevated levels of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia. Methods Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (µg/mL) on plasma lipids, cardiovascular disease, Lewy body dementia (LBD), as well as Parkinson’s dementia. Replication was sought by performed Apo-A1 and Apo-B weighted MR analyses of CETP variants. Genetic associations with protein expression in cerebrospinal fluid (CSF) and brain were consulted to identify potential associations of plasma CETP with dementia implicated proteins. Results MR analysis of lower CETP concentration (per µg/mL) recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on CHD (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96); Figure. Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson’s dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4+ participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81×10-4. The aforementioned associations were replicated using Apo-B and Apo-A1 weighted analyses; Figure. Additionally, MR was employed to link plasma CETP concentration to the levels of CSF and brain proteins such as EPHA2 and CSF-1, which are in development as dementia drug targets. Conclusion These results suggest that inhibition of CETP may be a viable strategy to treat dementia.

Lauric and Palmitic Acid-Enriched Diets have Minimal Impact on Serum Lipid and Lipoprotein Concentrations and Glucose Metabolism in Healthy Young Women

Fifteen healthy young women were fed diets enriched to 4% of energy with either palmitic acid (as palm oil) or lauric acid (as coconut oil). A randomized crossover study design was used so that subjects followed the two experimental diets for 4 wk, both preceded by consumption of a baseline diet for 2 wk. The experimental diets differed only with respect to the fatty acid composition: there was a substitution of 4% of energy intake with palmitic acid or lauric acid in the experimental diets for 4% of energy as monoenes in the baseline diet. There were no differences in the concentration of serum total or lipoprotein lipids, apolipoproteins A-I and B, and lipoprotein (a) or plasma cholesteryl ester transfer protein activity between the experimental diet periods. The VLDL cholesterol concentration (0.38 ± 0.05 vs. 0.51 ± 0.05 mmol/L, means ± SEM, P = 0.01] and plasma cholesteryl ester transfer protein activity [78 ± 5 vs. 88 ± 6 µmol/(h·L), P = 0.007) were greater at the end of the lauric acid diet period than at the end of the preceding baseline diet period. No differences were found in glucose effectiveness, insulin sensitivity index or insulin secretion measured by the intravenous glucose tolerance test (Minimal Model method). In conclusion, in terms of serum lipids, lipoproteins, and glucose metabolism, palmitic acid was equal to lauric acid at 4% of total energy intake exchange, and both of these saturated fatty acids were comparable to a 4% of total energy intake exchange with monoenes in healthy young women.

Purple perilla frutescens extracts containing α-asarone inhibit inflammatory atheroma formation and promote hepatic HDL cholesterol uptake in dyslipidemic apoE-deficient mice.

Dyslipidemia causes metabolic disorders such as atherosclerosis and fatty liver syndrome due to abnormally high blood lipids. Purple perilla frutescens extract (PPE) possesses various bioactive compounds such as α-asarone, chlorogenic acid and rosmarinic acid. This study examined whether PPE and α-asarone improved dyslipidemia-associated inflammation and inhibited atheroma formation in apolipoprotein E (apoE)-deficient mice, an experimental animal model of atherosclerosis. ApoE-deficient mice were fed on high cholesterol-diet (Paigen's diet) and orally administrated with 10-20 mg/kg PPE and α-asarone for 10 wk. The Paigen's diet reduced body weight gain in apoE-deficient mice, which was not restored by PPE or α-asarone. PPE or α-asarone improved the plasma lipid profiles in Paigen's diet-fed apoE-deficient mice, and despite a small increase in high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL)-cholesterol, and very LDL were significantly reduced. Paigen's diet-induced systemic inflammation was reduced in PPE or α-asarone-treated apoE-deficient mice. Supplying PPE or α-asarone to mice lacking apoE suppressed aorta atherogenesis induced by atherogenic diet. PPE or α-asarone diminished aorta accumulation of CD68- and/or F4/80-positive macrophages induced by atherogenic diet in apoE-deficient mice. Treatment of apoE-deficient mice with PPE and α-asarone resulted in a significant decrease in plasma cholesteryl ester transfer protein level and an increase in lecithin:cholesterol acyltransferase reduced by supply of Paigen's diet. Supplementation of PPE and α-asarone enhanced the transcription of hepatic apoA1 and SR-B1 reduced by Paigen's diet in apoE-deficient mice. α-Asarone in PPE inhibited inflammation-associated atheroma formation and promoted hepatic HDL-C trafficking in dyslipidemic mice.

Novel Role of CETP in Macrophages: Reduction of Mitochondrial Oxidants Production and Modulation of Cell Immune-Metabolic Profile.

Plasma cholesteryl ester transfer protein (CETP) activity diminishes HDL-cholesterol levels and thus may increase atherosclerosis risk. Experimental evidence suggests CETP may also exhibit anti-inflammatory properties, but local tissue-specific functions of CETP have not yet been clarified. Since oxidative stress and inflammation are major features of atherogenesis, we investigated whether CETP modulates macrophage oxidant production, inflammatory and metabolic profiles. Comparing macrophages from CETP-expressing transgenic mice and non-expressing littermates, we observed that CETP expression reduced mitochondrial superoxide anion production and H2O2 release, increased maximal mitochondrial respiration rates, and induced elongation of the mitochondrial network and expression of fusion-related genes (mitofusin-2 and OPA1). The expression of pro-inflammatory genes and phagocytic activity were diminished in CETP-expressing macrophages. In addition, CETP-expressing macrophages had less unesterified cholesterol under basal conditions and after exposure to oxidized LDL, as well as increased HDL-mediated cholesterol efflux. CETP knockdown in human THP1 cells increased unesterified cholesterol and abolished the effects on mitofusin-2 and TNFα. In summary, the expression of CETP in macrophages modulates mitochondrial structure and function to promote an intracellular antioxidant state and oxidative metabolism, attenuation of pro-inflammatory gene expression, reduced cholesterol accumulation, and phagocytosis. These localized functions of CETP may be relevant for the prevention of atherosclerosis and other inflammatory diseases.

The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration: Insights from the IMPROVE Study.

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMTmax; cIMTmean–max of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMTmean) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMTmax and cIMTmean–max, but not with PF CC-IMTmean, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMTmax or cIMTmean–max were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMTmax and cIMTmean–max when the CETP concentration was below the median (HDL-C × CETP interaction, p = 0.001 and p = 0.003 for cIMTmax and cIMTmean–max, respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMTmax. rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMTmax. In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMTmax. This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent.

Novel role of cholesteryl ester transfer protein (CETP): attenuation of adiposity by enhancing lipolysis and brown adipose tissue activity

ObjectiveThe systemic function of CETP has been well characterized. CETP plasma activity reduces HDL cholesterol and thus increases the risk of atherosclerosis. Here, we investigated whether CETP expression modulate adiposity. MethodsBody adiposity and energy metabolism related assays and gene/protein expression were compared in CETP transgenic and non-transgenic mice and in hamsters treated with CETP neutralizing antibody. ResultsWe found that transgenic mice expressing human CETP present less white adipose tissue mass and lower leptinemia than nontransgenic (NTg) littermates. No differences were found in physical activity, food intake, fat fecal excretion, lipogenesis or exogenous lipid accumulation in adipose depots. Nonetheless, adipose lipolysis rates and whole-body energy expenditure were elevated in CETP mice. In accordance, lipolysis-related gene expression and protein content were increased in visceral and brown adipose tissue (BAT). In addition, we verified increased BAT temperature and oxygen consumption. These results were confirmed in two other animal models: 1) hamsters treated with CETP neutralizing antibody and 2) an independent line of transgenic mice expressing simian CETP. ConclusionsThese findings reveal a novel anti-adipogenic role for CETP.

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.

Influence of CETP on High-Density Lipoprotein Subclasses in Patients with Coronary Heart Disease.

Inhibition of plasma cholesteryl ester transfer protein (CETP) can effectively reduce the risk of ath-erosclerotic cardiovascular disease by increasing high-density lipoprotein cholesterol (HDL-C) levels, but the effect of CETP on the distributions of HDL subclasses in patients with coronary heart disease (CHD) is still elusive. To investigate the correlation between the level of CETP and the distributions of HDL subclasses, 121 healthy controls and 139 patients with CHD were selected as study subjects. The plasma levels of CETP and each HDL subclass were respectively determined by enzyme-linked immunosorbent assay and two-dimensional gel electrophoresis associated with the immunodetection method. At the same time, blood biochemical data from all subjects were collected, including the levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C, apoA1, and apoB100. Correlation analysis and multiple regression analysis among the plasma HDL subclass values and biochemical parameters in subjects with CHD were conducted. As the plasma level of CETP increases, the contents of TC, TG, and apoB100/A1 were obviously elevated, while the levels of HDL-C and apoA1 decreased significantly. For distributions of HDL subclasses, large-sized HDL2a and HDL2b were markedly decreased in the middle CETP group (p < 0.05) and the high CETP group (p < 0.001) compared to the low CETP group, while the small-sized preβ1-HDL was obviously increased. Intriguingly, when the plasma concentration of TC or TG in patients with CHD was higher, the elevated preβ1-HDL and reduced HDL2a were more dependent on the increase in CETP. Furthermore, correlation analysis and multiple regression analysis also confirmed that plasma CETP was positively correlated with preβ1-HDL levels and negatively correlated with HDL2b levels. The distributions of HDL subclasses were associated with CETP in patients with CHD, especially in those with high levels of TC and TG. CETP levels were associated with an increase in small-sized preβ1-HDL and a decrease in large-sized HDL subclasses, which indicated that CETP might be a limiter of reverse cholesterol transport and HDL maturation.

Reduced CETP glycosylation and activity in patients with homozygous B4GALT1 mutations.

The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying the effects of defective glycosylation on plasma lipids in patients with B4GALT1‐CDG, caused by a mutation in B4GALT1 with defective N‐linked glycosylation. We studied plasma lipids, cholesteryl ester transfer protein (CETP) glyco‐isoforms with isoelectric focusing followed by a western blot and CETP activity in three known B4GALT1‐CDG patients and compared them with 11 age‐ and gender‐matched, healthy controls. B4GALT1‐CDG patients have significantly lowered non‐high density lipoprotein cholesterol (HDL‐c) and total cholesterol to HDL‐c ratio compared with controls and larger HDL particles. Plasma CETP was hypoglycosylated and less active in B4GALT1‐CDG patients compared to matched controls. Our study provides insight into the role of protein glycosylation in human lipoprotein homeostasis. The hypogalactosylated, hypo‐active CETP found in patients with B4GALT1‐CDG indicates a role of protein galactosylation in regulating plasma HDL and LDL. Patients with B4GALT1‐CDG have large HDL particles probably due to hypogalactosylated, hypo‐active CETP.

The Cholesteryl Ester Transfer Protein Inhibitor, des-Fluoro-Anacetrapib, Prevents Vein Bypass-induced Neointimal Hyperplasia in New Zealand White Rabbits

Coronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures. However, graft failure due to stenosis reduces the long-term benefit of the intervention. This study asks if elevating plasma high density lipoprotein cholesterol (HDL-C) levels by inhibition of cholesteryl ester transfer protein (CETP) activity with des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, prevents vein bypass-induced neointimal hyperplasia. NZW rabbits were placed on a normal chow diet or chow containing 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Bypass grafting of the jugular vein to the common carotid artery was performed 2 weeks after starting dietary des-fluoro-anacetrapib supplementation. The animals were euthanised 4 weeks post-bypass grafting. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma CETP activity by 89 ± 6.9%, increased plasma apolipoprotein A-I levels by 24 ± 5.5%, increased plasma HDL-C levels by 93 ± 26% and reduced intimal hyperplasia in the grafted vein by 38 ± 6.2%. Des-fluoro-anacetrapib treatment was also associated with decreased bypass grafting-induced endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), endothelial dysfunction, and smooth muscle cell (SMC) proliferation in the grafted vein. In conclusion, increasing HDL-C levels by inhibiting CETP activity is associated with inhibition of intimal hyperplasia in grafted veins, reduced inflammatory responses, improved endothelial function, and decreased SMC proliferation.

ApoF knockdown increases cholesteryl ester transfer to LDL and impairs cholesterol clearance in fat-fed hamsters

Cholesteryl ester transfer protein (CETP) regulates intravascular lipoprotein metabolism. In vitro studies indicate that ApoF alters CETP function by inhibiting its activity with LDL. To explore in vivo the complexities driving ApoF's effects on CETP, we developed a siRNA-based hamster model of ApoF knockdown. In both male and female hamsters on chow- or fat-fed diets, we measured lipoprotein levels and composition, determined CETP-mediated transfer of cholesteryl esters (CEs) between lipoproteins, and quantified reverse cholesterol transport (RCT). We found that apoF knockdown in chow-fed hamsters had no effect on lipoprotein levels or composition, but these ApoF-deficient lipoproteins supported 50-100% higher LDL CETP activity in vitro. ApoF knockdown in fat-fed male hamsters created a phenotype in which endogenous CETP-mediated CE transfer from HDL to LDL increased up to 2-fold, LDL cholesterol increased 40%, HDL declined 25%, LDL and HDL lipid compositions were altered, and hepatic LDLR gene expression was decreased. Diet-induced hypercholesterolemia obscured this phenotype on occasion. In fat-fed female hamsters, ApoF knockdown caused similar but smaller changes in plasma CETP activity and LDL cholesterol. Notably, ApoF knockdown impaired HDL RCT in fat-fed hamsters but increased sterol excretion in chow-fed animals. These in vivo data validate in vitro findings that ApoF regulates lipid transfer to LDL. The consequences of ApoF knockdown on lipoproteins and sterol excretion depend on the underlying lipid status. By minimizing the transfer of HDL-derived CE to LDL, ApoF helps control LDL cholesterol levels when LDL clearance mechanisms are limiting.

Molecular modeling and rational design of hydrocarbon-stapled/halogenated helical peptides targeting CETP self-binding site: Therapeutic implication for atherosclerosis

The human plasma cholesteryl ester transfer protein (CETP) collects triglycerides from very-/low-density lipoproteins (V/LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), which has recognized as an important therapeutic target for atherosclerosis. The protein has a C-terminal amphipathic α-helix that serves as self-binding peptide to fulfill biological function by dynamically binding to/unbinding from its cognate site (termed self-binding site) in the same protein. Previously, we successfully derived and halogenated the helical peptide to competitively disrupt the self-binding behavior of CETP C-terminal tail. However, the halogenated peptides have only a limited affinity increase as compared to native helical peptide (∼3-fold), thus exhibiting only a moderate competitive potency. Here, instead of optimizing the direct intermolecular interaction of peptide with CETP self-binding site we attempt to further improve the peptide competitive potency by reducing its conformational flexibility with hydrocarbon-stapling technique. Computational analysis reveals that the helical peptide has large intrinsic disorder in unbound free state, which would incur a considerable entropy penalty upon rebinding to the self-binding site. All-hydrocarbon bridge is designed and optimized on native and halogenated peptides in terms of the helical pattern and binding mode of self-binding peptide. Dynamics simulation and circular dichroism indicate that the stapling can considerably reduce peptide disorder in free state. Energetics calculation and fluorescence assay conform that the binding affinity of stapled/halogenated peptides is improved substantially (by > 5-fold), thus exhibiting an effective competition potency with native peptide for the self-binding site. Structural examination suggests that the binding modes and nonbonded interactions of native and halogenated peptides are not influenced essentially due to the stapling.

Steering the Lipid Transfer To Unravel the Mechanism of Cholesteryl Ester Transfer Protein Inhibition.

Human plasma cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids from antiatherogenic high-density lipoproteins (HDLs) to proatherogenic low-density lipoproteins (LDLs). Recent cryo-electron microscopy studies have suggested that CETP penetrates its N- and C-terminal domains in HDL and LDL to form a ternary complex, which facilitates the lipid transfer between different lipoproteins. Inhibition of CETP lipid transfer activity has been shown to increase the plasma HDL-C levels and, therefore, became an effective strategy for combating cardiovascular diseases. Thus, understanding the molecular mechanism of inhibition of lipid transfer through CETP is of paramount importance. Recently reported inhibitors, torcetrapib and anacetrapib, exhibited low potency in addition to severe side effects, which essentially demanded a thorough knowledge of the inhibition mechanism. Here, we employ steered molecular dynamics simulations to understand how inhibitors interfere with the neutral lipid transfer mechanism of CETP. Our study revealed that inhibitors physically occlude the tunnel posing a high energy barrier for lipid transfer. In addition, inhibitors bring about the conformational changes in CETP that hamper CE passage and expose protein residues that disrupt the optimal hydrophobicity of the CE transfer path. The atomic level details presented here could accelerate the designing of safe and efficacious CETP inhibitors.

Cholesteryl ester transfer protein (CETP), HDL capacity of receiving cholesterol and status of inflammatory cytokines in patients with severe heart failure

BackgroundHeart failure (HF) courses with chronic inflammatory process and alterations in lipid metabolism may aggravate the disease. The aim was to test whether the severity of HF, using brain natriuretic peptide (BNP) as a marker, is associated with alterations in functional aspects of HDL, such as lipid transfer, cholesterol ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT) concentration.MethodsTwenty-five HF patients in NYHA class I/II and 23 in class III/IV were enrolled. Plasma lipids, apolipoproteins, CETP, LCAT, oxidized-LDL (oxLDL) and paraoxonase-1 (PON-1) activity were determined. Lipid transfer from a donor artificial nanoparticle to HDL was measured by in vitro assay.ResultsTotal cholesterol (p = 0.049), LDL-C (p = 0.023), non-HDL-C (p = 0.029) and CETP, that promotes lipid transfer among lipoproteins (p = 0.013), were lower in III/IV than in I/II group. Triglycerides, HDL-C, apo A-I, apo B, oxLDL, LCAT, enzyme that catalyzes serum cholesterol esterification, PON-1 activity, and in vitro transfers of cholesterol, triglycerides and phospholipids to HDL, important steps in HDL metabolism, were equal. IL-8 was higher in III/IV (p = 0.025), but TNFα, IL-1β, IL-6 and MCP-1 were equal. BNP was negatively correlated with CETP (r = − 0.294; p = 0.042) and positively correlated with IL-8 (r = 0.299; p = 0.039).ConclusionsOur results disclosed the relationship between CETP levels and HF severity, by comparing two HF groups and by correlation analysis. Lower CETP levels may be a marker of HF aggravation and possibly of worse prognosis. Practical applications of this initial finding, as the issue whether CETP could be protective against HF aggravation, should be explored in larger experimental and clinical studies.

CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet.

In clinical trials, inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but does not robustly improve cardiovascular outcomes. Approximately two-thirds of trial participants are obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define whether CETP inhibition has different effects depending on the presence of obesity, we performed short-term anacetrapib treatment in chow- and HFD-fed CETP transgenic mice. Anacetrapib raised HDL cholesterol and improved aspects of HDL functionality, including reverse cholesterol transport, and HDL’s antioxidative capacity in HFD-fed mice was better than in chow-fed mice. Anacetrapib worsened the anti-inflammatory capacity of HDL in HFD-fed mice. The HDL proteome was markedly different with anacetrapib treatment in HFD- versus chow-fed mice. Despite benefits on HDL, anacetrapib led to liver triglyceride accumulation and insulin resistance in HFD-fed mice. Overall, our results support a physiologic importance of CETP in protecting from fatty liver and demonstrate context selectivity of CETP inhibition that might be important in obese subjects.

The effects of curcumin and a modified curcumin formulation on serum Cholesteryl Ester Transfer Protein concentrations in patients with metabolic syndrome: A randomized, placebo-controlled clinical trial

Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl ester from HDL-C to LDL-C and VLDL-C. The aim of the present trial was to evaluate the effect of curcumin and its modified formulation on serum CETP concentrations in patients with metabolic syndrome. Participants were randomly allocated to one of three groups of40 subjects receiving either unmodified curcumin or its phospholipid complex or placebo. Lipid profile and plasma CETP were measured at the start and six weeks after initiation of the treatment. The normality of data distribution was assessed by Kolmogorov-Smirnov test. Wilcoxon test was used for comparing the data before and after the intervention. The percent changes of CETP and biochemical factors among the three groups were compared using Kruskal-Wallis test. Serum CETP levels were not significantly altered among patients receiving curcumin. Curcumin and its complex had no significant effect on serum CETP concentrations.

Metabolic liver inflammation in obesity does not robustly decrease hepatic and circulating CETP

Background and aimsWe recently showed that plasma cholesteryl ester transfer protein (CETP) is mainly derived from VSIG4-positive Kupffer cells. Activation of these cells by the bacterial endotoxin lipopolysaccharide (LPS) strongly decreases CETP expression. As Kupffer cell activation plays a detrimental role in the progression of non-alcoholic fatty liver disease (NAFLD), we aimed to study if metabolic liver inflammation is also associated with a decrease in hepatic and circulating CETP. MethodsWe collected plasma and liver biopsy samples at various stages of NAFLD from 93 obese individuals who underwent bariatric surgery. Liver lobular inflammation was histologically determined, and liver CETP expression, CETP positive cells, circulating CETP concentrations, and liver VSIG4 expression were quantified. ResultsMean (SD) plasma CETP concentration was 2.68 (0.89) μg/mL. In the presence of liver inflammation, compared to the absence of pathology, the difference in hepatic CETP expression was −0.03 arbitrary units (95% CI -0.26, 0.20), the difference in number of hepatic CETP positive cells (range 11–140 per mm2) was −20.0 per mm2 (95% CI -41.6, 1.9), and the difference in plasma CETP was −0.35 μg/mL (95% CI -0.80, 0.10). Hepatic VSIG4 expression was not associated with liver inflammation (0.00; 95% CI -0.15, 0.15). ConclusionsWe found no strong evidence for a strong negative association between metabolic liver inflammation and CETP-related outcomes in obese individuals, although we observed consistent trends. These data indicate that metabolic liver inflammation does not mimic the strong effects of LPS on the hepatic expression and production of CETP by Kupffer cells.

Chronic Exercise Reduces CETP and Mesterolone Treatment Counteracts Exercise Benefits on Plasma Lipoproteins Profile: Studies in Transgenic Mice.

Regular exercise and anabolic androgenic steroids have opposing effects on the plasma lipoprotein profile and risk of cardio-metabolic diseases in humans. Studies in humans and animal models show conflicting results. Here, we used a mice model genetically modified to mimic human lipoprotein profile and metabolism. They under-express the endogenous LDL receptor gene (R1) and express a human transgene encoding the cholesteryl ester transfer protein (CETP), normally absent in mice. The present study was designed to evaluate the independent and interactive effects of testosterone supplementation, exercise training and CETP expression on the plasma lipoprotein profile and CETP activity. CETP/R1 and R1 mice were submitted to a 6-week swimming training and mesterolone (MEST) supplementation in the last 3weeks. MEST treatment increased markedly LDL levels (40%) in sedentary CETP/R1 mice and reduced HDL levels in exercised R1 mice (18%). A multifactorial ANOVA revealed the independent effects of each factor, as follows. CETP expression reduced HDL (21%) and increased non-HDL (15%) fractions. MEST treatment increased the VLDL concentrations (42%) regardless of other interventions. Exercise training reduced triacylglycerol (25%) and free fatty acids (20%), increased both LDL and HDL (25-33%), and reduced CETP (19%) plasma levels. Significant factor interactions showed that the increase in HDL induced by exercise is explained by reducing CETP activity and that MEST blunted the exercise-induced elevation of HDL-cholesterol. These results reinforce the positive metabolic effects of exercise, resolved a controversy about CETP response to exercise and evidenced MEST potency to counteract specific exercise benefits.