CETP inhibition enhances monocyte activation and bacterial clearance and reduces streptococcus pneumonia-associated mortality in mice.

Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae-induced sepsis in APOE*3-Leiden.CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune-mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis.

Cholesterol Ester Transfer Protein Taq1B Polymorphism and Its Association with Cardiovascular Risk Factors in Patients Undergoing Angiography in Yazd, Eastern Iran: A Cross-Sectional Study.

Background: Several studies assessed the relationship between the cholesterol ester transfer protein (CETP) Taq1B gene polymorphism (rs708272) with risk factors of cardiovascular diseases (CVDs). However, their findings were inconsistent. The present study investigated the relationship between CVD risk factors and the Taq1B variant in patients undergoing coronary angiography. Methods: This cross-sectional study was conducted on 476 patients aged 30-76 years old of both sexes from 2020-2021, in Yazd (Iran). The Taq1B polymorphism genotypes were evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on DNA extracted from whole blood. Standard protocols were used to measure cardio-metabolic markers. To determine the association between CVDs risk factors and the rs708272 variant, binary logistic regression was used in crude and adjusted models. Results: Taq1B polymorphism genotype frequencies were 10.7% for B1B1, 72.3% for B1B2, and 17% for B2B2. There was no significant association between abnormal levels of CVDs risk factors and different genotypes of the Taq1B variant, Gensini score (P=0.64), Syntax score (P=0.79), systolic blood pressure (P=0.55), diastolic blood pressure (P=0.58), and waist circumference (P=0.79). There was no significant association between genotypes of the rs708272 variant and any abnormal serum lipid levels. After adjusting for confounders, the results remained non-significant. Conclusion: There was no significant association between CVDs risk factors and CETP rs708272 polymorphism. The relationship between CETP gene variants and CVD occurrences varied across groups, implying that more research in different regions is required.A preprint version of this manuscript is available at https://www.researchsquare.com/article/rs-2575215/v1 with doi: 10.21203/rs.3.rs-2575215/v1.

Association of lipid-modifying therapy with risk of obstructive sleep apnea: A drug-target mendelian randomization study.

BACKGROUND: Obstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. METHODS: A drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. RESULTS: Genetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60-0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93-1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. CONCLUSIONS: The present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations.

Association of the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) Polymorphisms With Risk of Coronary Artery Disease in Iranian Patients.

BACKGROUND: Coronary artery disease (CAD) is a devastating illness and a leading cause of death worldwide, primarily caused by atherosclerosis resulting from a genetic-environmental interaction. This study aimed to investigate the relationship between the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) polymorphisms, lipid profile parameters, and CAD risk in a southeast Iranian population. METHODS: A total of 400 subjects (200 CAD patients with hyperlipidemia and 200 healthy controls) were enrolled in this case-control study. Five selected polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: For all single nucleotide polymorphisms (SNPs), the population under study was in the Hardy-Weinberg equilibrium. The T-risk allele frequency of rs2228570 was associated with an increased risk of CAD. The TT and CT genotypes of rs2228570 had also been associated with the risk of CAD. Additionally, the TT genotype was associated with higher serum low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels. The GG genotype of the rs3736234 was associated with higher body mass index (BMI) and triglyceride (TG) levels, and the AA genotype of the rs708272 was associated with higher HDL-c levels. Based on these findings, we propose that the VDR (rs2228570) polymorphism was associated with serum HDL-c and LDL-c levels and may serve as potential risk factors for CAD within the Iranian population. Moreover, rs3736234 and rs708272 influence the concentrations of TG and HDL-c, respectively. CONCLUSION: These findings provided insights into the complex interplay between genetic variations, cardiovascular risk, and lipid metabolism.

CETP-derived Peptide Seq-1, the Key Component of HB-ATV-8 Vaccine Prevents Stress Responses, and Promotes Downregulation of Pro-Fibrotic Genes in Hepatocytes and Stellate Cells.

BACKGROUND: The nasal vaccine HB-ATV-8 has emerged as a promising approach for NAFLD (non-alcoholic fatty liver disease) and atherosclerosis prevention. HB-ATV-8 contains peptide seq-1 derived from the carboxy-end of the Cholesteryl Ester Transfer Protein (CETP), shown to reduce liver fibrosis, inflammation, and atherosclerotic plaque formation in animal models. Beyond the fact that this vaccine induces B-cell lymphocytes to code for antibodies against the seq-1 sequence, inhibiting CETP's cholesterol transfer activity, we have hypothesized that beyond the modulation of CETP activity carried out by neutralizing antibodies, the observed molecular effects may also correspond to the direct action of peptide seq-1 on diverse cellular systems and molecular features involved in the development of liver fibrosis. METHODS: The HepG2 hepatoma-derived cell line was employed to establish an in vitro steatosis model. To obtain a conditioned cell medium to be used with hepatic stellate cell (HSC) cultures, HepG2 cells were exposed to fatty acids or fatty acids plus peptide seq-1, and the culture medium was collected. Gene regulation of COL1A1, ACTA2, TGF-ß, and the expression of proteins COL1A1, MMP-2, and TIMP-2 were studied. AIM: To establish an in vitro steatosis model employing HepG2 cells that mimics molecular processes observed in vivo during the onset of liver fibrosis. To evaluate the effect of peptide Seq-1 on lipid accumulation and pro-fibrotic responses. To study the effect of Seq-1-treated steatotic HepG2 cell supernatants on lipid accumulation, oxidative stress, and pro-fibrotic responses in HSC. RESULTS AND CONCLUSION: Peptide seq-1-treated HepG2 cells show a downregulation of COLIA1, ACTA2, and TGF-ß genes, and a decreased expression of proteins such as COL1A1, MMP-2, and TIMP-2, associated with the remodeling of extracellular matrix components. The same results are observed when HSCs are incubated with peptide Seq-1-treated steatotic HepG2 cell supernatants. The present study consolidates the nasal vaccine HB-ATV-8 as a new prospect in the treatment of NASH directly associated with the development of cardiovascular disease.

CETP gene polymorphisms and haplotypes are explanatory variables for HDL cholesterol level in sickle cell disease.

Variations in lipid profile have been observed in sickle cell disease (SCD) and understanding their relationship with disease severity is crucial. This study aimed to investigate the association of polymorphisms of the CETP gene and laboratory markers of disease severity with lipid profile in a pediatric population with SCD. Biochemical and anthropometric analyses and CETP and alpha-thalassemia genotyping were performed. The study included 133 children and adolescents with sickle cell anemia (SCA) or hemoglobin SC disease (SCC), in steady-state. The SCA and no hydroxyurea (no HU) groups had higher values of ApoB, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) compared to the SCC and HU groups. However, there were no significant differences in ApoA1 and HDL-C levels between the groups based on genotype. Furthermore, the groups with altered levels of ApoA1, HDL-C, and the triglyceride/HDL ratio exhibited lower hemoglobin (Hb) levels and higher white blood cell counts. Hb level was associated to HDL-C levels. Analysis of CETP gene variants showed that the minor alleles of rs3764261 (C>A), rs247616 (C>T), and rs183130 (C>T), as well as the TTA haplotype, are explanatory variables for HDL-C levels. These findings suggested that dyslipidemia in SCD, specifically related to HDL-C levels, may be influenced by individual genetic background. Additionally, further investigation is needed to determine if clinical manifestations are impacted by CETP gene variants.

Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments.

PURPOSE OF REVIEW: To discuss the history of cardiovascular outcomes trials of cholesteryl ester transfer protein (CETP) inhibitors and to describe obicetrapib, a next-generation, oral, once-daily, low-dose CETP inhibitor in late-stage development for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS: Phase 1 and 2 trials have evaluated the safety and lipid/lipoprotein effects of obicetrapib as monotherapy, in conjunction with statins, on top of high-intensity statins (HIS), and with ezetimibe on top of HIS. In ROSE2, 10 mg obicetrapib monotherapy and combined with 10 mg ezetimibe, each on top of HIS, significantly reduced low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total LDL particles, small LDL particles, small, dense LDL-C, and lipoprotein (a), and increased HDL-C. Phase 3 pivotal registration trials including a cardiovascular outcomes trial are underway. Obicetrapib has an excellent safety and tolerability profile and robustly lowers atherogenic lipoproteins and raises HDL-C. As such, obicetrapib may be a promising agent for the treatment of ASCVD.

Total Outflow of High-Density Lipoprotein-Cholesteryl Esters from Plasma Is Decreased in a Model of 3/4 Renal Mass Reduction.

(1) Background: Previous studies have enriched high-density lipoproteins (HDL) using cholesteryl esters in rabbits with a three-quarter reduction in functional renal mass, suggesting that the kidneys participate in the cholesterol homeostasis of these lipoproteins. However, the possible role of the kidneys in lipoprotein metabolism is still controversial. To understand the role of the kidneys in regulating the HDL lipid content, we determined the turnover of HDL-cholesteryl esters in rabbits with a three-quarter renal mass reduction. (2) Methods: HDL subclass characterization was conducted, and the kinetics of plasma HDL-cholesteryl esters, labeled with tritium, were studied in rabbits with a 75% reduction in functional renal mass (Ntx). (3) Results: The reduced renal mass triggered the enrichment of cholesterol, specifically cholesteryl esters, in HDL subclasses. The exchange of cholesteryl esters between HDL and apo B-containing lipoproteins (VLDL/LDL) was not significantly modified in Ntx rabbits. Moreover, the cholesteryl esters of HDL and VLDL/LDL fluxes from the plasmatic compartment tended to decrease, but they only reached statistical significance when both fluxes were added to the Nxt group. Accordingly, the fractional catabolic rate (FCR) of the HDL-cholesteryl esters was lower in Ntx rabbits, concomitantly with its accumulation in HDL subclasses, probably because of the reduced mass of renal cells requiring this lipid from lipoproteins.

Association of dyslipidemia with single nucleotide polymorphisms of the cholesteryl ester transfer protein gene and cardiovascular disease risk factors in a highly admixed population.

BACKGROUND AND AIMS: Cardiovascular diseases (CVD) are major causes of mortality worldwide, leading to premature deaths, loss of quality of life, and extensive socioeconomic impacts. Alterations in normal plasma lipid concentrations comprise important risk factors associated with CVD due to mechanisms involved in the pathophysiology of atherosclerosis. Genetic markers such as single nucleotide polymorphisms (SNPs) are known to be associated with lipid metabolism, including variants in the cholesteryl ester transfer protein (CETP) gene. Thus, the study's objective was to assess the relationship among lipid profile, socioeconomic and demographic characteristics, health status, inflammatory biomarkers, and CETP genetic variants in individuals living in a highly admixed population. METHODS: The study comprises an analysis of observational cross-sectional data representative at the population level from a highly admixed population, encompassing 901 individuals from three age groups (adolescents, adults, and older adults). Socioeconomic, demographic, health, and lifestyle characteristics were collected using semi-structured questionnaires. In addition, biochemical markers and lipid profiles were obtained from individuals' blood samples. After DNA extraction, genotyping, and quality control according to Affymetrix's guidelines, information on 15 SNPs in the CETP gene was available for 707 individuals. Lipid profile and CVD risk factors were evaluated by principal component analysis (PCA), and associations between lipid traits and those factors were assessed through multiple linear regression and logistic regression. RESULTS: There were low linear correlations between lipid profile and other individuals' characteristics. Two principal components were responsible for 80.8 % of the total variance, and there were minor differences in lipid profiles among individuals in different age groups. Non-HDL-c, total cholesterol, and LDL-c had the highest loadings in the first PC, and triacylglycerols, VLDL-c and HDL-c were responsible for a major part of the loading in the second PC;, whilst HDL-c and LDL-c/HDL-c ratio were significant in the third PC. In addition, there were minor differences between groups of individuals with or without dyslipidemia regarding inflammatory biomarkers (IL-1ß, IL- 6, IL-10, TNF-α, CRP, and MCP-1). Being overweight, insulin resistance, and lifestyle characteristics (calories from solid fat, added sugar, alcohol and sodium, leisure physical activity, and smoking) were strong predictors of lipid traits, especially HDL-c and dyslipidemia (p < 0.05). The CETP SNPs rs7499892 and rs12691052, rs291044, and rs80180245 were significantly associated with HDL-c (p < 0.05), and their inclusion in the multiple linear regression model increased its accuracy (adjusted R2 rose from 0.12 to 0.18). CONCLUSION: This study identified correlations between lipid traits and other CVD risk factors. In addition, similar lipid and inflammatory profiles across age groups in the population suggested that adolescents might already present a significant risk for developing cardiovascular diseases in the population. The risk can be primarily attributed to decreased HDL-c concentrations, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the CETP gene and HDL-c concentrations, as well as potential gene-diet interactions. Our findings underscore the significant impact of genetic and lifestyle factors on lipid profile within admixed populations in developing countries.

CETP and APOA2 polymorphisms are associated with weight loss and healthy eating behavior changes in response to digital lifestyle modifications.

Response to digital healthcare lifestyle modifications is highly divergent. This study aimed to examine the association between single nucleotide polymorphism (SNP) genotypes and clinical efficacy of a digital healthcare lifestyle modification. We genotyped 97 obesity-related SNPs from 45 participants aged 18-39 years, who underwent lifestyle modification via digital cognitive behavioral therapy for obesity for 8 weeks. Anthropometric, eating behavior phenotypes, and psychological measures were analyzed before and after the intervention to identify their clinical efficacy. CETP (rs9939224) SNP significantly predict "super-responders" with greater body mass index (BMI) reduction (p = 0.028; GG - 2.91%, GT - 9.94%), while APOA2 (rs5082) appeared to have some potential for predicting "poor-responders" with lower BMI reduction (p = 0.005; AA - 6.17%, AG + 2.05%, and GG + 5.11%). These SNPs was also associated with significant differences in eating behavior changes, healthy diet proportions, health diet diversity, emotional and restrained eating behavior changes. Furthermore, classification using gene-gene interactions between rs9939224 and rs5082 significantly predicted the best response, with a greater decrease in BMI (p = 0.038; - 11.45% for the best response group (CEPT GT/TT × APOA2 AA) vs. + 2.62% for the worst response group (CEPT GG × APOA2 AG/GG)). CETP and APOA2 SNPs can be used as candidate markers to predict the efficacy of digital healthcare lifestyle modifications based on genotype-based precision medicine.Trial registration: NCT03465306, ClinicalTrials.gov. Registered March, 2018.

Variants in the CETP gene affect levels of HDL cholesterol by reducing the amount, and not the specific lipid transfer activity, of secreted CETP.

BACKGROUND: Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters in plasma from high density lipoprotein (HDL) to very low density lipoprotein and low density lipoprotein. Loss-of-function variants in the CETP gene cause elevated levels of HDL cholesterol. In this study, we have determined the functional consequences of 24 missense variants in the CETP gene. The 24 missense variants studied were the ones reported in the Human Gene Mutation Database and in the literature to affect HDL cholesterol levels, as well as two novel variants identified at the Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital in subjects with hyperalphalipoproteinemia. METHODS: HEK293 cells were transiently transfected with mutant CETP plasmids. The amounts of CETP protein in lysates and media were determined by Western blot analysis, and the lipid transfer activities of the CETP variants were determined by a fluorescence-based assay. RESULTS: Four of the CETP variants were not secreted. Five of the variants were secreted less than 15% compared to the WT-CETP, while the other 15 variants were secreted in varying amounts. There was a linear relationship between the levels of secreted protein and the lipid transfer activities (r = 0.96, p<0.001). Thus, the secreted variants had similar specific lipid transfer activities. CONCLUSION: The effect of the 24 missense variants in the CETP gene on the lipid transfer activity was mediated predominantly by their impact on the secretion of the CETP protein. The four variants that prevented CETP secretion cause autosomal dominant hyperalphalipoproteinemia. The five variants that markedly reduced secretion of the respective variants cause mild hyperalphalipoproteinemia. The majority of the remaining 15 variants had minor effects on the secretion of CETP, and are considered neutral genetic variants.

Interaction between CETP Taq1B polymorphism and dietary patterns on lipid profile and severity of coronary arteries stenosis in patients under coronary angiography: a cross-sectional study.

AIM: Evidence indicates there are still conflicts regarding CETP Taq1B polymorphism and coronary artery disease risk factors. Current findings about whether dietary patterns can change the relationship of the Taq1B on lipid profile and the severity of coronary arteries stenosis appears to be limited. The present research made an attempt to investigate this possible relationship. METHODS: This cross-sectional study involved 453 male and female participants with a mean age of 57 years. A validated 178-item food frequency questionnaire (FFQ) was used to assess dietary usual intake. Dietary patterns were extracted through principal component analysis (PCA). Taq1B variant was genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Two-way ANOVA was used to test the interaction between Taq1B polymorphism and dietary patterns. RESULTS: Two dietary patterns were detected: the western dietary pattern (WDP) and the traditional dietary pattern (TDP). The frequency of Taq1B genotypes turned out to be 10.4, 72.4, and 17.2% for B1B1, B1B2, and B2B2, respectively. A significant difference was observed in TG and TG/HDL-C levels among TaqIB genotypes in higher adherence to TDP (P = 0.01 and P = 0.03, respectively). Taq1B showed a significant interaction with TDP for modulating TG levels and TG/HDL-C ratio (P = 0.02 and P = 0.04, respectively). Greater compliance to WDP demonstrated a significant difference in TG and TG/HDL-C levels across rs708272 genotypes (P = 0.03) after adjusting for confounding factors. Other lipid components and coronary arteries stenosis scores failed to show any relationship or significant difference across Taq1B genotypes or dietary patterns. CONCLUSION: Adherence to TDP may adjust the association between the Taq1B variant and TG and TG/HDL-C levels in patients undergoing coronary angiography. To better understand the relationships, we suggest prospective studies in different race groups with multivariate approaches.

Update of HDL in atherosclerotic cardiovascular disease / Nuevos conceptos de las HDL en la enfermedad cardiovascular aterosclerótica

Epidemiologic evidence supported an inverse association between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major cardiovascular risk factor and postulating diverse HDL vascular- and cardioprotective functions beyond their ability to drive reverse cholesterol transport. However, the failure of several clinical trials aimed at increasing HDL-C in patients with overt cardiovascular disease brought into question whether increasing the cholesterol cargo of HDL was an effective strategy to enhance their protective properties. In parallel, substantial evidence supports that HDLs are complex and heterogeneous particles whose composition is essential for maintaining their protective functions, subsequently strengthening the “HDL quality over quantity” hypothesis. The following state-of-the-art review covers the latest understanding as per the roles of HDL in ASCVD, delves into recent advances in understanding the complexity of HDL particle composition, including proteins, lipids and other HDL-transported components and discusses on the clinical outcomes after the administration of HDL-C raising drugs with particular attention to CETP (cholesteryl ester transfer protein) inhibitors. (AU)

Estudios epidemiológicos respaldan una asociación inversa entre los niveles de colesterol de lipoproteínas de alta densidad (c-HDL) y la enfermedad cardiovascular aterosclerótica (ECVA), identificando el c-HDL como un importante factor de riesgo cardiovascular y postulando diversas funciones vasculares y cardioprotectoras de las HDL más allá de su capacidad para promover el transporte reverso del colesterol. Sin embargo, el fracaso de varios ensayos clínicos dirigidos a aumentar el c-HDL en pacientes con enfermedad cardiovascular manifiesta, puso en duda el concepto que incrementar la carga de c-HDL fuera una estrategia eficaz para potenciar sus propiedades protectoras. Paralelamente, numerosos estudios han evidenciado que las HDL son partículas complejas y heterogéneas cuya composición es esencial para mantener sus funciones protectoras, lo que refuerza la hipótesis de que «la calidad de las HDL prima sobre la cantidad». En el siguiente manuscrito revisamos el estado del arte sobre los últimos avances en torno a las funciones de las HDL en la ECVA, nos adentramos en los avances recientes en la comprensión de la complejidad de la composición de las partículas de HDL, incluidas las proteínas, los lípidos y otros componentes transportados por las HDL, y revisamos los resultados clínicos tras la administración de inductores del c-HDL, especialmente los inhibidores de la proteína transportadora del colesterol esterificado (CETP). (AU)

Update of HDL in atherosclerotic cardiovascular disease.

Epidemiologic evidence supported an inverse association between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major cardiovascular risk factor and postulating diverse HDL vascular- and cardioprotective functions beyond their ability to drive reverse cholesterol transport. However, the failure of several clinical trials aimed at increasing HDL-C in patients with overt cardiovascular disease brought into question whether increasing the cholesterol cargo of HDL was an effective strategy to enhance their protective properties. In parallel, substantial evidence supports that HDLs are complex and heterogeneous particles whose composition is essential for maintaining their protective functions, subsequently strengthening the "HDL quality over quantity" hypothesis. The following state-of-the-art review covers the latest understanding as per the roles of HDL in ASCVD, delves into recent advances in understanding the complexity of HDL particle composition, including proteins, lipids and other HDL-transported components and discusses on the clinical outcomes after the administration of HDL-C raising drugs with particular attention to CETP (cholesteryl ester transfer protein) inhibitors.

Roles of peripheral lipoproteins and cholesteryl ester transfer protein in the vascular contributions to cognitive impairment and dementia.

This narrative review focuses on the role of cholesteryl ester transfer protein (CETP) and peripheral lipoproteins in the vascular contributions to cognitive impairment and dementia (VCID). Humans have a peripheral lipoprotein profile where low-density lipoproteins (LDL) represent the dominant lipoprotein fraction and high-density lipoproteins (HDL) represent a minor lipoprotein fraction. Elevated LDL-cholesterol (LDL-C) levels are well-established to cause cardiovascular disease and several LDL-C-lowering therapies are clinically available to manage this vascular risk factor. The efficacy of LDL-C-lowering therapies to reduce risk of all-cause dementia and AD is now important to address as recent studies demonstrate a role for LDL in Alzheimer's Disease (AD) as well as in all-cause dementia. The LDL:HDL ratio in humans is set mainly by CETP activity, which exchanges cholesteryl esters for triglycerides across lipoprotein fractions to raise LDL and lower HDL as CETP activity increases. Genetic and pharmacological studies support the hypothesis that CETP inhibition reduces cardiovascular risk by lowering LDL, which, by extension, may also lower VCID. Unlike humans, wild-type mice do not express catalytically active CETP and have HDL as their major lipoprotein fraction. As HDL has potent beneficial effects on endothelial cells, the naturally high HDL levels in mice protect them from vascular disorders, likely including VCID. Genetic restoration of CETP expression in mice to generate a more human-like lipid profile may increase the relevance of murine models for VCID studies. The therapeutic potential of existing and emerging LDL-lowering therapies for VCID will be discussed. Figure Legend. Cholesteryl Ester Transfer Protein in Alzheimer's Disease. CETP is mainly produced by the liver, and exchanges cholesteryl esters for triglycerides across lipoprotein fractions to raise circulating LDL and lower HDL as CETP activity increases. Low CETP activity is associated with better cardiovascular health, due to decreased LDL and increased HDL, which may also improve brain health. Although most peripheral lipoproteins cannot enter the brain parenchyma due to the BBB, it is increasingly appreciated that direct access to the vascular endothelium may enable peripheral lipoproteins to have indirect effects on brain health. Thus, lipoproteins may affect the cerebrovasculature from both sides of the BBB. Recent studies show an association between elevated plasma LDL, a well-known cardiovascular risk factor, and a higher risk of AD, and considerable evidence suggests that high HDL levels are associated with reduced CAA and lower neuroinflammation. Considering the potential detrimental role of LDL in AD and the importance of HDL's beneficial effects on endothelial cells, high CETP activity may lead to compromised BBB integrity, increased CAA deposits and greater neuroinflammation. Abbreviations: CETP - cholesteryl transfer ester protein; LDL - low-density lipoproteins; HDL - high-density lipoproteins; BBB - blood-brain barrier; CAA - cerebral amyloid angiopathy, SMC - smooth muscle cells, PVM - perivascular macrophages, RBC - red blood cells.

Genome-Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene.

Background The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent ASCVD carry cardioprotective genetic variants that contribute to ASCVD resilience. Methods and Results We performed a genome-wide association study using a 10-year predicted ASCVD risk score as a quantitative trait, calculated only in asymptomatic older individuals aged ≥70 years without prevalent ASCVD. Our discovery genome-wide association study of N=12 031 ASCVD event-free individuals from the ASPREE (Aspirin in Reducing Events in the Elderly) trial identified 2 independent variants, rs9939224 (P<5×10-8) and rs56156922 (P<10-6), in the CETP (cholesteryl ester transfer protein) gene. The CETP gene is a regulator of plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and lipoprotein(a) levels, and it is a therapeutic drug target. The associations were replicated in the UK Biobank (subpopulation of N=13 888 individuals aged ≥69 years without prevalent ASCVD). Carriers of the identified CETP variants (versus noncarriers) had higher plasma high-density lipoprotein cholesterol levels, lower plasma low-density lipoprotein cholesterol levels, and reduced risk of incident ASCVD events during follow-up. Expression quantitative trait loci analysis predicted the identified CETP variants reduce CETP gene expression across various tissues. Previously reported associations between genetic CETP inhibition and increased risk of age-related macular degeneration were not observed among the 3917 ASPREE trial participants with retinal imaging and genetic data available. Conclusions Common genetic variants in the CETP gene region are associated with cardiovascular resilience during aging. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.

Association between HMGCR, CRP, and CETP gene polymorphisms and metabolic/inflammatory serum profile in healthy adolescents.

BACKGROUND: The complex interplay between health, lifestyle and genetics represents a critical area of research for understanding and promoting human well-being. Importantly, genetics plays a key role in determining individual susceptibility to disease and response to lifestyle. The aim of the present study was to identify genetic factors related to the metabolic/inflammatory profile of adolescents providing new insights into the individual predisposition to the different effects of the substances from the environment. METHODS: Association analysis of genetic variants and biochemical parameters was performed in a total of 77 healthy adolescents recruited in the context of the DIMENU study. RESULTS: Polymorphisms of 3-hydroxy-3-methylglutaril coenzyme A reductase (HMGCR; rs142563098), C-reactive protein gene (CRP; rs1417938, rs1130864), cholesteryl ester transfer protein (CETP; rs5030708), interleukin (IL)-10 (IL-10; rs3024509) genes were significantly associated (p < 0.05) with various serum metabolic parameters. Of particular interest were also the correlations between the HMGCRpolymorphism (rs3846663) and tumor necrosis factor (TNF)-α levels, as well Fatty-acid desaturase (FADS) polymorphism (rs7481842) and IL-10 level opening a new link between lipidic metabolism genes and inflammation. CONCLUSION: In this study, we highlighted associations between single nucleotide polymorphisms (SNPs) and serum levels of metabolic and inflammatory parameters in healthy young individuals, suggesting the importance of genetic profiling in the prevention and management of chronic disease.

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.