Gene polymorphisms of cytochrome B-245 alpha chain (CYBA) and cholesteryl ester transfer protein (CETP) and susceptibility to generalized aggressive periodontitis / 北京大学学报(医学版)

OBJECTIVE@#To explore the correlation of cytochrome B-245 alpha chain (CYBA) rs4673 and cholesteryl ester transfer protein (CETP) rs12720922 polymorphisms with the susceptibility of gene-ralized aggressive periodontitis (GAgP).@*METHODS@#The study was a case-control trial. A total of 372 GAgP patients and 133 periodontally healthy controls were recruited. The CYBA rs4673 and CETP rs12720922 polymorphisms were detected by matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). Logistic regression models were used to analyze the correlation of CYBA rs4673 and CETP rs12720922 variants with the susceptibility of GAgP. The interaction between the two gene polymorphisms to the susceptibility of GAgP was analyzed by the likelihood ratio test. The interaction model adopted was the multiplication model.@*RESULTS@#The mean age of GAgP group and control group was (27.5±5.2) years and (28.8±7.1) years respectively. There was significant difference in age between the two groups (P < 0.05). The gender distribution (male/female) was 152/220 and 53/80 respectively, and there was no significant difference between GAgP group and controls (P>0.05). For CYBA rs4673, the frequency of CT/TT genotype in the GAgP group was significantly higher than that in the controls [18.0% (66/366) vs. 10.6% (14/132), P < 0.05]. After adjusting age and gender, the individuals with CT/TT genotype had a higher risk of GAgP (OR=1.86, 95%CI: 1.01-3.45, P < 0.05), compared with CC genotype. There was no statistically significant difference in distributions of the CETP rs12720922 genotypes (GG, AA/AG) between GAgP patients and healthy controls (P>0.05). A significant interaction between CYBA rs4673 and CETP rs12720922 in the susceptibility to GAgP was observed. The GAgP risk of the individuals with CYBA rs4673 CT/TT and CETP rs12720922 GG genotypes was significantly increased (OR=3.25, 95%CI: 1.36-7.75, P < 0.01), compared with those carrying CC and AA/AG genotypes.@*CONCLUSION@#CYBA rs4673 CT/TT genotype is associated with GAgP susceptibility. There is a significant interaction between CYBA rs4673 CT/TT genotype and CETP rs12720922 GG genotype in the susceptibility of GAgP.

Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis

Abstract Dyslipidemia is an abnormal lipid profile associated with many common diseases, including coronary heart disease and atherosclerosis. Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that is responsible for the transfer of cholesteryl ester from high-density lipoprotein athero-protective particles to pro-atherogenic very low-density lipoprotein and low-density lipoprotein particles. The requirement for new CETP inhibitors, which block this process has driven our current work. Here, the synthesis as well as the ligand-based and structure-based design of seven oxoacetamido-benzamides 9a-g with CETP inhibitory activity is described. An in vitro study demonstrated that most of these compounds have appreciable CETP inhibitory activity. Compound 9g showed the highest inhibitory activity against CETP with an IC50 of 0.96 µM. Glide docking data for compounds 9a-g and torcetrapib provide evidence that they are accommodated in the CETP active site where hydrophobic interactions drive ligand/CETP complex formation. Furthermore, compounds 9a-g match the features of known CETP active inhibitors, providing a rationale for their high docking scores against the CETP binding domain. Therefore, these oxoacetamido-benzamides show potential for use as novel CETP inhibitors

Effects of Obesity and Family History of Diabetes on the Association of CETP rs6499861 with HDL-C Level in Korean Populations

OBJECTIVES: The aim of this study was to examine the associations of cholesterol ester transfer protein (CETP) rs6499861 and rs12708980 with high-density lipoprotein cholesterol (HDL-C) considering obesity and family history of diabetes (FHD) in Korean men and women. METHODS: We analyzed the association of CETP single nucleotide polymorphisms (SNPs) with HDL-C among individuals selected from a hospital (n=4 294) and the Bundang-gu area in Korea (n=2 304). RESULTS: We found that the CETP SNP rs6499861 was associated with a lower HDL-C level (effect per allele: −2.044 mg/dL, p<0.0001). Individuals with a rs6499861 CG/GG genotype had a 1.45-fold higher risk of an abnormal level of HDL-C (<40 mg/dL) than those with a CC genotype. This genotype-HDL-C association was stronger in women (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.39–2.85) compared with men (OR, 1.33; 95% CI, 1.10–1.61) and in women with a FHD (OR, 4.82; 95% CI, 1.86–12.5; p=0.0012) compared with women without a family history. Relative to individuals with a CC genotype and body mass index (BMI) <25.69 kg/m², individuals with a CG/GG genotype and BMI ≥25.69 kg/m² had an OR (95% CI) of 2.61 (1.97–3.47). CONCLUSIONS: These findings indicate that CETP variants are linked to HDL-C level in Koreans and that this link is stronger in obese men and in women who have a FHD.

What Do We Get from Recent Statin and CETP Inhibitors Trials?

Recent clinical trials and meta-analyses have indicated that high-intensive statin treatment lowers low-density lipoprotein cholesterol (LDL-C) levels and reduces the risk of nonfatal cardiovascular (CV) events compared with moderate-intensity statin treatment. However, there are residual risks of CV events and safety concerns associated with high-intensity statin treatment. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study showed that ezetimibe plus moderate-intensity statin therapy after acute coronary syndromes incrementally lowers LDL-C levels and improved CV outcomes compared with moderate-intensity statin therapy. However, despite the LDL-C-lowering effects, a substantial residual CV risk still remains, which includes other lipid abnormalities such as low high-density lipoprotein cholesterol (HDL-C). The most representative agents that primarily increase HDL-C are cholesteryl ester transfer protein (CETP) inhibitors. Until now, 4 CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, and anacetrapib, have been introduced and all have significantly raised the HDL-C from 30% to 133%. However, the results for CV outcomes in clinical trials differed, based on the 4 agents. Torcetrapib increased the risk of CV events and total mortality in patients at high CV risk (ILLUMINATE trial). Dalcetrapib and evacetrapib did not result in lower rate of CV events in patients with recent acute coronary syndrome and high risk vascular disease, respectively (dal-OUTCOMES and ACCELERATE trials). However, anacetrapib significantly decreased the incidence of major coronary events in patients with atherosclerotic vascular disease (REVEAL trial). This topic summarizes the major results of recent statin and CETP inhibitor trials and provides framework to interpret and implement the trial results in real clinical practice.

Associations of Cerebrovascular Metabolism Genotypes With Neuropsychiatric Symptoms and Age at Onset of Alzheimer's Disease Dementia

Objective: To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer’s disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Methods: Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. Results: Considering 201 patients, only APOE-ɛ4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. Conclusion: Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD.

Down-regulation of single-stranded DNA-binding protein 1 expression induced by HCMV infection promotes lipid accumulation in cells

The objective of this study was to observe the infection of human cytomegalovirus (HCMV) to human umbilical vein endothelial cells, and its effect on the expression of single-stranded DNA-binding protein (SSBP1) and on lipid metabolism in endothelial cells. We screened the differential expression of mRNAs after HCMV infection by suppression subtractive hybridization and the expression levels of SSBP1 mRNA and protein after HCMV infection by real-time PCR and western blot. After verification of successful infection by indirect immunofluorescent staining and RT-PCR, we found a differential expression of lipid metabolism-related genes including LDLR, SCARB, CETP, HMGCR, ApoB and LPL induced by HCMV infection. The expression levels of SSBP1 mRNA and protein after HCMV infection were significantly down-regulated. Furthermore, we found that upregulation of SSBP1 inhibited the expression of atherosclerosis-associated LDLR, SCARB, HMGCR, CETP as well as the accumulation of lipids in the cells. The results showed that the inhibition of SSBP1 by HCMV infection promotes lipid accumulation in the cells.

Association of CETP gene I405V/D442G polymorphisms with cerebral hemorrhage and serum lipid profile in ethnic Han population from Changsha / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To assess the association between I405V and D442G polymorphisms of the CETP gene with cerebral hemorrhage (CH) and a related lipid profile among ethnic Han Chinese from Changsha.</p><p><b>METHODS</b>A case-control study was carried out, which enrolled 170 cerebral hemorrhage patients and 191 ethnicity-, age- and sex-matched health controls. Polymerase chain reaction-restricted fragments length polymorphism (PCR-RFLP) was used to determine the polymorphisms. Lipid profile was determined by means of oxidase method. Statistic analyses were performed with SPSS 16.0.</p><p><b>RESULTS</b>No significant difference was found in the CETP gene I405V and D442G genotypes and allelic distribution between the CH patients and controls (P>0.05). There was no association between CETP gene I405V polymorphism and lipid profile in both groups (P>0.05). CH patients with DG genotype of the D442G polymorphism had higher TC and low density lipoprotein-cholesterol (LDL-C) levels than those with a DD genotype(P<0.05).</p><p><b>CONCLUSION</b>CETP gene I405V polymorphism may not be associated with CH among ethnic Han Chinese from Changsha, while the D442G polymorphism of the CETP gene may be associated with TC and LDL levels in the same population.</p>

Cell cycle synchronization and BrdU incorporation as a tool to study the possible selective elimination of ErbB1 gene in the micronuclei in A549 cells

Lung cancer often exhibits molecular changes, such as the overexpression of the ErbB1 gene that encodes epidermal growth factor receptor (EGFR). ErbB1 amplification and mutation are associated with tumor aggressiveness and low response to therapy. The aim of the present study was to design a schedule to synchronize the cell cycle of A549 cell line (a non-small cell lung cancer) and to analyze the possible association between the micronuclei (MNs) and the extrusion of ErbB1 gene extra-copies. After double blocking, by the process of fetal bovine serum deprivation and vincristine treatment, MNs formation was monitored with 5-bromo-2-deoxyuridine (BrdU) incorporation, which is an S-phase marker. Statistical analyses allowed us to infer that MNs may arise both in mitosis as well as in interphase. The MNs were able to replicate their DNA and this process seemed to be non-synchronous with the main cell nuclei. The presence of ErbB1 gene in the MNs was evaluated by fluorescent in situ hybridization (FISH). ErbB1 sequences were detected in the MNs, but a relation between the MNs formation and extrusion of amplified ErbB1could not be established. The present study sought to elucidate the meaning of MNs formation and its association with the elimination of oncogenes or other amplified sequences from the tumor cells.

Onychomatricoma: a tumor unknown to dermatologists

A sixty-one year old white female was referred to the Dermatology Department to treat an ingrown nail in the inner corner of the left hallux. Examination of the entire nail unit showed the presence of xanthonychia in the outer corner besides thickening and increase in the transverse curvature of the nail plate. Dermoscopy and nuclear magnetic resonance of the free edge of the nail plate detected characteristic signs of onychomatricoma, a diagnosis that was later confirmed by anatomopathological exam.

Reassessing lipid metabolism and its potentialities in the prediction of cardiovascular risk

There are numerous particles, enzymes, and mechanisms in the lipid metabolism that are involved in the genesis of cardiovascular disease (CVD). Given its prevalence in populations and its impact on mortality, it is relevant to review the lipid metabolism as it may potentially provide subsidies to better prediction. This article reviews the importance of traditional cardiovascular risk factors and comments on the potential of novel lipid biomarkers involved in the physiopathology of CVD. The Framingham cohorts proved the role of traditional risk factors (physical inactivity, smoking, blood pressure, total cholesterol, LDL-C, HDL-C, plasma glucose) in the prediction of cardiovascular events. However, a significant number of individuals that suffer from a cardiovascular event has few or none of these factors. Such finding indicates the need for new biomarkers able to identify plaques that are more susceptible to rupture. Some of bloodstream biomarkers related to lipid metabolism are modified LDL particles, apolipoprotein AI (apo AI), apolipoprotein B, lipoprotein (a) [Lp (a)], cholesteryl ester transfer protein (CETP), subtypes of LDL and HDL particles, and lipoprotein-associated phospholipase A2 (Lp-PLA2). These factors participate in the atherosclerotic process, and are abnormal in individuals at high risk, or in those who suffered from a cardiovascular event. Lp (a) determination is already employed in clinical practice and should be included as a reference parameter for CVD monitoring. Furthermore, there are expectations for wider use of apo B, non-HDL cholesterol and total cholesterol / HDL-C determination to improve cardiovascular risk assessment.

Virtual screening for natural CETP inhibitors by structure-based pharmacophore / 中国中药杂志

Cholesterol ester transfer protein (CETP) is a key regulator of high density lipoprotein (HDL). Owing to its important role in the reverse of cholesterol transport, CETP has become a hotspot target in modulating lipid drug design. In this paper, structure based pharmacophore (SBP) models for CETP inhibitors were built based on the protein structure 4F2A from Protein Database (PDB). The best pharmacophore contained six hydrophobic features, one hydrogen bond acceptor feature and nine excluded volume features, with the N and CAI value was 3.33 and 2.31 respectively. Then the model was used to search the traditional Chinese medicine database (TCMD) and 629 compounds originated from 315 TCM herbs were obtained. Molecular docking was also used to validate SBP by analyzing the critical amino acid residue and the interaction between potential active compounds and receptor. In this study, several TCM herbs, like Lycii Frutus and Schisandrae chinensis fructus, which contained more optimal SBP based screening results, have been reported hypolipidemic effect, and need to be studied deeply in a more focused research on herbal active constituents. Therefore, this study could provide reliable fundamental data for exploring the action mechanisms of TCM, and be applicable to identify lead candidates, which can be utilized as starting scaffolds for natural CETP inhibitors.

Update on the Pharmacologic Agents for Dyslipidemia / 임상당뇨병

Although statins have demonstrated consistent and strong effects on cardiovascular prevention, non-statin drugs have failed to show additional clinical benefit. Consequently, statins are currently recommended as first-line therapy in dyslipidemia. On the contrary, non-statin drugs are indicated in limited cases in which statins are not sufficiently effective or intolerable. A recent trial on ezetimibe provides evidence supporting further prescription of this agent. Proprotein convertase subtilisin-kexin type 9 inhibitors have strong low-density lipoprotein-cholesterol-lowering effects and were just approved in Western countries. However, results of clinical outcomes are not yet available. Other non-statin lipid-modifying agents have their own roles and limitations. Thus, it is important to have correct knowledge on these agents for optimal treatment of dyslipidemic patients.

Efeitos da atorvastatina e do polimorfismo T-786C do gene eNOS sobre parâmetros do metabolismo lipídico plasmático / Effects of atorvastatin and T-786C polymorphism of eNOS gene on plasma metabolic lipid parameters

FUNDAMENTO: A atividade do óxido nítrico sintase endotelial (eNOS) pode ser modulada pelo colesterol da lipoproteína de alta densidade (HDL-C), estatinas ou polimorfismos, como o T-786C de eNOS. OBJETIVO: Este estudo teve como objetivo avaliar se o polimorfismo T-786C está associado a alterações nos efeitos da atorvastatina no perfil lipídico, nas concentrações de metabólitos de óxido nítrico (NO) e da proteína C reativa de alta sensibilidade (PCR-as). MÉTODOS: Trinta voluntários do sexo masculino, assintomáticos, com idade entre 18-56 anos foram genotipados e classificados de acordo com a ausência (TT, n = 15) ou presença (CC, n = 15) do polimorfismo. Eles foram selecionados aleatoriamente para a utilização de placebo e atorvastatina (10 mg/dia por 14 dias). Após cada tratamento foram medidos lípides, lipoproteínas, frações HDL2 e HDL3, atividade da proteína de transferência de colesteril éster (CETP), metabólitos de NO e PCR-as. RESULTADOS: As comparações entre genótipos após a administração de placebo mostraram aumento da atividade da CETP polimorfismo-dependente (TT, 12 ± 7; CC, 22 ± 12, p < 0,05). As análises da interação entre os tratamentos indicaram que a atorvastatina tem efeito sobre colesterol, LDL, nitrito e razões lípides/proteínas (HDL2 e HDL3) (p < 0,001) em ambos os genótipos. É interessante notar as interações genótipo/droga sobre a CETP (p < 0,07) e a lipoproteína (a) [Lp(a)] (p < 0,056), levando a uma diminuição limítrofe da CETP, embora sem afetar a Lp(a). A PRC-as não mostrou alterações. CONCLUSÃO: Os resultados sugerem que o tratamento com estatinas pode ser relevante para a prevenção primária da aterosclerose em pacientes com o polimorfismo T-786C do eNOS, considerando os efeitos no metabolismo lipídico.

BACKGROUND: Endothelial nitric oxide synthase (eNOS) activity may be modulated by high-density lipoprotein cholesterol (HDL-C), statins or polymorphisms, such as the T-786C of eNOS. OBJECTIVE: This study aimed at evaluating if the T-786C polymorphism is associated with changes of atorvastatin effects on the lipid profile, on the concentrations of metabolites of nitric oxide (NO) and of high sensitivity C-reactive protein (hsCRP). METHODS: Thirty male volunteers, asymptomatic, aged between 18 and 56 years were genotyped and classified according to absence (TT, n = 15) or presence (CC, n = 15) of the polymorphism. They were randomly selected for the use of placebo or atorvastatin (10 mg/day/14 days). After each treatment lipids, lipoproteins, HDL2 and HDL3 composition, cholesteryl ester transfer protein (CETP) activity, metabolites of NO and hsCRP were evaluated. RESULTS: The comparisons between genotypes after placebo showed an increase in CETP activity in a polymorphism-dependent way (TT, 12±7; CC, 22±12; p < 0.05). The interaction analyses between treatments indicated that atorvastatin has an effect on cholesterol, LDL, nitrite and lipid-protein ratios (HDL2 and HDL3) (p < 0.001) in both genotypes. Interestingly, we observed genotype/drug interactions on CETP (p < 0.07) and lipoprotein (a) (Lp(a)) (p < 0.056), leading to a borderline decrease in CETP, but with no effect on Lp(a). HsCRP showed no alteration. CONCLUSION: These results suggest that statin treatment may be relevant for primary prevention of atherosclerosis in patients with the T-786C polymorphism of eNOS, considering the effects on lipid metabolism.

Relationship between cholesteryl ester transfer protein gene -629C→A mutations with HDL-C levels and coronary heart disease / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the relationship between the -629C/A polymorphism in the promoter region of the CETP gene, serum Levels, lipid metabolism, and coronary heart disease (CHD) among Tianjin Han Chinese population.</p><p><b>METHODS</b>A hospital-based case-control study was conducted in Tianjin Chest Hospital from 2010 October to 2011 October. The subjects underwent angiography were divided into a case group (n = 429) and a control group (n = 275). The CETP gene promoter polymorphism at position -629 was determined by restricted fragment length polymorphism using the polymerase chain reaction (PCR-RFLP) method.The serum CETP levels was determined by enzyme-linked immunosorbent assay (ELISA) method.</p><p><b>RESULTS</b>(1)The lower frequency of -629A allele in Tianjin Han Chinese population was 0.408, significantly lower than that in other domestic and foreign populations (0.479-0.701, P < 0.05). (2) Variant AA genotype showed reduced CETP levels(P > 0.05) and higher HDL-C levels (P < 0.05), compared to wild CC genotype. (3) Although there was a negative trend correlation between serum CETP and HDL-C levels, it did not reach statistical significance(P > 0.05). (4)There were significant differences in the frequencies of CETP gene -629 genotype and allele between the two groups (P < 0.001),carries with CA/AA genotype and A allele showed higher risk of CHD, OR (95%CI) values were 4.627 (3.163-6.769), 8.779 (4.799-16.059) and 3.173 (2.453-4.104) respectively. There was no relationship between CETP-629C/A polymorphism and coronary artery stenosis degree(χ(2) = 3.588, P = 0.166).</p><p><b>CONCLUSION</b>The frequencies of CETP gene -629 genotype and allele in the Tianjin Han Chinese population was significantly different from that in Other domestic and foreign populations. Variant AA genotype, which showed reduced CETP levels and higher HDL-C levels, is paradoxically associated with increased risk of CHD. Thus, CETP gene variation may affect coronary risk apart from the level of HDL-C.</p>

Influence of CETP gene -629C/A polymorphism on the efficacy of atorvastatin treatment and clinical outcome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate cholesteryl ester transfer protein (CETP) gene polymorphism -629C/A among Han Chinese patients with coronary heart disease (CHD) in Tianjin region, and to assess the influence of genetic factors on therapeutic effect of atorvastatin and clinical outcome in order to provide a pharmacogenomic basis for personalized treatment.</p><p><b>METHODS</b>From October 2010 to July 2011, 232 patients with angiographically confirmed CHD were recruited. Polymorphism of position -629 of CETP gene promoter was determined with polymerase chain reaction - restricted fragment length polymorphism (PCR-RFLP) method. Serum level of CETP was determined with enzyme-linked immunosorbent assay (ELISA). Lipid level in all patients was determined at baseline and after 12 months of treatment with 20 mg/d atorvastatin. Clinical follow-up was carried out for more than a year (12-23 months). Major adverse cardiac events including death, non-fatal infarction, revascularization and stroke (MACE) were recorded. A Kaplan-Meier log-rank test was used to compare MACE-free survival for individuals with various genotypes.</p><p><b>RESULTS</b>The frequency of -629A allele was 0.408. Compared with CC or CA genotypes, individuals with AA genotype had lower CETP levels and higher high-density lipoprotein cholesterol (HDL-C) levels, albeit without statistical significance (F = 0.893, P = 0.411 and F = 1.279, P = 0.282, respectively). There also appeared to be a negative correlation between serum HDL-C and CETP levels, though no statistical significance was detected (r = -0.151, P = 0.081). After 12 months atorvastatin therapy, individuals with CC genotype had greater reduction of low-density lipoprotein cholesterol (LDL-C), reduced LP(a) and elevated HDL-C compared with CA or AA genotypes. LDL-C level has decreased by 35.41% in CC homozygotes, 18.84% in CA heterozygotes and 8.15% in AA homozygotes (P = 0.001). HDL-C level has increased by 14.37% in CC homozygotes, 10.48% in CA heterozygotes and 6.64% in AA homozygotes, respectively. However, above changes did not reach statistical significance (P = 0.470). The incidence of MACE after a mean follow-up of (18.66 ± 5.99) months was 7.76%, which included 2 (0.86%) deaths, 5 (2.16%) non-fatal infarctions, 9 (3.88%) revascularizations and 2 (0.86%) strokes. The cumulative MACE-free survival rates were 92.4%, 85.3% and 65.0% for CC, CA and AA genotypes, respectively (Log-rank P = 0.444).</p><p><b>CONCLUSION</b>Our results suggested that AA variant for the -629A allele of CETP gene had higher HDL-C levels and reduced CETP levels, though patients with CC genotype appeared to have better benefited from statin therapy with reduction in LDL-C and LP(a) levels. Long-term clinical prognosis was however not affected by the 3 genotypes.</p>

Avaliação da influência dos polimorfismos genéticos APOE e CETP na resposta ao tratamento com Garcinia cambogia / Evaluation of influence of APOE and CETP genetic polymorphisms on response to treatment with Garcinia cambogia

Objetivo - Avaliar se polimorfismos nos genes CETP (proteína transferidora de ésteres de colesterol) e APOE (apolipoproteína E) influenciam no peso e na resposta do perfil lipídico ao tratamento com G. cambogia. Métodos - Trinta e três pacientes com sobrepeso ou obesidade receberam diariamente uma dose de 2,4g de extrato padronizado de G. cambogia (52,4% de ácido-hidroxicítrico). Antes do início do tratamento e após oito semanas, dados antropométricos e perfil lipídico foram obtidos. Resultados - Após o período de tratamento, não foi possível perceber diferenças na resposta sobre o perfil lipídico entre portadores e não portadores do alelo APOE*2, ou do alelo APOE*4. Uma diferença modesta, porém não significante, foi encontrada na comparação entre portadores e não portadores do alelo B2 (gene CETP) para os níveis de colesterol HDL (p=0,086) e triglicerídeos (p= 0,098). Em relação ao peso, não foram detectadas diferenças na resposta ao tratamento entre os genótipos. Conclusão - Os resultados sugerem que a variante no gene CETP pode estar envolvida na modulação dos níveis de HDL-c após o tratamento com G. cambogia. Entretanto, uma investigação em uma amostra maior será necessária para confirmar esses resultados.

Objective - To investigate the influence of polymorphisms of the CETP (cholesterol ester transfer protein) and APOE (apolipoprotein E) genes on weight changes and lipid levels during the treatment with G. cambogia. Methods - Thirty three patients with overweight or obesity received a daily dose of 2.4 grams of a standardized extract of G. cambogia (52.4% hydroxycitric acid). Before the start of treatment and after eight weeks, lipid profile and anthropometric data were obtained. Results - After the treatment, there were no significant differences in the response of serum lipids between carriers and noncarriers of the allele APOE*2 and APOE*4. A slight difference, but not significant, was observed in the comparison between carriers and noncarriers of allele B2 (CETP gene) for HDL cholesterol levels (p=0,086) and triglycerides levels (p= 0,098). There were no significant differences in the weight after treatment according to genotypes. Conclusion - The results suggest that the variant in the CETP gene may be associated with levels of HDL-c after treatment with G. cambogia. However, an investigation in a larger sample is needed to confirm these results.

A Korean Family with Cholesterol Ester Transfer Protein Deficiency

A 32-year-old female patient and her sister show high levels of high density lipoprotein (HDL) cholesterol in regular health checkups, since female patient was 11 years old. The patient's serum total cholesterol was 285 mg/dL and HDL cholesterol was 113 mg/dL. Her sister's total cholesterol was 240 mg/dL and the HDL cholesterol measured to be 90 mg/dL. Lipoprotein pattern and cholesteryl ester transfer activity gene analysis were examined in these patients. We found c.1321+1G>A (IVS14+1G/A) hetero mutation in cholesteryl ester transfer protein (CETP) genes. Generally, CETP mediates transfer and exchange of triglycerides and cholesteryl ester between plasma lipoproteins. Also we investigated a key role of HDL-CE and Apo A-1 metabolism. Patients with low levels of CETP have increased serum HDL levels. We hereby report two Korean cases of CETP deficiency in a family. Brief literature review ensues with the cases.

Inhibición de la proteína de transferencia de ésteres de colesterol para el manejo de la enfermedad cardiovascular ateroesclerótica: el segundo acto "Una esperanza que renace" / Cholesteryl ester transfer protein inhibition in the management of atherosclerotic cardiovascular disease: second act "A rebirth of hope"

Despite the clinical use of statins to reduce serum levels of LDL cholesterol and treat atherosclerotic cardiovascular disease, a high proportion of patients remain at significant residual cardiovascular risk. In this context, low HDL cholesterol levels are an additional risk factor and intervention studies suggest that a fraction of the cardiovascular protection achieved with pharmacotherapy is explained specifically by the increase in serum levels of HDL cholesterol. Pharmacological inhibitors of the cholesteryl ester transfer protein (CETP) can induce a significant elevation in HDL cholesterol and, potentially, lead to better control of residual cardiovascular risk beyond the benefit demonstrated by statins. While the use of torcetrapib had unexpected side effects, dalcetrapib and anacetrapib are new CETP inhibitors with a better safety profile and are currently under study to evaluate their effects on vascular lesions and clinical events in patients at high cardiovascular risk. If these studies show positive findings, we will witness a new biomedical advance as significant as was the clinical.

Study on the correlation between Chinese medical syndrome types and serum levels of PLTP and CETP in coronary heart disease patients / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the correlation between the serum levels of phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), and Chinese medical syndrome types of coronary heart disease (CHD) patients, thus probing a new pathway for the objectivity of CHD syndrome typing and developing therapeutic drugs.</p><p><b>METHODS</b>201 patients with CHD confirmed by coronary angiography were selected. The comprehensive analysis database by the four examination methods was established using generally accepted standard for Chinese medical syndrome typing. Twenty healthy subjects were randomly recruited as the control group. Serum samples were separated from venous blood. The serum activities of PLTP and CETP were assayed by ELISA. The triglyceride (TG) content was determined using acetic acetone coloring method. Contents of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were determined using precipitation floating enzyme couplet method.</p><p><b>RESULTS</b>Serum levels of PLTP, CETP, and TC of CHD patients of all Chinese medical syndrome types were significantly higher than those of the control group, showing statistical difference (P<0.05, P<0.01). Statistical difference existed in serum levels of TG, HDL-C, and LDL-C of all Chinese medical syndrome types when compared with the control group (P<0.05, P<0.01). Statistical difference existed in serum levels of PLTP between the sthenia in superficiality groups of all Chinese medical syndrome types and the asthenia in origin groups of all Chinese medical syndrome types (P< 0.05). Statistical difference existed in serum levels of TG, HDL-C, and LDL-C between the sthenia in superficiality groups of all Chinese medical syndrome types and the asthenia in origin groups of all Chinese medical syndrome types (P<0.05, P<0.01).</p><p><b>CONCLUSIONS</b>The serum PLTP levels of CHD patients of sthenia in superficiality significantly increased. Changes in serum lipids was more significant in CHD patients of the sthenia in superficiality syndrome than in those of the asthenia in origin syndrome.</p>

O treinamento físico aeróbico acelera o transporte reverso de colesterol de macrófagos em camundongos selvagens e transgênicos para CETP humana / Aerobic exercise training improves the macrophage reverse cholesterol transport in wild-type and in CETP transgenic mice

O papel do exercício físico na prevenção da doença macrovascular aterosclerótica é atribuído em parte à melhoria no metabolismo de lípides, com evidências para regressão e prevenção no desenvolvimento de aterosclerose. Neste estudo, avaliamos o efeito de 6 semanas de treinamento físico aeróbio (protocolo diário em esteira 15 m/min, 30 min, 5 vezes na semana) sobre o transporte reverso de colesterol (TRC) em camundongos C57BL/6 selvagens e transgênicos para CETP humana (CETP-tg). Estes últimos constituem modelo experimental de TRC que se assemelha aos humanos, pela presença da CETP. O TRC é um sistema antiaterogênico, por meio do qual o colesterol é removido de células periféricas e transportado ao fígado para eliminação na bile e excreção fecal. A metodologia utilizada consistiu na injeção intraperitoneal de macrófagos J774 enriquecidos em LDL-acetilada e 3H-colesterol em animais selvagens e CETP-tg sedentários e treinados, após as 6 semanas de estudo. O perfil lipídico não foi modificado após o treinamento físico, no entanto, apenas no grupo CETP-tg treinado houve aumento na concentração de HDL colesterol ao final do estudo. O treinamento físico aeróbio acelerou o TRC em camundongos selvagens, refletido pela maior recuperação de 3H-colesterol no plasma (após 24 h e 48 h da injeção intraperitoneal) e no fígado (após 48 h), em comparação aos animais selvagens sedentários. Este evento associou-se ao aumento de 60% na expressão dos receptores hepáticos SR-BI, em relação ao grupo sedentário. Nos animais CETP-tg, o treinamento físico aumentou o TRC, com maior recuperação de 3H-colesterol - advindo dos macrófagos - no plasma, fígado e também nas fezes (após 24 h e 48 h), em comparação aos animais transgênicos sedentários. Embora a expressão de SR-BI não tenha sido alterada pelo treinamento físico nos animais CETPtg, observou-se nestes animais aumento na expressão hepática do receptor B-E, contribuindo para a maior remoção de colesterol pelo fígado...

Regular exercise prevents the development of atherosclerosis. We analyzed the role of a six-week aerobic exercise training program in the macrophage reverse cholesterol transport in wild-type (WT) and in human CETP transgenic (CETP-tg) mice. Animals were randomly assigned to sedentary and trained groups (treadmill 15 m/min, 30-min sessions, 5 sessions per week). Plasma lipids were not modified after training, although HDL-cholesterol concentrations levels increased in trained CETP-tg mice only. Plasma CETP activity was not modified after training. A greater recovery of 3H-cholesterol from J774 macrophages injected into peritoneal cavities of mice was found in plasma and in the liver from exercised WT and CETP animals in comparison to sedentary groups. Exercise training induced a greater excretion of 3H-cholesterol in feces only in the CETP-tg mice. The SR-BI expression in the liver was increased and unchanged in trained WT and CETP-tg mice, respectively. The liver expression of LDL receptor was higher in both groups after training. Alternatively, liver X receptor (LXR) increased only in trained WT mice. Aerobic exercise training improves the macrophage RCT in mice, thereby contributing to the prevention and regression of atherosclerosis. The benefit of exercise on the cholesterol excretion in feces in mice was attained only in the presence of CETP, which elucidates the importance of exercise in the prevention of atherosclerosis in humans.