Cholesteryl Ester Transfer Protein Research Articles

Genetic association of lipid and lipid-lowing drug targets with uterine fibroids.

Observational studies suggest that blood lipids are a risk factor for uterine fibroids (UFs) and that lipid-lowering drugs are beneficial for the treatment and prevention of UF; however, the conclusions are inconsistent. We aimed to determine the causal effects of lipids and lipid-lowering drugs on UFs using Mendelian randomization (MR). Genetic variants from genome-wide association studies (GWAS) of lipid traits and variants in genes encoding lipid-lowering drug targets were extracted, and two independent UF GWAS were set as the outcome. Their effects on UF risk and related traits were estimated using the inverse variance weighted method. The MR analysis revealed that high density lipoprotein cholesterol (HDL-C, OR=0.88, 95% CI: 0.83-0.93, P=3.58E-6) and triglycerides (TG, OR=1.14, 95% CI: 1.07-1.21, P=6.83E-5) were protective factors and risk factors for UF, respectively. Drug-targeted MR analysis results indicated that genetically predicted inhibition of cholesteryl ester transfer protein (CETP) was associated with a lower UF risk (OR=0.95, 95% CI: 0.92-0.98, P=7.83E-4), as well as reduced levels or risk of other UF-associated clinical traits, including estradiol level, excessive menstruation, abdominal and pelvic pain, myomectomy, and miscarriage. Our study provides evidence that HDL-C and TG levels were causally associated with UF risk. Genetically proxied CETP inhibition may have a protective effect against UF, which warrants further investigation.

Lipoprotein(a) and Atrial Fibrillation: Mechanistic Insights and Therapeutic Approaches.

Elevated lipoprotein(a) [Lp(a)] levels are increasingly recognized as a significant risk factor for cardiovascular diseases and may also contribute to atrial fibrillation (AF). This review investigated the indirect mechanisms through which Lp(a) may influence AF, including proatherogenic, prothrombotic, and proinflammatory pathways. Traditional lipid-lowering therapies, such as lifestyle modifications and statins, have limited effects on Lp(a) levels. Emerging treatments, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipoprotein apheresis, small interfering RNA, antisense oligonucleotides, cholesterol ester transfer protein inhibitors, and interleukin-6 receptor monoclonal antibodies, are promising alternatives. Notably, only PCSK9 inhibitors and lipoprotein apheresis have been shown to reduce both Lp(a) levels and cardiovascular events. Research indicates varying associations between Lp(a) and AF across different populations, underscoring the need for diverse, large-scale studies to elucidate these differences. Ongoing trials aim to provide clearer insights into these relationships. Addressing these gaps is essential for developing targeted therapies to manage elevated Lp(a) and mitigate the risk of AF and associated cardiovascular events.

Vaccination as a Promising Approach in Cardiovascular Risk Mitigation: Are We Ready to Embrace a Vaccine Strategy?

Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and adaptive immune systems play vital roles in its progression, either exacerbating or alleviating disease development. This intricate interplay positions the immune system as a compelling therapeutic target. Consequently, immunomodulatory strategies have gained increasing attention, though none have yet reached widespread clinical adoption. Safety concerns, particularly the suppression of host immune defenses, remain a significant barrier to the clinical application of anti-inflammatory therapies. Recent decades have revealed the significant role of adaptive immune responses to plaque-associated autoantigens in atherogenesis, opening new perspectives for targeted immunological interventions. Preclinical models indicate that vaccines targeting specific atherosclerosis-related autoantigens can slow disease progression while preserving systemic immune function. In this context, numerous experimental studies have advanced the understanding of vaccine development by exploring diverse targeting pathways. Key strategies include passive immunization using naturally occurring immunoglobulin G (IgG) antibodies and active immunization targeting low-density lipoprotein cholesterol (LDL-C) and apolipoproteins, such as apolipoprotein B100 (ApoB100) and apolipoprotein CIII (ApoCIII). Other approaches involve vaccine formulations aimed at proteins that regulate lipoprotein metabolism, including proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and angiopoietin-like protein 3 (ANGPTL3). Furthermore, the literature highlights the potential for developing non-lipid-related vaccines, with key targets including heat shock proteins (HSPs), interleukins (ILs), angiotensin III (Ang III), and a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS-7). However, translating these promising findings into safe and effective clinical therapies presents substantial challenges. This review provides a critical evaluation of current anti-atherosclerotic vaccination strategies, examines their proposed mechanisms of action, and discusses key challenges that need to be overcome to enable clinical translation.

Insulin resistance in childhood obesity: The role of dietary habits and their association with novel markers of cardiovascular disease

Background Childhood obesity presents numerous comorbidities such as insulin resistance (IR) and dyslipidemia, and could be associated with alterations in novel markers of cardiovascular (CV) risk like: (1) the activities of associated enzymes such as lipoprotein associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON 1), (2) reverse cholesterol transport (RCT), which comprises cellular cholesterol efflux (CCE), in addition to lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities, and (3) high density lipoprotein (HDL) antioxidant capacity. Moreover, IR could worsen these cardiometabolic alterations. The objective of the present study was to characterize the effect of IR on novel CV markers in a pediatric population with obesity. Methods Twenty-five obese children and adolescents with IR, and 25 without IR took part in the study. Anthropometric parameters, Tanner stage and dietary habits were registered. Glucose, insulin, non-esterified fatty acid (NEFA), lipid, and high sensitivity C reactive protein (hsCRP) levels, plus Lp-PLA2, LCAT, CETP and PON 1 activities, as well as CCE and HDL antioxidant capacity were measured. A cutoff point of 3.16 in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) determined the presence of IR. Results No differences were observed in age, sex and Tanner stage. Expectedly, the group with IR displayed higher insulin and NEFA levels (p < 0.05). They also presented increased Lp-PLA2 and decreased PON activities (p < 0.05). Importantly, these differences were associated with dietary habits (p < 0.05). Conclusion IR present in pediatric obesity associated with vascular specific inflammation and reduced PON 1 activity, in addition to alterations in glucose metabolism, thus increasing CV risk in adulthood. These proatherogenic disturbances were conditioned by dietary habits.

Optimizing treatment of cardiovascular risk factors in cerebral small vessel disease using genetics.

Cerebral small vessel disease (cSVD) causes lacunar stroke (LS), intracerebral haemorrhage, and is the most common pathology underlying vascular dementia. However, there are few trials examining whether treating conventional cardiovascular risk factors reduce stroke risk in cSVD, as opposed to stroke as a whole. We used Mendelian randomization techniques to investigate which risk factors are causally related to cSVD and to evaluate whether specific drugs may be beneficial in cSVD prevention. We identified genetic proxies for blood pressure traits, lipids, glycaemic markers, anthropometry measures, smoking, alcohol consumption, and physical activity from large-scale genome-wide association studies of European ancestry. We also selected genetic variants as proxies for drug target perturbation in hypertension, dyslipidaemia, hyperglycaemia, and obesity. Mendelian randomization was performed to assess their associations with LS from the GIGASTROKE Consortium (n = 6811) and in a sensitivity analysis in a cohort of patients with MRI-confirmed LS (n = 3306). We also investigated associations with three neuroimaging features of cSVD, namely, white matter hyperintensities (n = 55 291), fractional anisotropy (n = 36 460), and mean diffusivity (n = 36 012). Genetic predisposition to higher systolic and diastolic blood pressure was associated with LS and cSVD imaging markers. Genetically predicted liability to diabetes, obesity, smoking, higher triglyceride levels, and the ratio of triglycerides to high density lipoprotein (HDL) also showed detrimental associations with LS risk, while genetic predisposition to higher HDL concentrations and moderate-to-vigorous physical activity showed protective associations. Genetically proxied blood pressure-lowering through calcium channel blockers (CCBs) was associated with cSVD imaging markers, while genetically proxied HDL-raising through Cholesteryl Ester Transfer Protein (CETP) inhibitors, triglyceride-lowering through lipoprotein lipase (LPL), and weight-lowering through gastric inhibitory polypeptide receptor (GIPR) were associated with lower risk of LS. Our findings highlight the importance of some conventional cardiovascular risk factors, including blood pressure and BMI, in cSVD, but not other e.g. LDL. The findings further demonstrate the potential beneficial effects of CCBs on cSVD imaging markers and CETP inhibitors, LPL enhancement, and GIPR obesity-targeted drugs on LS. They provide useful information for initiating future clinical trials examining secondary prevention strategies in cSVD.

Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity.

To review the evidence and describe the biological plausibility for the benefits of inhibiting cholesteryl ester transfer protein (CETP) on multiple organ systems through modification of lipoprotein metabolism. Results from observational studies, Mendelian randomization analyses, and randomized clinical trials support the potential of CETP inhibition to reduce atherosclerotic cardiovascular disease (ASCVD) risk through a reduction of apolipoprotein B-containing lipoproteins. In contrast, raising high-density lipoprotein (HDL) particles, as previously hypothesized, did not contribute to ASCVD risk reduction. There is also an expanding body of evidence supporting the benefits of CETP inhibition for safeguarding against other conditions associated with aging, particularly new-onset type 2 diabetes mellitus and dementia, as well as age-related macular degeneration, septicemia, and possibly chronic kidney disease. The latter are likely mediated through improved functionality of the HDL particle, including its role on cholesterol efflux and antioxidative, anti-inflammatory, and antimicrobial activities. At present, there is robust clinical evidence to support the benefits of reducing CETP activity for ASCVD risk reduction, and plausibility exists for the promotion of longevity by reducing risks of several other conditions. An ongoing large clinical trial program of the latest potent CETP inhibitor, obicetrapib, is expected to provide further insight into CETP inhibition as a therapeutic target for these various conditions.

Obicetrapib Alone and in Combination with Ezetimibe Reduces Non-HDL-Cholesterol by Enhanced LDL-Receptor-Mediated VLDL Clearance and Increased Net Fecal Sterol Excretion in ApoE*3-Leiden.CETP Mice

Background and Aims: Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor in clinical development for the treatment of hypercholesterolemia and cardiovascular risk. It reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and increases high-density lipoprotein cholesterol (HDL-C). Ezetimibe reduces absorption of biliary and dietary cholesterol from the small intestine, also reducing LDL-C levels. The current study elucidates the mechanism for decreases in non-HDL-C by obicetrapib alone and with ezetimibe in a mouse model for hyperlipidemia and atherosclerosis.Methods: Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib (2 mg/kg/day), ezetimibe (1 mg/kg/day), or obicetrapib with ezetimibe.Results: Obicetrapib, ezetimibe, and the combination reduced total plasma cholesterol levels (-42%, -23% and -62%).Obicetrapib alone and in combination with ezetimibe nearly completely blocked CETP activity (-99% and -100%) resulting in increased HDL-C (+260% and +245%) and ApoA1 (98% and 81%). Obicetrapib, ezetimibe, and the combination enhanced clearance of VLDL-like particles (half-life: -44%, -23% and -57%) and enhanced hepatic LDL receptor expression (+63% and +74%). Increased bile acid excretion in obicetrapib-treated mice (+41%) and increased neutral sterol excretion in ezetimibe-treated mice was observed, and was more pronounced in combination with obicetrapib (+68% and +100%), resulting in a net fecal sterol loss.Conclusions: Obicetrapib alone and with ezetimibe reduced non-HDL-C levels by increased VLDL lipolysis, increased VLDL clearance and elevated LDL receptor levels, and enhanced fecal bile acid and neutral sterol excretion.

Fluorinated Diaryl Sulfonamides: Molecular Modeling, Synthesis, and In Vitro Validation as New CETP Inhibitors.

Hyperlipidemia, a cardiovascular disease risk factor, is characterized by a rise in low-density lipoprotein (LDL), triglycerides and total cholesterol, and a decrease in high-density lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) enables the transfer of cholesteryl ester from HDL to LDL and very low-density lipoprotein. CETP inhibition is a promising approach to prevent and treat cardiovascular diseases. By inhibiting lipid transport activity, it increases HDL levels and decreases LDL levels. Herein, diaryl sulfonamides 6a-6g and 7a-7g were prepared, and the structure of these compounds was fully determined using different spectroscopic techniques. These compounds underwent biological evaluation in vitro and showed different inhibitory activities against CETP; 100% inhibitory activity was observed for compounds 7a-7g, while activities of compounds 6a-6g ranged up to 42.6% at 10 μM concentration. Pharmacophore mapping agreed with the bioassay results where the four aromatic ring compounds 7a-7g possessed higher fit values against Hypo4/8 and the shape-complemented Hypo4/8 in comparison to compounds 6a-6g. Docking of the synthesized compounds using libdock and ligandfit engines revealed that compounds 7a-7g formed п-п stacking and hydrophobic interactions with the binding pocket, while compounds 6a-6g missed these hydrophobic interactions with amino acids Leu206, Phe265, and Phe263.

Obicetrapib Alone and in Combination with Ezetimibe Reduces Atherosclerotic Lesion Prevalence, Size and Severity in ApoE*3-Leiden.CETP Mice

Background and Aims: Obicetrapib is a selective, potent, cholesteryl ester transfer protein (CETP) inhibitor in clinical development for the treatment of hypercholesterolemia and reduction of cardiovascular risk. It strongly reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and increases plasma high-density lipoprotein cholesterol (HDL-C). Ezetimibe is a potent, selective inhibitor of biliary and dietary cholesterol absorption from the small intestine, also reducing LDL-C levels. The current study evaluated the effect of obicetrapib monotherapy and in combination with ezetimibe on atherosclerosis development in a mouse model for hyperlipidemia and atherosclerosis.Methods: Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib alone (2 mg/kg/day), ezetimibe alone (on average 0.6 mg/kg/day), or the combination of obicetrapib and ezetimibe. After 28 weeks of treatment, atherosclerosis development was measured in the aortic roots.Results: Obicetrapib, ezetimibe, and the combination reduced total plasma cholesterol levels (-31%, -19% and -53%), mainly attributed to a decrease in non-HDL-C levels (-53%, -19% and -75%). Obicetrapib and combination treatment nearly completely blocked CETP activity (-98% and -98%). Obicetrapib, ezetimibe, and the combination reduced atherosclerotic lesion size (-90%, -50% and -98%) and reduced severe lesions (-82%, -31% and -98%). The percentage of unaffected segments was increased by obicetrapib and the combination treatment (+347%, +442%).Conclusions: Obicetrapib alone and the combination with ezetimibe robustly lowers non-HDL-C levels and impedes atherosclerosis development through a large decrease in atherosclerotic lesion size and severity.

Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non-human primate studies and clinical trials.

Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half-life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre-clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13-week recovery period. In healthy humans receiving 1-25 mg of obicetrapib, the mean terminal half-life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6-fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post-treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half-life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management.

Obicetrapib Demonstrates Significant Deductions of LP(A) on Top of High-Intensity Statins

Background and Aims: Elevated lipoprotein (a) [Lp(a)] leads to increased cardiovascular disease (CVD) risk. There are no pharmacologic therapies approved for reducing Lp(a). Previous cholesteryl ester transfer protein (CETP) inhibitors and approved lipid agents have modest Lp(a) effects. We examined the effects of obicetrapib, a novel CETP inhibitor, on Lp(a).Methods: ROSE1 and ROSE2 are phase 2 trials of obicetrapib on top of high-intensity statins by persons without CVD and low-density lipoprotein cholesterol >70 mg/dL. In ROSE1 120 subjects received 5 or 10 mg obicetrapib or placebo; in ROSE2 119 received 10 mg obicetrapib, 10 mg obicetrapib + 10 mg ezetimibe or placebo. Lp(a) was measured by immunoturbidimetry in ROSE1 and by the UCSD isoform independent assay using monoclonal antibody LPA-KIV9 in ROSE2.Results: Median baseline Lp(a) for 10 mg obicetrapib and placebo was 29.9 and 45.3 nmol/L in ROSE1 and 44.0 and 37.8 nmol/L in ROSE2, respectively. Median % changes from baseline for obicetrapib 10 mg and placebo, respectively, were -56.5 and +4.00 in ROSE1 and -47.2 and +2.3 in ROSE2. Pooled (N=127) median difference in % change corrected for placebo was 57.1% (p<0.001). In both trials >50% of obicetrapib subjects had a >60% reduction in Lp(a).Conclusions: Obicetrapib 10 mg on top of high-intensity statin significantly lowered Lp(a) by 57% vs. placebo in a pooled analysis, a substantially greater reduction than with proprotein convertase subtilisin kexin type 9 inhibitors (15-30%), niacin (30%) or other CETP inhibitors (25%).

Correlation analysis of LXR and its target genes COX2 and CETP with the severity of OSAHS in obese young rats.

To analyse the relationships between the expression levels of liver X receptor (LXR), cyclooxygenase-2(COX2) and cholesterol ester transfer protein (CETP) and the severity of obstructive sleep apnoea hypopnoea syndrome (OSAHS) in obese young rats, to obtain information for basic research on OSAHS in obese children. Twenty-four 3-4-week-old young rats were randomly assigned to the normal control group, obesity group, OSAHS group, obesity and OSAHS group. We used polysomnography to measure the obstructive apnoea hypopnoea index (OAHI) to assess the severity of OSAHS and western blotting to test the expression levels of LXRα, COX2, and CETP in the liver, heart, kidney, and brain tissues. LXR, COX2, and CETP expression levels in the remaining groups were considerably higher than those in the control group (P < 0.05). Compared with those in the obesity group, LXRα, COX2, and CETP expression levels in the obesity and OSAHS group were considerably greater in the liver, kidney, and heart tissues (P < 0.05); the brain tissues of the obesity and OSAHS group showed considerably higher expression levels of COX2 and CETP (P < 0.05). Compared with those in the OSAHS group, LXRα, COX2, and CETP expression levels in the obesity and OSAHS group were significantly greater in all tissues (P < 0.05). The expression levels of LXRα, COX2, and CETP and obesity increased with increasing OSAHS severity (r = 0.777, P < 0.01; r = 0.728, P < 0.01; r = 0.793, P < 0.01; r = 0.786, P < 0.01; and r = 0.698, P < 0.01), and the oxygen concentration increased with decreasing OSAHS severity(r=-0.576, P < 0.01). LXR, COX2, and CETP expression levels were significantly increased in the liver, kidney, heart, and brain tissues of young rats with obesity and OSAHS, and were positively correlated with the severity of OSAHS.

Abstract 4120854: Case Report: Elevated HDL in Familial Hyper-Alpha-Lipoproteinemia: Atheroprotective or Atherogenic?

Introduction: Familial hyper-alpha-lipoproteinemia (HALP) is a heterogenous genetic lipid disorder that is found in only 8% of the population and manifests as elevated HDL levels above the 90 th percentile. HALP is due to mutations in various genes including cholesteryl ester transfer protein (CETP), hepatic lipase, or apolipoprotein C-III (APOC3). While epidemiological studies have noted an inverse relationship between high HDL and the development of coronary artery disease, recent data have shown a lack of causal atheroprotective effects. We present a case of a patient with significantly elevated HDL and peripheral vascular disease. Case Description: Patient is a 64-year-old female with past medical history of peripheral artery disease with occlusion of the left femoral artery and popliteal arteries status post angioplasty, hypertension, type 2 diabetes, alcohol use, and CKD Stage 4 who presented to the advanced lipid clinic for management of elevated lipoproteins. Patient’s laboratory data was significant for total cholesterol (TC) of 375 mg/dL, a high-density lipoprotein (HDL) of &gt;200 mg/dL, triglycerides (TG) of 66 mg/dL, and a low-density lipoprotein (LDL) of 175 mg/dL. Further testing revealed elevated apolipoprotein A-I of 231 mg/dL. Patient was subsequently initiated on a high intensity statin with improvement in her lipid panel with a TC of 247 mg/dL, HDL of 133 mg/dL, TG of 50 mg/dL, and LDL of 106 mg/dL, with plan for further uptitration of lipid therapy to target LDL &lt;70 mg/dL. Discussion: CETP exchanges cholesteryl esters from HDL for TG, making HDL smaller and more TG-rich. Studies have shown that in vitro addition of CETP and hepatic lipase, which hydrolyzes phospholipids and TG, into CETP-deficient patients led to the development of very small HDL particles that were able to remove cholesterol from lipid laden macrophages. Conversely, larger HDL molecules seen in CETP-deficient patients did not have such anti-atherogenic properties. In addition to recognizing HALP in the setting of elevated HDL, it is also important to exclude secondary causes of elevated HDL, such as primary biliary cirrhosis and high-dose niacin. Genetic testing should also be considered.

Correlation of Eight (8) Polymorphisms and Their Genotypes with the Risk Factors of Cardiovascular Disease in a Black Elderly Population.

Single nucleotide polymorphisms (SNPs) have been associated with the development of cardiovascular diseases (CVDs). This study correlated eight SNPs with the risk factors of CVD in a black elderly population. Genotyping was used to detect eight polymorphisms; rs675 (ApoA-IV), rs699 (Angiotensinogen (AGT)), rs247616 and rs1968905 (Cholesteryl ester transfer protein (CETP)), rs1801278 (Insulin receptor substrate 1 (IRS-1)), rs1805087 (Methylenetetrahydrofolate reductase (MTHFR)) and rs28362286 and rs67608943 (Proprotein convertase subtilisin/kexin type 9 (PCSK9)), as well as their genotypes in deoxyribonucleic acid (DNA) extracted from peripheral blood. The cardiovascular risk (CVR) measurements were conducted on a Konelab 20i Thermo Scientific autoanalyzer and an enzyme-linked immunoassay (ELISA) assay. International Business Machines Corporation (IBM)® Statistical Package for the Social Sciences ® (SPSS) version 28 was used for statistical analysis. The heterozygous and homozygous genotypes of the eight polymorphisms were detected with the corresponding CVD risk factors. Subgroup analysis indicated that certain genotype carriers exhibited variations in their concentrations of CVR factors compared to others; however, these differences did not reach statistical significance. For example, carriers of the G genotype of the rs699 polymorphism showed marginally different blood pressure readings compared to the AG genotype carriers. The multiple linear regression analysis indicated that the only significant association was between PCSK9 and the rs28362286 (p = 0.029) polymorphism. The findings of our study show that single nucleotide polymorphisms are disseminated across the human genome. The heterozygous and homozygous genotypes of the SNPs require further investigation as they may have independent and possible collective roles in increasing the risk of CVDs.

Interaction of CETP rs708272 Polymorphism on Trans Fatty Acid Intake and Glucose Metabolism Markers.

Dietary fats influence gene expression and several metabolic pathways. Therefore, it is crucial to study the role of personal genotypes in the interaction between fat consumption and cardiometabolic markers. This research aimed to determine the interaction of the rs708272 polymorphism of CETP and the fatty acid intake with changes in the HOMA-IR in adults living with overweight or obesity. The current study was a secondary analysis of an 8-week controlled clinical trial. The final sample for this analysis comprised 78 Mexican adults with the Cholesteryl Ester Transfer Protein (CETP) rs708272 polymorphism who followed a dietary intervention. Using an interaction analysis, we evaluated the fatty acid intake and the genotypes of rs708272, with changes in blood glucose, insulin, and the HOMA-IR from baseline to endpoint. Our findings suggest a significant interaction between the trans fatty acid intake and the GG genotype with changes in glucose (p = 0.024), insulin (p = 0.004), and the HOMA-IR (p = 0.002). The higher the consumption of trans fatty acids, the less these markers of glucose metabolism were reduced. carriers of the GG genotype may benefit from limiting dietary trans fatty acid intake, as there was no reduction in plasma glucose and insulin despite a hypocaloric dietary intervention in adults with overweight and obesity.

Association of CETP gene polymorphisms and haplotypes with acute heart rate response to exercise

Abstract Background Polymorphisms in the cholesteryl ester transfer protein (CETP) gene are known to be strongly associated with increased cardiovascular risk, primarily through their effects on the lipid profile, and consequently on atherosclerotic risk. The acute heart rate response (AHRR) to physical activity is closely related to individual cardiovascular fitness. This study aimed to investigate the effect of CETP gene polymorphisms on AHRR. Methods Our analysis examines the association of five single nucleotide polymorphisms (SNPs; rs1532624, rs5882, rs708272, rs7499892 and rs9989419) and their haplotypes (H) known to be associated with cardiovascular risk in the CETP gene with AHRR in 607 individuals from the Hungarian population. Individual AHRR in the present study was assessed using the YMCA 3-minute step test and was measured as the difference between resting and post-exercise heart rate, i.e. delta heart rate (ΔHR). To exclude the direct confounding effect of the CETP gene on the lipid profile, adjustments for TG and HDL-C levels were applied in the statistical analyses. Results Among the five SNPs examined, two showed a significant association with lower ΔHR (rs1532624-Cdom: B = -8.15, p &amp;lt; 0.001; rs708272-Gdom: B = -8.09, p &amp;lt; 0.001) and reduced the risk of adverse AHRR (rs1532624-A: OR = 2.26, p &amp;lt; 0.001; rs708272-A: OR = 2.17, p &amp;lt; 0.001). Among the ten haplotypes, two showed significant association with lower ΔHR (H3 - CAGCA: B = -6.79, p = 0.003; H9 - CGGCG: B = -14.79, p = 0.014) and lower risk of adverse AHRR (H3 - CAGCA: OR = 0.58, p = 0.038; H9 - CGGCG: OR = 0.05, p = 0.008) compared to the reference haplotype (H1 - AGACG). Conclusions Our study is the first to report a significant association between polymorphisms and their haplotypes in the CETP gene and AHRR. It also confirms that the effect of the CETP gene on cardiovascular risk is expressed through the acute heart rate response to physical activity, in addition to its effect on the lipid profile. Key messages • Certain polymorphisms and haplotypes in the CETP gene show a significant association with AHRR. • The CETP gene polymorphisms exert their effect on cardiovascular risk not only by altering the lipid profile, but also by modifying the heart rate response to physical activity.

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.

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

BackgroundElevated concentrations 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.MethodsDrug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (μg/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson’s dementia.ResultsMR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (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). 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.ConclusionsThese results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in APOE-ε4 carriers.

HMGCR as a promising molecular target for therapeutic intervention in aortic aneurisms: a mendelian randomization study

BackgroundDespite the exploration of the connections between serum low-density lipoprotein cholesterol (LDL-C) levels and aneurisms in epidemiological studies, causality remains unclear. Therefore, this study aimed to assess the causal impact of LDL-C-lowering targets (HMGCR, PCSK9, NPC1L1, CETP, APOB, and LDLR) on various forms of aneurisms using Mendelian Randomization (MR) analysis.MethodsTwo genetic instruments acted as proxies for exposure to LDL-C-lowering drugs: expression quantitative trait loci of drug target genes and genetic variants linked to LDL-C near drug target genes. Summary-data-based MR (SMR), inverse-variance-weighted MR (IVW-MR), and multivariable MR (MVMR) methods were employed to compute the effect estimates.ResultsThe SMR analysis revealed substantial associations between increased HMGCR expression and a heightened risk of aortic aneurism (odds ratio [OR] = 1.603, 95% confidence interval [CI] = 1.209–2.124), thoracic aortic aneurism (OR = 1.666, 95% CI = 1.122–2.475), and abdominal aortic aneurism (OR = 1.910, 95% CI = 1.278–2.856). Likewise, IVW-MR analysis demonstrated positive correlations between HMGCR-mediated LDL-C and aortic aneurism (OR = 2.228, 95% CI = 1.702–2.918), thoracic aortic aneurism (OR = 1.751, 95% CI = 1.191–2.575), abdominal aortic aneurism (OR = 4.784, 95% CI = 3.257–7.028), and cerebral aneurism (OR = 1.993, 95% CI = 1.277–3.110). Furthermore, in the MVMR analysis, accounting for body mass index, smoking, and hypertension, a significant positive relationship was established between HMGCR-mediated LDL-C levels and the development of aortic aneurisms, encompassing both thoracic and abdominal subtypes. Similarly, consistent positive associations were observed for PCSK9 and CETP genes, as well as PCSK9-mediated and CETP-mediated LDL-C levels, with the occurrence of aortic aneurism and abdominal aortic aneurism. Nonetheless, the evidence for potential associations between APOB, NPC1L1 and LDLR with specific subtypes of aortic aneurisms lacked consistent support from both SMR and IVW-MR analyses.ConclusionsOur MR analysis offered compelling evidence of a plausible causal link between HMGCR and an increased risk of aortic aneurism, encompassing both thoracic and abdominal types. These groundbreaking findings further bolster the case for the deployment of HMGCR inhibitors in the treatment of aortic aneurisms, including both thoracic and abdominal variants.

Synthesis, Molecular Modeling and Biological Evaluation of Novel Trifluoromethyl Benzamides as Promising CETP Inhibitors.

Hyperlipidemia is considered a major risk factor for the progress of atherosclerosis. Cholesteryl ester transfer protein (CETP) facilitates the relocation of cholesterol esters from HDL to LDL. CETP inhibition produces higher HDL and lower LDL levels. Synthesis of nine benzylamino benzamides 8a-8f and 9a-9c was performed. In vitro biological study displayed potential CETP inhibitory activity, where compound 9c had the best activity with an IC50 of 1.03 μM. Induced-fit docking demonstrated that 8a-8f and 9a-9c accommodated the CETP active site and hydrophobic interaction predominated ligand/ CETP complex formation. Pharmacophore mapping showed that this scaffold endorsed CETP inhibitors features and consequently elaborated the high CETP binding affinity.