Cholesteryl Ester Transfer Protein Activity Research Articles

Efficacy, Safety, Tolerability, and Pharmacokinetic Profile of Evacetrapib Administered as Monotherapy or in Combination With Atorvastatin in Japanese Patients With Dyslipidemia

The cholesteryl ester transfer protein (CETP) inhibitor evacetrapib has been previously shown to increase high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels, as monotherapy or in combination with statins. In this study, 165 Japanese patients with elevated LDL-C or low HDL-C levels were randomly assigned to receive placebo, evacetrapib monotherapy 30 mg, 100 mg, or 500 mg, atorvastatin 10 mg, or evacetrapib 100 mg in combination with atorvastatin 10 mg. After 12 weeks, evacetrapib monotherapy increased HDL-C levels by 74%, 115%, and 136% and decreased LDL-C levels by 15%, 23%, and 22% and CETP activity by 50%, 83%, and 95% (for the 30-mg, 100-mg, and 500-mg dose groups, respectively) versus placebo. In combination with atorvastatin 10 mg, evacetrapib 100 mg increased HDL-C levels by 103% and decreased LDL-C levels by 15% and CETP activity by 68% versus atorvastatin alone. After a 4- to 6-week washout, HDL-C, LDL-C, and CETP mass and activity returned to baseline levels in the evacetrapib-treated groups, and most patients had evacetrapib concentrations below the quantitation limit. Evacetrapib monotherapy or in combination with atorvastatin was not likely to be associated with any significant change in blood pressure and did not have any adverse effects on mineralocorticoid or glucocorticoid measures. Notably, plasma evacetrapib concentrations were mostly undetectable, and all pharmacodynamic biomarkers (HDL-C and LDL-C levels and CETP mass and activity) returned to baseline after a 4- to 6-week washout. In conclusion, evacetrapib as monotherapy or in combination with atorvastatin effectively decreased CETP activity and LDL-C levels and increased HDL-C levels after 12 weeks in Japanese patients with dyslipidemia.

Cholesteryl Ester Transfer Protein rs1532624 Gene Polymorphism is Associated with Reduced Response to Statin Therapy

The aim of the study was to determine the allele and genotype frequencies of rs1532624 SNP of the cholesteryl ester transfer protein gene (CETP) among 116 Jordanian patients taking statins, and to study the impact of the genotypes on response to statin therapy. The study was approved by the Institutional review Board (IRB) of The Jordan University Hospital. An informed consent was signed by every participant. A single fragment encoding a 307 bp sequence of the CETP gene, including the SNP of interest at position 14645 in intron 7, was amplified using a polymerase chain reaction (PCR) technique directly from whole blood. The PCR product was then subjected to DNA sequencing. The frequencies of the genotypes of the homozygous minor allele (AA), the homozygous major allele (CC), and the heterozygous allele (CA) were 0.121, 0.405, and 0.474, respectively. The minor allele (A) frequency was 0.358. The frequencies did not deviate from Hardy-Weinberg equilibrium. The lipid profile before the start of statin therapy was similar for all genotypes regarding total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglycerides, while high density lipoprotein cholesterol (HDL-C) was significantly higher in the AA genotype. The AA genotype was also associated with significantly lower CETP activity than the other genotypes. The response to statin therapy was less in the AA genotype than the other genotypes for TC and LDL-C. In conclusion, the homozygous minor allele subjects have higher base line HDL-C, and lower CETP activity than the other genotypes (CA and CC). They also have less reduction in TC and LDL-C after statin therapy.

Elevated cholesteryl ester transfer protein (CETP) activity, a major determinant of the atherogenic dyslipidemia, and atherosclerotic cardiovascular disease in South Asians

Why South Asians are at increased risk of premature atherosclerotic cardiovascular diseases compared with other ethnic groups is not fully understood. Atherogenic dyslipoproteinemia - hypertriglyceridemia, elevated numbers of low-density lipoprotein (LDL) particles and low high-density lipoprotein cholesterol (HDL-C) - is more common in South Asians but the mechanisms responsible have not been explicated. Here we examined whether the circulating lipid transfer protein, cholesteryl ester transfer protein (CETP), plays a role in the pathogenesis of the atherogenic dyslipoproteinemia among South Asians. CETP activity was determined by exogenous substrate assay in the serum of healthy, metabolically well-characterized individuals of South Asian and European descent (N = 244 and 238, respectively). Serum and lipoprotein lipids and apolipoproteins were measured and lipoprotein particle number and size were quantified via nuclear magnetic resonance spectroscopy. All the elements of the atherogenic dyslipoproteinemia were more severe in South Asians and CETP activity was significantly greater by 30% in South Asians compared with Europeans, adjusted for age, sex, body mass index and waist circumference (p < 0.0001). CETP activity was directly associated with serum triglycerides and inversely with HDL-C in the whole population. CETP activity was also directly related to apoB and LDL particle number. Finally, increased CETP activity was associated with pro-atherogenic reductions in HDL and LDL particle size. We identified novel associations between elevated CETP activity and the triad of quantitative and qualitative lipoprotein abnormalities in the atherogenic dyslipidemia in South Asians, a major contributor of increased atherosclerotic cardiovascular diseases in South Asians.

Fibrates and fish oil, but not corn oil, up-regulate the expression of the cholesteryl ester transfer protein (CETP) gene

Cholesteryl ester transfer protein (CETP) is a plasma protein that reduces high density lipoprotein (HDL)-cholesterol (chol) levels and may increase atherosclerosis risk. n-3 and n-6 polyunsaturated fatty acids (PUFAs) are natural ligands, and fibrates are synthetic ligands for peroxisome proliferator activated receptor-alpha (PPARα), a transcription factor that modulates lipid metabolism. In this study, we investigated the effects of PUFA oils and fibrates on CETP expression. Hypertriglyceridemic CETP transgenic mice were treated with gemfibrozil, fenofibrate, bezafibrate or vehicle (control), and normolipidemic CETP transgenic mice were treated with fenofibrate or with fish oil (FO; n-3 PUFA rich), corn oil (CO, n-6 PUFA rich) or saline. Compared with the control treatment, only fenofibrate significantly diminished triglyceridemia (50%), whereas all fibrates decreased the HDL-chol level. Elevation of the CETP liver mRNA levels and plasma activity was observed in the fenofibrate (53%) and gemfibrozil (75%) groups. Compared with saline, FO reduced the plasma levels of nonesterified fatty acid (26%), total chol (15%) and HDL-chol (20%). Neither of the oil treatments affected the plasma triglyceride levels. Compared with saline, FO increased the plasma adiponectin level and reduced plasma leptin levels, whereas CO increased the leptin levels. FO, but not CO, significantly increased the plasma CETP mass (90%) and activity (23%) as well as increased the liver level of CETP mRNA (28%). In conclusion, fibrates and FO, but not CO, up-regulated CETP expression at both the mRNA and protein levels. We propose that these effects are mediated by the activation of PPARα, which acts on a putative PPAR response element in the CETP gene.

OP-032 Comparison of CETP Mass and Activity Levels Between Patients with Coronary Atherosclerosis and Healthy Subjects Although Having Higher HDL-C Levels

A B S T R A C T S the leading disease, follow by arrhythmia, then congestive heart failure. Congestive heart failure was diagnosed in 19,6% cases. Congenital heart diseases was diagnosed in 5,9% of studied population. The most diagnosed pathology was isolated ventricular septal defect and tetralogy of Fallot. Post-rheumatic valvulopathies and congenital heart diseases are the first aetiological factor of congestive heart failure in young. Results: Patients with severe hypertension, congestive heart failure, symptomatic arrhythmias were admitted for more investigations and proper care. After the compensation drug treatment, patient needed surgery, underwent surgical procedure. The hospital mortality rate was 0,2%. The poor compliance and limited finances gives the follow-up difficult. Conclusion: This study confirms that rheumatic heart disease still accounts for a major proportion of all cardiovascular diseases in children and young adults in African countries. Rapid urbanization and transition from agrarian life to the wage-earning economy of city life continue to fuel increases in average blood pressure levels and prevalence of hypertension.

Glycation of Apolipoprotein C1 Impairs Its CETP Inhibitory Property: Pathophysiological Relevance in Patients With Type 1 and Type 2 Diabetes

OBJECTIVE Apolipoprotein (apo)C1 is a potent physiological inhibitor of cholesteryl ester transfer protein (CETP). ApoC1 operates through its ability to modify the electrostatic charge at the lipoprotein surface. We aimed to determine whether the inhibitory ability of apoC1 is still effective in vivo in patients with diabetes and whether in vitro glycation of apoC1 influences its electrostatic charge and its CETP inhibitory effect. RESEARCH DESIGN AND METHODS ApoC1 concentrations and CETP activity were measured in 70 type 1 diabetic (T1D) patients, 113 patients with type 2 diabetes, and 83 control subjects. The consequences of in vitro glycation by methylglyoxal on the electrostatic properties of apoC1 and on its inhibitory effect on CETP activity were studied. An isoelectric analysis of apoC1 was performed in patients with T1D and in normolipidemic-normoglycemic subjects. RESULTS An independent negative correlation was found between CETP activity and apoC1 in control subjects but not in patients with diabetes. HbA1c was independently associated with CETP activity in T1D patients. In vitro glycation of apoC1 modified its electrostatic charge and abrogated its ability to inhibit CETP activity in a concentration-dependent manner. The isoelectric point of apoC1 in T1D patients was significantly lower than that in control subjects. CONCLUSIONS The ability of apoC1 to inhibit CETP activity is impaired in patients with diabetes. Glycation of apoC1 leads to a change in its electrostatic properties that might account, at least in part, for a loss of constitutive CETP inhibition and an increase in plasma CETP activity in patients with diabetes.

Enhanced cholesterol efflux to HDL through the ABCA1 transporter in hypertriglyceridemia of type 2 diabetes

ObjectiveOur objective was to examine the role of hypertriglyceridemia on the capacity of HDL to facilitate ABCA-1 mediated cholesterol efflux in type 2 diabetes (T2DM). MethodsHDL mediated cholesterol efflux through the ABCA-1 transporter was measured using BHK cell lines in samples of 71 participants with T2DM in the presence or absence of high triglyceride levels (TG). Additionally, HDL mediated efflux was measured in 13 diabetic and non-diabetic participants fasting and four hours after a high-fat test challenge. ResultsHDL mediated cholesterol efflux function was increased in participants with T2DM with hypertriglyceridemia when compared to participants with T2DM without hypertriglyceridemia (efflux ratio mean±standard deviation (SD), T2DM+TG: 1.17±0.25 vs. T2DM − TG: 1.03±0.19, p=0.0098). In the fat challenge study, we observed a significant increase in ABCA-1 mediated cholesterol efflux capacity following an ingestion of high-fat test meal by participants in both groups of T2DM (n=6, efflux ratio, mean±SD, pre: 0.86±0.4 vs. post: 1.34±0.6, p=0.01) and non-diabetic participants (n=7, efflux ratio mean±SD pre: 1.24±0.31 vs. post: 1.39±0.42, p=0.04) that was partly explained by the difference in CETP activity (r=0.6, p=0.03). ConclusionOur study suggests that high triglyceride levels facilitate ABCA-1 mediated efflux function of HDL in part by activating CETP.

Study of Cholesteryl Ester Transfer Protein (CETP) I405v Genotype and Its Association with Lipid Fractions in Myocardial Infarction Patients: A Case Control Study.

We determine the significant relation of HDL cholesterol and total cholesterol/HDL cholesterol between CETP I405V genotypes and activity of CETP. CETP is an essential for transfer of cholesterol ester to the liver from peripheral tissues which facilitating its transfer to TG rich VLDL. Reduction activity of CETP I405V may associate with genotypes of CETP I405V. This study is undertaken to assess the presence and impact of CETP I405V genotype in our population. In this study 100 acute myocardial infarction patients and 100 normal age & sex matched healthy individuals were included. Serum Lipid profile was estimated by using universal standard methods whereas CETP I405V genotype was studied by ARMS PCR. There is presence of CETP 405Val genotype both in patient as well as in control group. RESULTs show that HDL cholesterol (p<0.0001) and ratio of total cholesterol/HDL cholesterol are significantly (p<0.0043) associated with Val/Val genotype. In addition to that the CETP I405V genotype is associated with inhibition of CETP activity with higher HDL-C level and decreased total cholesterol/HDL cholesterol ratio. Our results show that the CETP I405V genotypes are very much significantly determinant of HDL cholesterol in patients with CHD.

Rapid Development of Atherosclerosis in the World’s Smallest Microminipig Fed a High-Fat/High-Cholesterol Diet

Experimental studies of human atherogenesis require an appropriate animal model that mimics human physiology and pathology. Because swine physiology is similar to human physiology, we developed a hyperlipidemia-induced atherosclerosis model using the recently developed world's smallest Microminipig(TM). These animals weigh only 5kg at 3months of age, much smaller than any other miniature pig. We found that the administration of a high-fat/high-cholesterol diet containing at least 0.2% cholesterol without cholic acid for as little as eight weeks induces hypercholesterolemia and subsequent atherosclerosis in these animals. The serum levels of low-density lipoprotein cholesterol(LDL-C) and the percent distribution of cholesterol in the LDL fractions were markedly increased. The hepatic expression of LDL receptor and hydroxymethylglutaryl-CoA reductase was coordinately decreased. The cholesteryl ester transfer protein activity, which plays a role in reverse cholesterol transport, was detected in the serum of the Microminipigs. Niemann-Pick C1-like 1 protein was expressed in both the liver and small intestine; however, hepatic apoB mRNA editing enzyme was not expressed. As in humans, and in contrast to that observed in mice, most of the hepatic lipase activity was localized in the liver. These results suggest that the hyperlipidemia-induced gene expression profile linked to cholesterol homeostasis and atherogenesis is similar in Microminipigs and humans. We conclude that the characteristics of the Microminipig, including its easy handling size, make it an appropriate model for studies of atherosclerosis and related conditions.

Genetic variants affecting alternative splicing of human cholesteryl ester transfer protein

Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport, with decreased CETP activity increasing HDL levels. Formation of an alternative splice form lacking exon 9 (Δ9-CETP) has been associated with two single nucleotide polymorphisms (SNPs) in high linkage disequilibrium with each other, namely rs9930761 T>C located in intron 8 in a putative splicing branch site and rs5883 C>T in a possible exonic splicing enhancer (ESE) site in exon 9. To assess the relative effect of rs9930761 and rs5883 on splicing, mini-gene constructs spanning CETP exons 8 to 10, carrying all four possible allele combinations, were transfected into HEK293 and HepG2 cells. The minor T allele of rs5883 enhanced splicing significantly in both cell lines whereas the minor C allele of rs9930761 did not. In combination, the two alleles did not yield greater splicing than the rs5883 T allele alone in HepG2 cells. These results indicate that the genetic effect on CETP splicing is largely attributable to rs5883. We also confirm that Δ9-CETP protein is expressed in the liver but fails to circulate in the blood.

Korean red ginseng combined with nattokinase ameliorates dyslipidemia and the area of aortic plaques in high cholesterol-diet fed rabbits

Male white rabbits were fed a high cholesterol diet supplemented with red ginseng (RG) or red ginseng plus nattokinase (RGNK). RG and RGNK significantly reduced increased serum triglycerides levels and aortic plaque area in a hypercholesterol diet fed rabbits. Moreover, only RGNK reduced hepatic cholesterol and cholesteryl ester transfer protein activity levels. Therefore, the present study suggests RGNK might be a potential therapeutic approach for atherogenesis.

Metabolism of plasma cholesterol and lipoprotein parameters are related to a higher degree of insulin sensitivity in high HDL-C healthy normal weight subjects

BackgroundWe have searched if plasma high density lipoprotein-cholesterol (HDL-C) concentration interferes simultaneously with whole-body cholesterol metabolism and insulin sensitivity in normal weight healthy adult subjects.MethodsWe have measured the activities of several plasma components that are critically influenced by insulin and that control lipoprotein metabolism in subjects with low and high HDL-C concentrations. These parameters included cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), lecithin cholesterol acyl transferase (LCAT), post-heparin lipoprotein lipase (LPL), hepatic lipase (HL), pre-beta-1HDL, and plasma sterol markers of cholesterol synthesis and intestinal absorption.ResultsIn the high-HDL-C group, we found lower plasma concentrations of triglycerides, alanine aminotransferase, insulin, HOMA-IR index, activities of LCAT and HL compared with the low HDL-C group; additionally, we found higher activity of LPL and pre-beta-1HDL concentration in the high-HDL-C group. There were no differences in the plasma CETP and PLTP activities.ConclusionsThese findings indicate that in healthy hyperalphalipoproteinemia subjects, several parameters that control the metabolism of plasma cholesterol and lipoproteins are related to a higher degree of insulin sensitivity.

Relation of atrial fibrillation (AF) and change of lipoproteins: Male patients with AF exhibited severe pro-inflammatory and pro-atherogenic properties in lipoproteins

ObjectivesThis study was designed to search putative biomarkers for detection of relatively young-onset atrial fibrillation (AF). Design and methodsWe analyzed serum lipoproteins from male patients with paroxysmal AF (48±9years old, n=29) and controls with similar age (50±10years old, n=27), who visited our hospital for radiofrequency catheter ablation due to paroxysmal supraventricular tachycardia. ResultsAlthough the AF group showed normal serum cholesterol level, they exhibited 16% lower HDL-cholesterol and 13% higher serum cholesteryl ester transfer protein activity than those of the control group. The AF group showed elevated levels of serum triglyceride (TG) and C-reactive protein with hyperuricemia. However, there was no difference between serum levels of creatinine, troponin I, and serum amyloid A. All lipoproteins from the AF group contained higher level of TG, oxidized species, and advanced glycated end products. LDL from the AF group (AF-LDL) showed 2.7-fold more content of malondialdehyde than the control group (p<0.04) and exhibited higher sensitivity of oxidation. HDL-associated paraoxonase from the AF group showed impaired antioxidant ability and lowered expressional level of apoA-I (p<0.01) and paraoxonase (p<0.005) in HDL3. ConclusionLipoprotein properties were severely impaired in the AF group with increased extent of oxidation and inflammation. The modified lipoprotein properties with impaired antioxidant functions can be used as a putative biomarker for prognostic detection for the relatively young onset AF.

PS13 - 7. Plasma cholesteryl ester transfer protein: a biomarker for hepatic macrophages

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from HDL to LDL and high CETP activity results in an atherogenic lipid phenotype. Thus, inhibiting CETP is a target for dyslipidemia treatment. However, the true origin of CETP in humans is uncertain. We aimed to elucidate the cellular origin of CETP and the relative contribution of adipose tissue and liver to plasma CETP levels.

Expression of Type IIA Secretory Phospholipase A 2 Inhibits Cholesteryl Ester Transfer Protein Activity in Transgenic Mice

High circulating levels of group IIA secretory phospholipase A2 (sPLA2-IIA) activity and mass are independent cardiovascular risk factors. Therefore, inhibition of sPLA2-IIA may be a target for the treatment of atherosclerotic cardiovascular disease. The present study evaluated the effects of sPLA2-IIA inhibition with varespladib acid in a novel mouse model, human apolipoprotein B (apoB)/human cholesteryl ester transfer protein (CETP)/human sPLA2-IIA triple transgenic mice (TTT) fed a Western-type diet. sPLA2-IIA expression increased atherosclerotic lesion formation in TTT compared with human apoB/human CETP double transgenic mice (P<0.01). Varespladib acid effectively inhibited plasma sPLA2-IIA activity. Surprisingly, however, administration of varespladib acid to TTT had no impact on atherosclerosis, which could be attributed to a proatherogenic plasma lipoprotein profile that appears in response to sPLA2-IIA inhibition because of increased plasma CETP activity. In the TTT model, sPLA2-IIA decreased CETP activity by reducing the acceptor properties of sPLA2-IIA-modified very low-density lipoproteins specifically because of a significantly lower apoE content. Increasing very low-density lipoprotein-apoE content by means of adenovirus-mediated gene transfer in sPLA2-IIA transgenic mice restored the acceptor properties for CETP. These data show that in a humanized triple transgenic mouse model with hypercholesterolemia, sPLA2-IIA inhibition increases CETP activity via increasing the very low-density lipoprotein-apoE content, resulting in a proatherogenic lipoprotein profile.

Antisense oligonucleotide inhibition of cholesteryl ester transfer protein enhances RCT in hyperlipidemic, CETP transgenic, LDLr-/- mice

Due to their ability to promote positive effects across all of the lipoprotein classes, cholesteryl ester transfer protein (CETP) inhibitors are currently being developed as therapeutic agents for cardiovascular disease. In these studies, we compared an antisense oligonucleotide (ASO) inhibitor of CETP to the CETP small molecule inhibitor anacetrapib. In hyperlipidemic CETP transgenic (tg) mice, both drugs provided comparable reductions in total plasma cholesterol, decreases in CETP activity, and increases in HDL cholesterol. However, only mice treated with the antisense inhibitor showed an enhanced effect on macrophage reverse cholesterol transport, presumably due to differences in HDL apolipoprotein composition and decreases in plasma triglyceride. Additionally, the ASO-mediated reductions in CETP mRNA were associated with less accumulation of aortic cholesterol. These preliminary findings suggest that CETP ASOs may represent an alternative means to inhibit that target and to support their continued development as a treatment for cardiovascular disease in man.

High cholesteryl ester transfer protein (CETP) activity in acute phase of myocardial infarction predicts short-term mortality by inducing endothelial dysfunction and reduced microvascular perfusion

Background: Recently, much effort has been centered on the development of cholesteryl ester transfer protein (CETP) inhibitors, based on CETP proatherogenic role. However, some evidence indicates exacerbated CETP activity (CETPa) may also favor arterial thrombogenicity and impair endothelial function. In this context, we investigated the relation between CETPa and: 1) endothelial dysfunction; 2) coronary blood flow/myocardial perfusion after reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI). Methods: Consecutive thrombolytic-treated STEMI patients (n=116) were followed prospectively. Plasma C-reactive protein (CRP), IL-2, TNFα, 8-isoprostane, nitric oxide (NOx) levels and CETPa (%) were measured in the first 24 hours (D1) and at 5th day (D5) after MI onset. Culprit artery percutaneous coronary angioplasty (PCA) was performed at a mean 6 days after MI, when pre- and post-procedure myocardial blush grade (MBG) and TIMI flow were measured. At D30 we measured brachial artery flow-mediated dilation (FMD) by ultrasonography. In addition, all patients were genotyped for eNOS polymorphism rs1799983 (G/T). Results: Although admission CETPa had no relation with the change between D1 and D5 in CRP, IL-2, TNFα or 8-isoprostane plasma levels, patients with higher CETPa presented both poor coronary flow (TIMI flow<3, adjusted OR of 22.1 95% CI 2.7–180; p=0.004) and myocardial perfusion (MBG<3, OR 20.4 CI 1.8–101; p=0.001), compared to those with lower CETP activity. Logistic regressions showed admission plasma CETPa higher than median as an independent predictor of cardiac death and new MI in 30 days (OR=12.8, CI 1.25–132, p=0.032), as well as endothelial dysfunction (OR=3.08, CI 1.01–9.37,p=0.048). Consistently, the rise in NOx levels between D1 and D5 was less intense in patients with exacerbated CETPa (5.5 (-1; 12) vs 3.5 (-1; 10); p<0.001). In addition, in order to evaluate if eNOS activity would be critical for the association between CETP and endothelial dysfunction, we observed that only in the presence of the functional eNOS T allele polymorphism the correlation between CETP and FMD was maintained (R2=-0.4, p=0.002). T allele patients with admission CETPa lower than median also presented FMD of 12.2±4 vs 6.0±3mm in those with high CETPa (p=0.040). Conclusions: This is the first study to suggest a relation between high plasma CETP activity in acute STEMI and increased clinical outcomes at 30 days. Our study also indicates a positive association between exacerbated CETP activity in MI and both endothelial dysfunction and poor reperfusion quality post-angioplasty.

Infusion of CSL112, a novel formulation of human apolipoprotein A-I, in healthy subjects removes tissue cholesterol and directs its clearance

Purpose: The ability of HDL to promote cholesterol efflux from atherosclerotic plaque is thought to underpin its potential for cardioprotection. CSL112 is apoA-I, the active component of HDL, purified from human plasma and reconstituted to form HDL-particles suitable for infusion. CSL112 is in development for the treatment of ACS, and this study measures the ability of CSL112 to promote cholesterol movement. Methods and results: We studied PK and biomarkers of cholesterol movement following a single infusion of 5 to 135 mg/kg CSL112 in 42 of 57 enrolled healthy subjects, all other subjects received placebo ([NCT01129661][1]). We previously showed that infusion of CSL112 caused an immediate and large elevation in serum cholesterol efflux capacity. Consistent with this finding, during the initial 24 h interval, HDL-cholesterol increased in a dose-dependent manner while non-HDL-cholesterol did not change. These observations demonstrate movement of tissue cholesterol to HDL. Here, we investigated the fate of that HDL cholesterol. During the first 24 h following the infusion we observed a progressive conversion of unesterified cholesterol (UC) in HDL to esterified cholesterol (EC), indicating the action of LCAT. The predominant clearance path for HDL EC involves transport to non-HDL cholesterol by CETP, an enzyme that removes HDL EC in exchange for triglyceride (TG). Two findings support the action of this pathway after infusion of CSL112. In the first 24 h we observed a transient, dose-dependent increase in TG in the HDL-fraction. Second, we observed a transient rise in CETP activity after the infusion of CSL112. Further studies showed that enhanced CETP activity did not lead to an increase in non-HDL-cholesterol indicating that there was no saturation of the hepatic LDL-receptor mediated catabolism of LDL. Conclusion: Infusion of CSL112 caused an immediate rise in apoA-I, cholesterol efflux capacity and exit of tissue cholesterol into plasma. Newly effluxed cholesterol appears to follow a normal route of clearance with passage to non-HDL lipoproteins via CETP. CSL112 may thus provide a novel option to rapidly transport cholesterol from atherosclerotic plaque to the liver and reduce early recurrent events following ACS. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01129661&atom=%2Fehj%2F34%2Fsuppl_1%2F1947.atom

Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice

Cholesteryl ester transfer protein (CETP) activity results in a proatherogenic lipoprotein profile. In cholestatic conditions, farnesoid X receptor (FXR) signaling by bile acids (BA) is activated and plasma HDL cholesterol (HDL-C) levels are low. This study tested the hypothesis that FXR-mediated induction of CETP contributes to this phenotype. Patients with cholestasis and high plasma BA had lower HDL-C levels and higher plasma CETP activity and mass compared with matched controls with low plasma BA (each P < 0.01). BA feeding in APOE3*Leiden transgenic mice expressing the human CETP transgene controlled by its endogenous promoter increased cholesterol within apoB-containing lipoproteins and decreased HDL-C (each P < 0.01), while hepatic CETP mRNA expression and plasma CETP activity and mass increased (each P < 0.01). In vitro studies confirmed that FXR agonists substantially augmented CETP mRNA expression in hepatocytes and macrophages dependent on functional FXR expression (each P < 0.001). These transcriptional effects are likely mediated by an ER8 FXR response element (FXRE) in the first intron. In conclusion, using a translational approach, this study identifies CETP as novel FXR target gene. By increasing CETP expression, FXR activation leads to a proatherogenic lipoprotein profile. These results have clinical relevance, especially when considering FXR agonists as emerging treatment strategy for metabolic disease and atherosclerosis.

상황버섯, 상황버섯균사체배양쌀 추출물의 비만 및 당뇨 억제 효과

본 연구에서는 상황버섯(PL)과 상황버섯균사체를 접종시켜 20일간 배양한 상황버섯균사체배양쌀 추출물(PLM)의 항당뇨와 항비만 효과를 규명하고자 하였다. 지방축적 억제 효과를 확인하기 위하여 분화유도 후 8일째에 Oil Red O 염색을 통해 세포 내 형성된 lipid droplet을 isopropanol에 용출하여 500 nm에서 흡광도를 측정한 결과 PL 3, 30, 100, 300 μg/mL에서 P<0.01 수준에서 유의한 억제 효과가 나타났다. PLM은 농도 의존적으로 P<0.01 수준에서 유의한 저해효과가 나타났다. CETP 저해 활성을 측정한 결과 PL 300 μg/mL에서 P<0.05 수준에서 유의한 저해효과가 나타났다. PLM은 100 μg/mL에서 P<0.05 수준에서 유의한 저해효과가 나타났으며, PLM 300 μg/mL에서는 P<0.01 수준에서 유의한 저해효과가 나타났다. 인슐린에 의한 세포내 신호전달에 있어서 인슐린의 효과를 저해하는 PTP1B의 활성을 측정한 결과, PL은 10, 30, 100 μg/mL에서 통계적으로 P<0.05 수준에서의 유의한 저해효과가 나타났으며 PL 1,000 μg/mL에 있어서는 P<0.01 수준에서 유의한 저해효과가 나타났다. PLM은 대조군에 비하여 PLM 1 μg/mL에서 통계적으로 P<0.05 수준에서의 유의한 저해효과가 나타났으며 PLM 3, 10, 30, 100, 300, 1,000 μg/mL에 있어서는 P<0.01 수준에서 유의한 저해효과가 나타났다. 또한 고지방식이에 PL과 PLM을 28일간 경구투여 하였을 때 총콜레스테롤은 HFD군에 비해 PL, PLM군 모두 유의적인 감소를 나타내었고(P<0.05), 혈청의 중성지방(triglyceride) 농도는 HFD군에 비해 PL군, PLM군은 모두 감소하는 경향을 나타내었으며 통계적으로 P<0.05 수준에서 유의적인 감소를 나타내었다. 혈청의 HDL-cholesterol은 HFD처리군보다 시료처리군에서 증가를 보였으며, PLM처리군에서 유의적인 증가를 나타내었다(P<0.01). LDL-cholesterol은 HFD군에 비해 PL군, PLM군에서 감소하였으며, 유의적인 차이는 없었다. 이상의 결과로 보아 상황버섯과 상황버섯균사체 배양쌀은 지방세포의 분화를 억제시키며 PL과 PLM이 혈청지질 조정을 개선시키는데 효과가 있음을 알 수 있다. 앞으로 항비만, 항당뇨 생리활성을 나타내는 식품소재로서의 개발에 가능성이 있을 것으로 생각된다.