Increased Atherosclerosis in ApoE and LDL Receptor Gene Knock-Out Mice as a Result of Human Cholesteryl Ester Transfer Protein Transgene Expression

Plump, Andrew S.; Masucci-Magoulas, L.; Bruce, Can; Bisgaier, Charles L.; Breslow, Jan L.; Tall, Alan R.

doi:10.1161/01.atv.19.4.1105

Cited by 214 publications

(127 citation statements)

References 47 publications

(46 reference statements)

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“…Studies in rabbits, which develop high CETP plasma levels on a high-cholesterol diet, 28 have shown that CETP inhibition by JTT-705 can protect against atherosclerosis. [11][12][13] Studies in mice, which are CETP deficient by nature, however, showed that expression of human CETP can be either atherogenic 29,30 or antiatherogenic. 31 To date, the precise role of CETP in human atherogenesis and how its activity relates to coronary artery disease risk is still unclear, 32,33 but JTT-705 is an effective tool to study these relations.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans

et al. 2002

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Background-Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans. Methods and Results-In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity (PϽ0.0001), a 34% increase in HDL cholesterol (PϽ0.0001), and a 7% decrease in LDL cholesterol (Pϭ0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL 2, HDL 3 , and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests. Conclusions-We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects (Pϭ0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans

et al. 2002

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“…In other studies, both ApoE and LDL receptor knockout mice developed more extensive atherosclerosis when crossed with CETP transgenic mice. 30 Westerterp et al recently demonstrated that in mice bearing the apoE Leiden gene, resulting in defective apoB lipoprotein clearance, CETP expression increases atherosclerosis. 31 Thus, by promoting cholesterol enrichment of ApoB-containing lipoproteins, high plasma CETP activity has proatherogenic effects if the clearance of these particles is impaired.…”

Section: Discussionmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein (CETP) Expression Protects Against Diet Induced Atherosclerosis in SR-BI Deficient Mice

Harder

Lau

Meng

et al. 2007

ATVB

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Objective— To determine whether expression of the human CETP transgene protects against diet-induced atherosclerosis in SR-BI deficient mice. Methods and Results— SR-BI deficient (−/−) mice were crossed with CETP transgenic (CETPtg) mice to produce a colony of SR-BI −/− × CETPtg mice in a C57Bl/6 background. Age and sex matched groups of genetically modified and wild-type C57Bl/6 mice were fed a high fat, high cholesterol diet for 22 weeks. In both wild-type and SR-BI −/− mice, expression of the CETP transgene reduced the cholesterol content and increased the density of lipoprotein particles in the HDL density range. In SR-BI −/− × CETPtg mice, CETP activity inversely correlated with total plasma cholesterol levels and shifted the buoyant HDL typical of SR-BI deficiency toward a more normal density HDL particle. Atherosclerosis at the level of the aortic arch was evident in both male and female SR-BI deficient mice but occurred to a greater extent in the females. Expression of CETP markedly attenuated the development of atherosclerosis in SR-BI deficient mice fed an atherogenic diet ( P <0.003). Conclusions— Expression of the human CETP transgene protects SR-BI deficient mice from atherosclerosis, consistent with a role for CETP in remodeling HDL and providing an alternative pathway for the selective uptake of HDL-CE by the liver.

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“…In wild-type mice as well as in hypercholesterolemic mouse models, overexpression of CETP increased atherosclerosis. 204,205 By contrast, in hypertriglyceridemic mouse models and in mice overexpressing LCAT, CETP overexpression reduced atherosclerosis despite lowering HDL-cholesterol. 204,205 In rabbits, vaccination against CETP 206 as well as CETP inhibition with either JTT705 (= dalcetrapib), 207 torcetrapib, 208 or antisense-nucleotides 209 were found to increase HDL-cholesterol and reduce atherosclerosis.…”

Section: Fibratesmentioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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Increased Atherosclerosis in ApoE and LDL Receptor Gene Knock-Out Mice as a Result of Human Cholesteryl Ester Transfer Protein Transgene Expression

Cited by 214 publications

References 47 publications

Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans

Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans

Cholesteryl Ester Transfer Protein (CETP) Expression Protects Against Diet Induced Atherosclerosis in SR-BI Deficient Mice

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

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