Cholesteryl Ester Transfer Protein Activity Research Articles

Cholesteryl Ester Transfer Protein (CETP) Variations in Relation to Lipid Profiles and Cardiovascular Diseases: An Update.

Lipid metabolism plays an essential role in the pathogenesis of cardiovascular and metabolic diseases. Cholesteryl ester transfer protein (CETP) is a crucial glycoprotein involved in lipid metabolism by transferring cholesteryl esters (CE) and triglycerides (TG) between plasma lipoproteins. CETP activity results in reduced HDL-C and increased VLDL- and LDL-C concentrations, thus increasing the risk of cardiovascular and metabolic diseases. In this review, we discuss the structure of CETP and its mechanism of action. Furthermore, we focus on recent experiments on animal CETP-expressing models, deciphering the regulation and functions of CETP in various genetic backgrounds and interaction with different external factors. Finally, we discuss recent publications revealing the association of CETP single nucleotide polymorphisms (SNPs) with the risk of cardiovascular and metabolic diseases, lifestyle factors, diet and therapeutic interventions. While CETP SNPs can be used as effective diagnostic markers, diet, lifestyle, gender and ethnic specificity should also be considered for effective treatment.

Transfer Proteins, Lipoprotein Remodeling, and Antioxidant Action on Pregnant Women: Comparison from the First to the Third Trimester of Gestation

Introduction: During pregnancy, maternal lipid metabolism undergoes several transformations originated by hormonal changes. There are two distinct phases: initial and late, finally driven to hypertriglyceridemia. Maternal hyperlipidemia, especially hypertriglyceridemia, is associated with an increased hepatic very-low-density lipoprotein (VLDL) synthesis stimulated by high estrogen levels during gestation. Objectives: This study aimed to evaluate the action of possible lipoproteins remodeling modulators, such as phospholipid and cholesteryl-ester transfer proteins (PLTP and CETP), paraoxonase-1 (PON-1), and apolipoproteins (apo), during gestation. Methods: An observational prospective cohort study composed of 40 pregnant women was conducted. Blood samples were collected in two moments: at the first and third trimesters of gestation, followed by the biochemical determination of apo A-I, apo B, lipid profile, PON-1, PLTP and CETP activities, and HDL particle size. Results: The majority of pregnant women in the third trimester showed dyslipidemia, mainly hypertriglyceridemia. In the third trimester of gestation, we observed an increase in CETP activity (70.5 ± 9.6 pmol/µL/h; p <0.001) and TG/HDL-C ratio (2.7 [2.0-3.8]), but on the other hand, PON-1 activity (65.4 [46.5-105] nMol of p-nitrophenol/min/mL) decreased. High-density level lipoprotein (HDL) particle size and PLTP activity did not differ in the two studied moments. The serum triglyceride concentration and CETP activity showed a positive linear correlation in the first trimester of gestation (r2=0.65, p<0.001). Conclusion: Data suggest that the CETP activity, antioxidant profile, and low-density lipoprotein (LDL) remodeling are modified by physiological metabolic changes during an uncomplicated gestational period.

Seasonal Factors Are Associated with Activities of Enzymes Involved in High-Density Lipoprotein Metabolism among Pregnant Females in Ghana

BackgroundSmall-quantity lipid-based nutrient supplements (SQ-LNS) during pregnancy and postnatally were previously shown to improve high-density lipoprotein (HDL) cholesterol efflux capacity (CEC) and length in the children of supplemented mothers at 18 mo of age in the International Lipid-Based Nutrient Supplements (iLiNS) DYAD trial in Ghana. However, the effects of SQ-LNS on maternal HDL functionality during pregnancy are unknown. ObjectiveThe goal of this cross-sectional, secondary outcome analysis was to compare HDL function in mothers supplemented with SQ-LNS vs. iron and folic acid (IFA) during gestation. MethodsHDL CEC and the activities of 3 HDL-associated enzymes were analyzed in archived plasma samples (N = 197) from a subsample of females at 36 weeks of gestation enrolled in the iLiNS-DYAD trial in Ghana. Correlations between HDL function and birth outcomes, inflammatory markers C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP), and the effects of season were explored to determine the influence of these factors on HDL function in this cohort of pregnant females. ResultsThere were no statistically significant differences in HDL CEC, plasma lecithin-cholesterol acyltransferase (LCAT) activity, cholesteryl ester transfer protein (CETP) activity, or phospholipid transfer protein (PLTP) activity between mothers supplemented with SQ-LNS compared with IFA control, and no statistically significant relationships between maternal HDL function and childbirth outcomes. LCAT activity was negatively correlated with plasma AGP (R = -0.19, P = 0.007) and CRP (R = -0.28, P < 0.001), CETP and LCAT activity were higher during the dry season compared to the wet season, and PLTP activity was higher in the wet season compared to the dry season. ConclusionsMothers in Ghana supplemented with SQ-LNS compared with IFA during gestation did not have measurable differences in HDL functionality, and maternal HDL function was not associated with childbirth outcomes. However, seasonal factors and markers of inflammation were associated with HDL function, indicating that these factors had a stronger influence on HDL functionality than SQ-LNS supplementation during pregnancy. Clinical Trial Registry numberThe study was registered as NCT00970866. https://clinicaltrials.gov/study/NCT00970866

CETP Expression in Bone-Marrow-Derived Cells Reduces the Inflammatory Features of Atherosclerosis in Hypercholesterolemic Mice.

CETP activity reduces plasma HDL-cholesterol concentrations, a correlate of an increased risk of atherosclerotic events. However, our recent findings suggest that CETP expression in macrophages promotes an intracellular antioxidant state, reduces free cholesterol accumulation and phagocytosis, and attenuates pro-inflammatory gene expression. To determine whether CETP expression in macrophages affects atherosclerosis development, we transplanted bone marrow from transgenic mice expressing simian CETP or non-expressing littermates into hypercholesterolemic LDL-receptor-deficient mice. The CETP expression did not change the lipid-stained lesion areas but decreased the macrophage content (CD68), neutrophil accumulation (LY6G), and TNF-α aorta content of young male transplanted mice and decreased LY6G, TNF-α, iNOS, and nitrotyrosine (3-NT) in aged female transplanted mice. These findings suggest that CETP expression in bone-marrow-derived cells reduces the inflammatory features of atherosclerosis. These novel mechanistic observations may help to explain the failure of CETP inhibitors in reducing atherosclerotic events in humans.

THU335 Hyperinsulinemia Is Associated With An Atherogenic Lipoprotein Profile In Humans With Selective Insulin Resistance And An Atheroprotective Profile In Humans With Non-selective Insulin Resistance

Abstract Disclosure: D. Walzer: None. M. Lightbourne: None. M. Walter: None. Y. Dai: None. R.D. Shamburek: None. R.J. Brown: None. Insulin resistance (IR), a major risk factor for cardiovascular disease (CVD), leads to hyperglycemia and dyslipidemia. In obesity-associated IR, dyslipidemia attributed to increased stimulation of hepatic lipogenesis by insulin, whereas IR in glucoregulatory pathways leads to hyperglycemia. This dichotomy in insulin signaling pathways is termed selective IR. Lipodystrophy syndromes (LD) are rare conditions of severe, selective IR in which, like obesity, hyperinsulinemia with excess insulin receptor signaling is thought to cause high triglycerides (TG) &amp; low HDL. By contrast, in the rare condition of insulin receptor pathogenic variants (INSR) (nonselective IR) lack of insulin signaling through its receptor despite hyperinsulinemia leads to low TG and high HDL. Rodents with hepatic INSR k/o have an atherogenic lipid profile, but the lipoprotein profile in humans with INSR is unknown. Factors influencing atherogenicity of lipoprotein particles, including cholesteryl ester transfer protein (CETP) activity and adiponectin, have not been explored in these human models of severe selective vs. non-selective IR. We characterized atherogenicity of lipoprotein particles and factors influencing these particles in subjects with LD matched 2:1 with subjects with INSR based on age and sex. All subjects had fasting lipoprotein profiles by NMR spectroscopy, apolipoproteins AI (ApoI) and B (ApoB), total adiponectin by ELISA, and CETP activity by fluorometric assay. Subjects with LD (N=24, 75% female; 8 generalized, 16 partial) had a more atherogenic lipoprotein profile vs INSR (N=12, 50% female; 6 homozygous, 6 heterozygous), with 45-fold higher large TRLP, 20-fold higher medium TRLP, 15-fold higher very small TRLP (representing IDL), 3-fold higher small LDLP, 4-fold lower large HDLP, 1.7—fold higher ApoB, and 1.4—fold lower ApoAI (p &amp;lt;0.05 for all). CETP activity was comparable in INSR and LD. Adiponectin was 5.9- fold lower in LD vs INSR (p &amp;lt;0.0001). Among all subjects, adiponectin was positively associated with HDL-C, large HDLP, HDL size, and ApoA-I (p=0.001), and negatively correlated with TRLP number &amp; size, small LDLP, and very small TRLP (p&amp;lt;0.0001). Selective IR in LD is associated with an atherogenic lipoprotein particle profile. By contrast, non-selective IR in INSR is associated with an atheroprotective profile, which differs from rodent models. These divergent lipid phenotypes are not explained by different CETP activity. Although preclinical studies suggest that adiponectin promotes a favorable lipoprotein profile consistent with our observed associations, a causal link in humans is not supported by Mendelian randomization studies or rare ADIPOQ gene deletions. Overall, these findings suggest a key role of selective insulin resistance in the development of an atherogenic lipid profile. Further studies are needed to see if this profile leads to increased CVD risk. Presentation: Thursday, June 15, 2023

Impaired Reverse Cholesterol Transport is Associated with Changes in Fatty Acid Profile in Children and Adolescents with Abdominal Obesity

BackgroundAbdominal obesity is an important cardiovascular disease risk factor. Plasma fatty acids display a complex network of both pro and antiatherogenic effects. High density lipoproteins (HDL) carry out the antiatherogenic pathway called reverse cholesterol transport (RCT), which involves cellular cholesterol efflux (CCE), and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities. ObjectivesOur aim was to characterize RCT and its relation to fatty acids present in plasma in pediatric abdominal obesity. MethodsSeventeen children and adolescents with abdominal obesity and 17 healthy controls were studied. Anthropometric parameters were registered. Glucose, insulin, lipid levels, CCE employing THP-1 cells, LCAT and CETP activities, plus fatty acids in apo B-depleted plasma were measured. ResultsThe obese group showed a more atherogenic lipid profile, plus lower CCE (Mean±Standard Deviation) (6 ± 2 vs. 7 ± 2%; P < 0.05) and LCAT activity (11 ± 3 vs. 15 ±5 umol/dL.h; P < 0.05). With respect to fatty acids, the obese group showed higher myristic (1.1 ± 0.3 vs. 0.7 ± 0.3; P < 0.01) and palmitic acids (21.5 ± 2.8 vs. 19.6 ± 1.9; P < 0.05) in addition to lower linoleic acid (26.4 ± 3.3 vs. 29.9 ± 2.6; P < 0.01). Arachidonic acid correlated with CCE (r = 0.37; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05), palmitioleic acid with CCE (r = -0.35; P < 0.05), linoleic acid with CCE (r = 0.37; P < 0.05), lauric acid with LCAT (r = 0.49; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05) ecoisatrienoic acid with CCE (r = 0.40; P < 0.05) and lignoseric acid with LCAT (r = -0.5; P < 0.01). ConclusionsChildren and adolescents with abdominal obesity presented impaired RCT, which was associated with modifications in proinflammatory fatty acids, such as palmitoleic and myristic, thus contributing to increased cardiovascular disease risk.

Impaired HDL-associated enzymes and proteins in children and adolescents with weight disorders and their association with novel cardiometabolic indexes

Background and aimsOverweight/obesity (OW/OB) is associated with modifications in lipoprotein (Lp)-associated enzymes and proteins, such as cholesteryl ester transfer protein (CETP), Lp-associated phospholipase A2 (LpPLA2) and paraoxonase (PON)1. No evidence is available regarding underweight (UW). The following indexes have been proposed to better assess atherogenic risk related to weight alterations: triglycerides-glucose index (TyG), visceral adiposity index (VAI) and height-corrected lipid accumulation product (HLAP). Aim: To analyze the presence of alterations in Lp-associated enzymes and proteins in children and adolescents with UW and OW/OB and their relation to novel cardiometabolic indexes. Methods and resultsThirty male children and adolescents with UW, 66 with normal weight (NW) and 30 with OW/OB were included. Anthropometric parameters, glucose, Lp profile and the activities of CETP, LpPLA2 and PON1 were evaluated. Body mass index (BMI)-z, TyG, VAI and HLAP were calculated. UW and NW showed lower CETP activity than OW/OB (Mean ± SD) (218 ± 38vs.224 ± 26vs.237 ± 26%/mL.h; p < 0.05). UW and OW/OB showed lower PON1 activity than NW (318 ± 170vs.409 ± 200vs.310 ± 184 nmol/mL.min; p < 0.05). TyG was higher in OW/OB than UW (p < 0.01), whilst both HLAP (p < 0.05) and VAI (p < 0.01) followed a linear trend across weight categories. After adjusting for age and BMI-z, TyG was an independent predictor of CETP (r2 = 0.25, β = −0.22, p < 0.01) and LpPLA2 (r2 = 0.21,β = −0.21,p < 0.05), while VAI (r2 = 0.21,β = −0.32,p < 0.01) and HLAP (r2 = 0.20,β = −0.31,p < 0.01) of CETP. ConclusionsBoth UW and OW/OB showed impaired antioxidant PON1 activity. Moreover, TyG, VAI and HLAP were all capable of predicting alterations in crucial modulators of Lp metabolism and vascular inflammation in children and adolescents with varying degrees of alterations in body weight.

The effect of cholesteryl ester transfer protein (CETP) activity on cardiometabolic and non-cardiometabolic diseases in East-Asian and European populations

The effect of cholesteryl ester transfer protein (CETP) activity on cardiometabolic and non-cardiometabolic diseases in East-Asian and European populations

CETP inhibitor evacetrapib enters mouse brain tissue.

High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer's disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer's disease. Thus, pharmacological CETP inhibitors could be repurposed for the treatment of Alzheimer's disease as they are safe and effective at lowering CETP activity and LDL-C. Although CETP is mostly expressed by the liver and secreted into the bloodstream, it is also expressed by astrocytes in the brain. Therefore, it is important to determine whether CETP inhibitors can enter the brain. Here, we describe the pharmacokinetic parameters of the CETP inhibitor evacetrapib in the plasma, liver, and brain tissues of CETP transgenic mice. We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5h after a 40mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer's disease.

Adcy9 Gene Inactivation Improves Cardiac Function After Myocardial Infarction in Mice.

Polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the benefits of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on cardiovascular events after acute coronary syndrome. We hypothesized that Adcy9 inactivation could improve cardiac function and remodelling following myocardial infarction (MI) in absence of CETP activity. Wild-type (WT) and Adcy9-inactivated (Adcy9Gt/Gt) male mice, transgenic or not for human CETP (tgCETP+/-), were subjected to MI by permanent left anterior descending coronary artery ligation and studied for 4 weeks. Left ventricular (LV) function was assessed by echocardiography at baseline, 1, and 4 weeks after MI. At sacrifice, blood, spleen and bone marrow cells were collected for flow cytometry analysis, and hearts were harvested for histologic analyses. All mice developed LV hypertrophy, dilation, and systolic dysfunction, but Adcy9Gt/Gt mice exhibited reduced pathologic LV remodelling and better LV function compared with WT mice. There were no differences between tgCETP+/- and Adcy9Gt/Gt tgCETP+/- mice, which both exhibited intermediate responses. Histologic analyses showed smaller cardiomyocyte size, reduced infarct size, and preserved myocardial capillary density in the infarct border zone in Adcy9Gt/Gt vs WT mice. Count of bone marrow T cells and B cells were significantly increased in Adcy9Gt/Gt mice compared with the other genotypes. Adcy9 inactivation reduced infarct size, pathologic remodelling, and cardiac dysfunction. These changes were accompanied by preserved myocardial capillary density and increased adaptive immune response. Most of the benefits of Adcy9 inactivation were only observed in the absence of CETP.

A Polynesian-specific missense CETP variant alters the lipid profile.

Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Māori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236mmol/L and lower LDL-C by 0.133mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.

Bound Phospholipids Assist Cholesteryl Ester Transfer in the Cholesteryl Ester Transfer Protein.

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that assists the transfer of cholesteryl esters (CEs) from antiatherogenic high-density lipoproteins (HDLs) to proatherogenic low-density lipoproteins (LDLs), initiating cholesterol plaques in the arteries. Consequently, inhibiting the activity of CETP is therefore being pursued as a novel strategy to reduce the risk of cardiovascular diseases (CVDs). The crystal structure of CETP has revealed the presence of two CEs running in the hydrophobic tunnel and two plugged-in phospholipids (PLs) near the concave surface. Other than previous animal models that rule out the PL transfer by CETP and PLs in providing the structural stability, the functional importance of bound phospholipids in CETP is not fully explored. Here, we employ a series of molecular dynamics (MD) simulations, steered molecular dynamics (SMD) simulations, and free energy calculations to unravel the effect of PLs on the functionality of the protein. Our results suggest that PLs play an important role in the transfer of neutral lipids by transforming the unfavorable bent conformation of CEs into a favorable linear conformation to facilitate the smooth transfer. The results also suggest that the making and breaking interactions of the hydrophobic tunnel residues with CEs with a combined effort from PLs are responsible for the transfer of CEs. Further, the findings demonstrate that the N-PL has a more pronounced effort on CE transfer than C-PL but efforts from both PLs are essential in the transfer. Thus, we propose that the functionally important PLs can be considered with potential research interest in targeting cardiovascular diseases.

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.

CETP Inhibitors: Should We Continue to Pursue This Pathway?

For more than 20years there has been considerable interest in the development of pharmacological inhibitors of cholesteryl ester transfer protein (CETP) by virtue of their ability to raise levels of high-density lipoprotein cholesterol. This review endeavors to integrate existing data from prior clinical trials with emerging data to understand whether there is a pathway forward to develop CETP inhibitors to prevent cardiovascular disease. Large clinical trials have proved disappointing with successive reports of a failure to reduce cardiovascular events. The one clinical development program that did demonstrate a reduction in cardiovascular risk found adipose tissue accumulation and did not proceed for regulatory approval. More recent observations suggest that less CETP activity may prevent cardiovascular events, but due to lipid lowering rather than raising high-density lipoprotein cholesterol. In addition, treatment with CETP inhibitors appears to have a beneficial impact on glycemic control in the setting of diabetes. Advances in the field of CETP inhibition suggest a potentially protective effect on the risk of both cardiovascular disease and diabetes. This has implications for how to best design future clinical development programs and leaves the door open to potentially bring CETP inhibitors to the preventive cardiology clinic.

HDL metabolism and functions impacting on cell cholesterol homeostasis are specifically altered in patients with abdominal aortic aneurysm.

BackgroundThe etiopathogenesis of abdominal aortic aneurysm (AAA) is still unclarified, but vascular inflammation and matrix metalloproteases activation have a recognized role in AAA development and progression. Circulating lipoproteins are involved in tissue inflammation and repair, particularly through the regulation of intracellular cholesterol, whose excess is associated to cell damage and proinflammatory activation. We analyzed lipoprotein metabolism and function in AAA and in control vasculopathic patients, to highlight possible non-atherosclerosis-related, specific abnormalities.MethodsWe measured fluorometrically serum esterified/total cholesterol ratio, as an index of lecithin-cholesterol acyltransferase (LCAT) activity, and cholesteryl ester transfer protein (CETP) activity in patients referred to vascular surgery either for AAA (n=30) or stenotic aortic/peripheral atherosclerosis (n=21) having similar burden of cardiovascular risk factors and disease. We measured high-density lipoprotein (HDL)-cholesterol efflux capacity (CEC), through the ATP-binding cassette G1 (ABCG1) and A1 (ABCA1) pathways and serum cell cholesterol loading capacity (CLC), by radioisotopic and fluorimetric methods, respectively.ResultsWe found higher LCAT (+23%; p < 0.0001) and CETP (+49%; p < 0.0001) activity in AAA sera. HDL ABCG1-CEC was lower (−16%; p < 0.001) and ABCA1-CEC was higher (+31.7%; p < 0.0001) in AAA. Stratification suggests that smoking may partly contribute to these modifications. CEC and CETP activity correlated with CLC only in AAA.ConclusionsWe demonstrated that compared to patients with stenotic atherosclerosis, patients with AAA had altered HDL metabolism and functions involved in their anti-inflammatory and tissue repair activity, particularly through the ABCG1-related intracellular signaling. Clarifying the relevance of this mechanism for AAA evolution might help in developing new diagnostic parameters and therapeutic targets for the early management of this condition.

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 cholesteryl ester transfer protein (CETP) raises cholesterol levels in the brain

The cholesteryl ester transfer protein (CETP) is a lipid transfer protein responsible for the exchange of cholesteryl esters and triglycerides between lipoproteins. Decreased CETP activity is associated with longevity, cardiovascular health, and maintenance of good cognitive performance. Interestingly, mice lack the CETP-encoding gene and have very low levels of LDL particles compared with humans. Currently, the molecular mechanisms induced because of CETP activity are not clear. To understand how CETP activity affects the brain, we utilized CETP transgenic (CETPtg) mice that show elevated LDL levels upon induction of CETP expression through a high-cholesterol diet. CETPtg mice on a high-cholesterol diet showed up to 22% higher cholesterol levels in the brain. Using a microarray on mostly astrocyte-derived mRNA, we found that this cholesterol increase is likely not because of elevated de novo synthesis of cholesterol. However, cholesterol efflux is decreased in CETPtg mice along with an upregulation of the complement factor C1Q, which plays a role in neuronal cholesterol clearance. Our data suggest that CETP activity affects brain health through modulating cholesterol distribution and clearance. Therefore, we propose that CETPtg mice constitute a valuable research tool to investigate the impact of cholesterol metabolism on brain function.

Association study between polymorphisms in MIA3, SELE, SMAD3 and CETP genes and coronary artery disease in an Iranian population

BackgroundCoronary artery disease (CAD) is the most common heart disease. Several studies have shown association between some polymorphism in different genes with CAD. Finding this association can be used in order to early diagnosis and prevention of CAD.Method101 CAD patients with ≥ 50% luminal stenosis of any coronary vessel as case group and 111 healthy individuals as control group were selected. the polymorphisms were evaluated by ARMS-PCR and RFLP-PCR methods.ResultThe results of this study show that there is no significant association between rs17228212, rs17465637, and rs708272 and risk of CAD. But there is significant association between risk of CAD and rs5355 (p-value = 0.022) and rs3917406 (p-value = 0.006) in total cases, and rs5882 (p-value = 0.001) in male cases.ConclusionsOur findings revealed a significant interaction between CETP SNPs and CETP activity for affecting HDL-C levels. The SELE gene is a known cell adhesion molecule with a significant role in inflammation. Studies about possible linkage between SELE gene polymorphisms and the development of CAD are conflicting. We have found a significant association between polymorphisms of SELE gene and risk of CAD.

Efficacy of using walnuts as statin adjuvants in hypertension management

ABSTRACT Background Due to the widespread unorthodox use of nuts to improve cardiovascular health, this clinical trial was carried out to evaluate the efficacy of walnut as an adjuvant statin in hypertensive subjects. Method A single-blind placebo-controlled randomized clinical trial that lasted for 3 months. Forty-five screened hypertensive subjects on treatment, aged 45–65 years, were randomized into intervention and placebo groups according to their blood pressure defined by the American Heart Association criteria. Fifteen (15) normotensive subjects were also recruited for this study. The participants in the intervention group included daily 7 g of boiled walnut taken as snacks. The study was not controlled for type of diet and frequency of meals in a day. Low-density lipoprotein cholesterol (LDLc) was the primary endpoint for this study. Results The mean LDLc levels of the intervention groups (84.6 mg/dl and 79.7 mg/dl, respectively) were significantly (p < .005) lower than the placebo (137.6 mg/dl). The high-density lipoprotein cholesterol (HDLc) levels of the intervention groups were significantly higher than the placebo. The mean total cholesterol levels of the intervention groups were significantly lower than the placebo group. The intervention groups recorded a significantly lower systolic and diastolic blood pressure compared to the placebo. The supplementation of walnut significantly decreased the apolipoprotein E (APOE), proprotein convertase subtilisin kexin 9 (PCSK9), and cholesteryl ester transfer protein (CETP) activities relative to the placebo. Conclusion The use of walnut as a statin adjuvant during hypertension treatment reduced LDLc levels within 42.1% and improved HDL levels by 33.6%, and the LDLc decrease related to reduced PCSK9 and APOE activities while the HDLc increase related to reduced CETP activities.

Anorexia Nervosa Is Associated with a Shift to Pro-Atherogenic Low-Density Lipoprotein Subclasses.

Anorexia nervosa (AN) is a severe eating disorder affecting primarily female adolescents and younger adults. The energy deprivation associated with AN has been shown to alter lipoprotein metabolism, which may affect cardiovascular risk. However, the mechanisms leading to alterations in the composition, structure, and function of lipoproteins in AN patients are not well-understood yet. Here, we investigated the lipid abnormalities associated with AN, particularly changes in the distribution, composition, metabolism, and function of lipoprotein subclasses. In this exploratory study, we analyzed serum samples of 18 women diagnosed with AN (BMI < 17.5 kg/m2) and 24 normal-weight women (BMI from 18.5–24.9 kg/m2). Using the Quantimetrix Lipoprint® system, we determined low-density lipoprotein (LDL) subclass distribution, including quantitative measurements of very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and high-density lipoprotein (HDL) subclass distribution. We quantified the most abundant apolipoproteins of HDL and assessed lecithin-cholesterol acyltransferase (LCAT) and cholesteryl-ester transfer protein (CETP) activities. In addition, anti-oxidative capacity of apoB-depleted serum and functional metrics of HDL, including cholesterol efflux capacity and paraoxonase activity were assessed. The atherogenic lipoprotein subclasses VLDL and small LDL particles were increased in AN. Levels of VLDL correlated significantly with CETP activity (rs = 0.432, p = 0.005). AN was accompanied by changes in the content of HDL-associated apolipoproteins involved in triglyceride catabolism, such as apolipoprotein C-II (+24%) and apoA-II (−27%), whereas HDL-associated cholesterol, phospholipids, and triglycerides were not altered. Moreover, AN did not affect HDL subclass distribution, cholesterol efflux capacity, and paraoxonase activity. We observed a shift to more atherogenic lipoprotein subclasses in AN patients, whereas HDL functionality and subclass distribution were not altered. This finding underpins potential detrimental effects of AN on lipid metabolism and the cardiovascular system by increasing atherosclerotic risk factors.