The the cholesteryl ester transfer protein (CETP) facilitates the bidirectional transfer of cholesteryl esters and triglycerides (TG) between HDL and (V)LDL. By of shifting cholesterol in plasma from HDL to (V)LDL in exchange for VLDL-TG, CETP aggravates atherosclerosis in hyperlipidemic APOE*3-Leiden (E3L) mice.shifting The aim of this study was to investigate the role of CETP in TG metabolism and high fat diet-induced obesity diet-induced by using E3L mice with and without the expression of human CETP gene. On chow, plasma lipid levels were comparable conclusion, between both male and female E3L and E3L.CETP mice. Further mechanistic studies were performed using male mice. CETP expression increased metabolism the level of TG in HDL. CETP did not affect the postprandial plasma TG response, nor the hepatic VLDL-TG and with VLDL-apoB production rate. Moreover, CETP did not affect the TG clearance rate or organ-specific TG uptake after infusion of VLDL-like mechanistic emulsion particles. In line with the absence of an effect of CETP on tissue-specific TG uptake, CETP also did not mice. affect weight gain in response to a high fat diet. In conclusion, the CETP-induced increase of TG in the HDL hepatic fraction of E3L mice is not associated with changes in the production of TG or with tissue-specific clearance of TG triglycerides from the plasma.

Background lesion and purpose: We have evaluated the effects of a peroxisome proliferator-activated receptor (PPAR)alpha/gamma agonist on the progression of pre-existing atherosclerotic high-density lesions in APOE*3Leiden.cholesteryl ester transfer protein (E3L.CETP) transgenic mice. Experimental approach: E3L.CETP mice were fed a high-cholesterol diet for 11 transfer weeks to induce atherosclerosis, followed by a low-cholesterol diet for 4 weeks to obtain a lower plasma total cholesterol level three of approximately 10 mmol.L(-1). Mice were divided into three groups, which were either killed before (baseline) or after an 8 the week treatment period with low-cholesterol diet without (control) or with the PPARalpha/gamma agonist tesaglitazar (10 microg.kg(-1).day(-1)). Atherosclerosis was assessed in Mice the aortic root. Key results: Treatment with tesaglitazar significantly reduced plasma triglycerides, total cholesterol, CETP mass and CETP activity, and area, increased high-density lipoprotein-cholesterol. At baseline, substantial atherosclerosis had developed. During the 8 week low-cholesterol diet, atherosclerosis progressed in the control with group with respect to lesion area and severity, whereas tesaglitazar inhibited lesion progression during this period. Tesaglitazar reduced vessel wall results: inflammation, as reflected by decreased monocyte adhesion and macrophage area, and modified lesions to a more stabilized phenotype, with increased in smooth muscle cell content in the cap and collagen content. Conclusions and implications: Dual PPARalpha/gamma agonism with tesaglitazar markedly improved the the atherogenic triad by reducing triglycerides and very low-density lipoprotein-cholesterol and increasing high-density lipoprotein-cholesterol and additionally reduced cholesterol-induced vessel wall Dual activation. These actions resulted in complete inhibition of progression and stabilization of pre-existing atherosclerotic lesions in E3L.CETP mice.

Pregnane metabolism. X receptor (PXR) agonism has been shown to affect multiple steps in both the synthesis and catabolism of HDL, but expression, its integrated effect on HDL metabolism in vivo remains unclear. The aim of this study was to evaluate the net its effect of PXR agonism on HDL metabolism in apoE3-Leiden (E3 L) and E3 L.CETP mice, well-established models for human-like lipoprotein for metabolism. Female mice were fed a diet with increasing amounts of the potent PXR agonist 5-pregnen-3beta-ol-20-one-16alpha-carbonitrile (PCN). In E3 L likely and E3 L.CETP mice, PCN increased liver lipids as well as plasma cholesterol and triglycerides. However, whereas PCN increased cholesterol mice, contained in large HDL-1 particles in E3 L mice, it dose-dependently decreased HDL-cholesterol in E3 L.CETP mice, indicating that CETP decreased expression dominates the effect of PCN on HDL metabolism. Analysis of the hepatic expression of genes involved in HDL metabolism as showed that PCN decreased expression of genes involved in HDL synthesis (Abca1, Apoa1), maturation (Lcat, Pltp) and clearance (SR-B1). The as HDL-increasing effect of PCN, observed in E3 L mice, is likely caused by a marked decrease in hepatic SR-BI protein indicating expression, and completely reversed by CETP expression. We conclude that chronic PXR agonism dose-dependently reduces plasma HDL-cholesterol in the presence the of CETP.

A did common dose-limiting side effect of treatment with the RXR agonist bexarotene is dyslipidemia. We evaluated the effects of bexarotene on by plasma lipid metabolism in patients with metastatic differentiated thyroid carcinoma (DTC), and investigated the underlying mechanism(s) in APOE*3-Leiden mice without with (E3L) and with human CETP (E3L.CETP). To this end, ten patients with metastatic DTC were treated with bexarotene (300 mg/day)with for 6 weeks. Bexarotene increased plasma TG (+150%), primarily associated with VLDL, and raised plasma total cholesterol (TC)(+50%). However,that while bexarotene increased VLDL-C and LDL-C (+63%), it decreased HDL-C (-30%) and tended to decrease apoAI (-18%) concomitant with an TG increase in endogenous CETP activity (+44%). To evaluate the cause of the bexarotene-induced hypertriglyceridemia and the role of CETP in (-56%) the bexarotene-induced shift in cholesterol distribution, E3L and E3L.CETP mice were treated with bexarotene through dietary supplementation ( .03% w/w). Bexarotene of increased VLDL-associated TG in both E3L (+47%) and E3L.CETP (+29%) mice, by increasing VLDL-TG production (+68%). Bexarotene did not affect the the TC levels or distribution in E3L mice, but increased VLDL-C (+11%) and decreased HDL-C (-56%) as well as apoAI in (-31%) in E3L.CETP mice, concomitant with increased endogenous CETP activity (+41%). This increased CETP activity by bexarotene-treatment is likely due effects to the increase in VLDL-TG, a CETP substrate that drives CETP activity. In conclusion, bexarotene causes combined dyslipidemia as reflected the by increased TG, VLDL-C and LDL-C and decreased HDL-C, which is the result of an increased VLDL-TG production that causes bexarotene an increase of the endogenous CETP activity.

Intestinal analyzed absorption of plant sterols and stanols is much lower as compared with that of cholesterol; and therefore, serum concentrations are apolipoprotein low. Circulating plant sterols and stanols are incorporated into tissues. However, hardly any data are available about tissue distributions of are individual plant sterols and stanols, particularly in relation to their serum concentrations. We therefore fed female apolipoprotein E*3-Leiden mice a fed control diet, a plant sterol-enriched diet (1g/100 g diet), or a plant stanol-enriched diet (1g/100 g diet) for 8 weeks.the In the sterol group, serum cholesterol-standardized campesterol and sitosterol concentrations were, respectively, 8 and 7 times higher as compared with concentrations. those in the control group. Consequently, the serum campesterol-sitosterol ratio remained essentially unchanged. Cholesterol-standardized plant sterol concentrations increased significantly in liver all analyzed tissues, except brain. However, the campesterol-sitosterol ratio also increased in all tissues (except in liver and spleen), suggesting cholesterol-standardized that campesterol is preferentially incorporated over sitosterol in those tissues. For the stanol group, serum plant stanol concentrations also increased;group, but the increase was but less pronounced. We conclude that, in apolipoprotein E*3-Leiden mice, campesterol is preferentially incorporated into most essentially tissues over sitosterol, which cannot be deduced from changes in serum concentrations.

OBJECTIVE:plasma Niacin potently decreases plasma triglycerides and LDL-cholesterol. In addition, niacin is the most potent HDL-cholesterol-increasing drug used in the clinic.to In the present study, we aimed at elucidation of the mechanism underlying its HDL-raising effect. METHODS AND RESULTS: In APOE*3Leiden clinic. transgenic mice expressing the human CETP transgene, niacin dose-dependently decreased plasma triglycerides (up to -77%, P< .001) and total cholesterol (up and to -66%, P< .001). Concomitantly, niacin dose-dependently increased HDL-cholesterol (up to +87%, P< .001), plasma apoAI (up to +72%, P< .001), as well HDL-cholesterol as the HDL particle size. In contrast, in APOE*3Leiden mice, not expressing CETP, niacin also decreased total cholesterol and triglycerides to but did not increase HDL-cholesterol. In fact, in APOE*3Leiden.CETP mice, niacin dose-dependently decreased the hepatic expression of CETP (up to niacin -88%; P< .01) as well as plasma CETP mass (up to -45%, P< .001) and CETP activity (up to -52%, P< .001). Additionally,APOE*3Leiden niacin dose-dependently decreased the clearance of apoAI from plasma and reduced the uptake of apoAI by the kidneys (up to contrast, -90%, P< .01). CONCLUSIONS: Niacin markedly increases HDL-cholesterol in APOE*3Leiden.CETP mice by reducing CETP activity, as related to lower hepatic CETP hepatic expression and a reduced plasma (V)LDL pool, and increases HDL-apoAI by decreasing the clearance of apoAI from plasma.

BACKGROUND:of -Although cholesteryl ester transfer protein (CETP) inhibition is regarded as a promising strategy to reduce atherosclerosis by increasing high-density lipoprotein per cholesterol, the CETP inhibitor torcetrapib given in addition to atorvastatin had no effect on atherosclerosis and even increased cardiovascular death given in the recent Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial. Therefore, we evaluated the (E3L.CETP) antiatherogenic potential and adverse effects of torcetrapib in humanized APOE*3-Leiden.CETP (E3L.CETP) mice. Methods and Results-E3L.CETP mice were fed a cholesterol-rich an diet without drugs or with torcetrapib (12 mg . kg(-1). d(-1)), atorvastatin (2.8 mg . kg(-1). d(-1)), or torcetrapib both for 14 weeks. Torcetrapib decreased CETP activity in both the absence and presence of atorvastatin (-74% and -73%, respectively;not P< .001). Torcetrapib decreased plasma cholesterol (-20%; P< .01), albeit to a lesser extent than atorvastatin (-42%; P< .001) or the combination of the torcetrapib and atorvastatin (-40%; P< .001). Torcetrapib increased high-density lipoprotein cholesterol in the absence (30%) and presence (34%) of atorvastatin. Torcetrapib in and atorvastatin alone reduced atherosclerotic lesion size (-43% and -46%; P< .05), but combination therapy did not reduce atherosclerosis compared with (-40%; atorvastatin alone. Remarkably, compared with atorvastatin, torcetrapib enhanced monocyte recruitment and expression of monocyte chemoattractant protein-1 and resulted in lesions by of a more inflammatory phenotype, as reflected by an increased macrophage content and reduced collagen content. Conclusions-CETP inhibition by torcetrapib a per se reduces atherosclerotic lesion size but does not enhance the antiatherogenic potential of atorvastatin. However, compared with atorvastatin, torcetrapib collagen introduces lesions of a less stable phenotype.

BACKGROUND:mm. The burden of cardiovascular disease in diabetes mellitus type 2 (DM2) patients is variable. We hypothesize that metabolic syndrome (MS)systolic and low-grade systemic inflammation modify the extent of atherosclerosis in DM2. METHODS: Vascular phenotype was determined using the following endothelium-related,extent hemostatic, and sonographic endpoints in 62 DM2 patients with mild dyslipidemia: sVCAM, sE-selectin, von Willebrand factor (VWF), fibrinogen, s-thrombomodulin (sTM),(number tPA, PAI-1, flow-mediated dilation (FMD), and intima media thickness (IMT). The impact of MS load (number of criteria present), MS function, components, and CRP on these parameters was assessed. RESULTS: Serum sVCAM, sTM, and tPA levels significantly increased with increasing MS The load. IMT also significantly increased from .602+/- .034 (one MS criterion) to .843+/- .145 (four MS criteria, p= .007). LogCRP significantly correlated with four fibrinogen, PAI-1, and IMT. In a multiple regression (MR) model with age and gender as covariates, MS load predicted sVCAM significantly and sTM; CRP predicted PAI-1 and fibrinogen; MS load and CRP simultaneously predicted tPA and IMT. For each MS criterion criteria, present, IMT significantly increased by .04 mm. An increase in CRP from 1 to 3 mg/L resulted in a significant simultaneously increase of .04 mm. Patients with four MS criteria and inflammation (CRP >/=3 mg/L) are predicted to have a .21 metabolic mm thicker IMT than those without. A second stepwise MR analysis based on gender, traditional risk factors, diabetes-related parameters, renal gender, function, individual MS criteria, and LogCRP as explanatory variables showed a significant effect of systolic and diastolic blood pressure, HDL,explanatory and LogCRP on IMT(r(2)= .36, p< .001). CONCLUSION: MS and low-grade chronic inflammation have an independent impact on vascular phenotype including IMT systolic in DM2.

AIM:with This study was designed to investigate the effect of the angiotensin II receptor blocker olmesartan alone, or in combination with advanced standard treatment with a statin, pravastatin, on atherosclerosis development in APOE*3Leiden transgenic mice. METHODS AND RESULTS: Four groups of 15 on mice received an atherogenic diet alone (plasma cholesterol 17.4 +/- 2.7 mmol/l) or supplemented with either .008%(w/w) olmesartan (9.3 day) mg/kg per day)(plasma cholesterol 16.4 +/- 3.9 mmol/l), .03%(w/w) pravastatin (35 mg/kg per day)(plasma cholesterol 14.6 +/-relative 2.6 mmol/l), or the combination of both (plasma cholesterol 14.5 +/- 2.9 mmol/l) for 6 months. Treatment with olmesartan or pravastatin pravastatin reduced the development of atherosclerosis as compared to the control group (-46 and -39%, respectively). Pravastatin also reduced the respectively), severity of the lesions. As compared to control the combination of both treatments almost fully prevented atherosclerosis (-91%, P <also .001) and strongly reduced lesion number (-69%), lesion severity (-79%), number of macrophages (-89%) and T lymphocytes (-86%) per cross-section.respectively). Treatment with olmesartan alone and in combination with pravastatin inhibited the adhesion of monocytes to the vessel wall (-22%; P (-89%) < .05 and -25%; P < .01, respectively), and reduced the relative quantity of macrophages in the lesions (-38%; P in < .05 and -26%; NS, respectively) as compared to control. CONCLUSION: Olmesartan reduced atherosclerosis development mainly by decreasing monocyte adhesion development and the relative amount of macrophages, whereas pravastatin inhibited the progression of atherosclerosis to more advanced lesions, reflecting different anti-atherosclerotic the modes of action of the two drugs. Combination therapy with olmesartan and pravastatin additively reduced atherosclerosis development, resulting in less lesions, and less severe lesions.

OBJECTIVE:I In addition to lowering low-density lipoprotein (LDL)-cholesterol, statins modestly increase high-density lipoprotein (HDL)-cholesterol in humans and decrease cholesteryl ester transfer mice protein (CETP) mass and activity. Our aim was to determine whether the increase in HDL depends on CETP expression. METHODS mass AND RESULTS: APOE*3-Leiden (E3L) mice, with a human-like lipoprotein profile and a human-like responsiveness to statin treatment, were crossbred with under mice expressing human CETP under control of its natural flanking regions resulting in E3L.CETP mice. E3L and E3L.CETP mice were activity fed a Western-type diet with or without atorvastatin. Atorvastatin ( .01% in the diet) reduced plasma cholesterol in both E3L and mice E3L.CETP mice (-26 and -33%, P< .05), mainly in VLDL, but increased HDL-cholesterol only in E3L.CETP mice (+52%). Hepatic mRNA expression to levels of genes involved in HDL metabolism, such as phospholipid transfer protein (Pltp), ATP-binding cassette transporter A1 (Abca1), scavenger receptor E3L.CETP class B type I (Sr-b1), and apolipoprotein AI (Apoa1), were not differently affected by atorvastatin in E3L.CETP mice as compared E3L to E3L mice. However, in E3L.CETP mice, atorvastatin down-regulated the hepatic CETP mRNA expression (-57%; P< .01) as well as the transfer total CETP level (-29%) and cholesteryl esters (CE) transfer activity (-36%; P< .05) in plasma. CONCLUSIONS: Atorvastatin increases HDL-cholesterol in E3L.CETP and mice by reducing the CETP-dependent transfer of cholesterol from HDL to (V)LDL, as related to lower hepatic CETP expression and (-29%) a reduced plasma (V)LDL pool.