The effect of cholesteryl ester transfer protein overexpression and inhibition on reverse cholesterol transport

Tchoua, Urbain; D’Souza, Wilissa; Mukhamedova, Nigora; Blum, Denise; Niesor, Eric J.; Mizrahi, Jacques; Maugeais, Cyrille; Sviridov, Dmitri

doi:10.1093/cvr/cvm087

Cited by 69 publications

(58 citation statements)

References 29 publications

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“…This method utilizes J774 macrophages labeled in vitro with 3 H-cholesterol and oxidized LDL and monitors the movement of 3 H-tracer into cholesterol and bile acid pools in plasma, liver, and feces following injection into animals. This method has been used in hamsters to examine the effects of several pharmacotherapies on macrophageto-feces RCT, including liver X receptor activation ( 22 ) and CETP inhibition with torcetrapib ( 29 ). To comprehensively assess the effects of a pharmacological intervention on cholesterol handling and excretion, it is important not only to study macrophage-to-feces RCT but also to take into account the bulk movement of cholesterol mass within lipoproteins and in the fecal compartment.…”

Section: Discussionmentioning

confidence: 99%

Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters

Castro-Perez

Briand

Gagen

et al. 2011

Journal of Lipid Research

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Despite therapies such as statins, which reduce circulating levels of low density lipoprotein cholesterol (LDL-C), cardiovascular event rates remain high. Numerous epidemiological studies (e.g., the Framingham Heart Study) indicate that high density lipoprotein cholesterol (HDL-C) levels are inversely correlated with cardiovascular risk ( 1-6 ). Therefore, therapies that increase HDL-C have gained recent attention as possible treatments for dyslipidemia and atherosclerosis.Cholesteryl ester transfer protein (CETP) mediates transfer of cholesteryl ester (CE) and triglyceride (TG) between HDL and apoB-containing lipoproteins such as LDL and therefore, represents an attractive target for increasing HDL-C and reducing LDL-C. Indeed, initial clinical trials with torcetrapib established the validity of CETP inhibition as a mechanism for elevation of HDL-C ( 7, 8 ). However, the phase III outcome trial ILLUMINATE demonstrated that torcetrapib treatment was associated with an increase in cardiovascular events and overall mortality, possibly due to off-target effects on blood pressure and circulating adrenal hormones ( 9 ). A series of preclinical studies further corroborated that torcetrapib had compoundspecifi c off-target activity that was unrelated to CETP inhibition ( 10-12 ).Anacetrapib (ANA) is a potent CETP inhibitor that has not demonstrated the off-target activities of torcetrapib in preclinical or clinical studies ( 10,(13)(14)(15). ANA treatment increases HDL-C by over 100% and lowers LDL-C by 30-40% as a monotherapy and when coadministered with statins ( 13-15 ). In a recent 1.5 year safety study in ‫ف‬ 1,600 patients with cardiovascular disease ( 15 ) Cardiovascular disease continues to be a major contributor to morbidity and mortality throughout the world. 29 July 2011. Published, JLR Papers in Press, August 14, 2011 DOI 10.1194 Manuscript received 13 April 2011 and in revised form

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Section: Discussionmentioning

confidence: 99%

Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters

Castro-Perez

Briand

Gagen

et al. 2011

Journal of Lipid Research

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“…However, animal studies that have been undertaken to demonstrate a direct contribution of CETP in accelerating macrophage to feces RCT have led to contradictory results (14 -18). Studies that reported a role of CETP in RCT have used either [ 3 H]cholesterol-labeled RAW264.7 or J774 cells in their in vivo RCT assay (14,15). These macrophage cell lines do not produce APOE (35).…”

Section: Discussionmentioning

confidence: 99%

“…A kinetic study in humans notably suggested that most of the CE output to liver occurred through APOB-containing lipoproteins, with very little from HDL (13). These data, which favor a role of CETP in promoting RCT, are supported by studies performed in mice overexpressing CETP by adenoviral-or adenoassociated virus-mediated gene transfer (14,15). However, a lack of effect of CETP in modulating RCT in CETP-expressing mice has also been reported and is in contradiction with the latter findings (16 -18).…”

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confidence: 93%

Cholesteryl Ester Transfer Protein Expression Partially Attenuates the Adverse Effects of SR-BI Receptor Deficiency on Cholesterol Metabolism and Atherosclerosis

Bouhassani

Gilibert

Moreau

et al. 2011

Journal of Biological Chemistry

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Scavenger receptor SR-BI significantly contributes to HDL cholesterol metabolism and atherogenesis in mice. However, the role of SR-BI may not be as pronounced in humans due to cholesteryl ester transfer protein (CETP) activity. To address the impact of CETP expression on the adverse effects associated with SR-BI deficiency, we cross-bred our SR-BI conditional knock-out mouse model with CETP transgenic mice. CETP almost completely restored the abnormal HDL-C distribution in SR-BI-deficient mice. However, it did not normalize the elevated plasma free to total cholesterol ratio characteristic of hepatic SR-BI deficiency. Red blood cell and platelet count abnormalities observed in mice liver deficient for SR-BI were partially restored by CETP, but the elevated erythrocyte cholesterol to phopholipid ratio remained unchanged. Complete deletion of SR-BI was associated with diminished adrenal cholesterol stores, whereas hepatic SR-BI deficiency resulted in a significant increase in adrenal gland cholesterol content. In both mouse models, CETP had no impact on adrenal cholesterol metabolism. In diet-induced atherosclerosis studies, hepatic SR-BI deficiency accelerated aortic lipid lesion formation in both CETP-expressing (4-fold) and non-CETP-expressing (8-fold) mice when compared with controls. Impaired macrophage to feces reverse cholesterol transport in mice deficient for SR-BI in liver, which was not corrected by CETP, most likely contributed by such an increase in atherosclerosis susceptibility. Finally, comparison of the atherosclerosis burden in SR-BI liver-deficient and fully deficient mice demonstrated that SR-BI exerted an atheroprotective activity in extra-hepatic tissues whether CETP was present or not. These findings support the contention that the SR-BI pathway contributes in unique ways to cholesterol metabolism and atherosclerosis susceptibility even in the presence of CETP.Epidemiological studies have demonstrated that high density lipoprotein cholesterol is a strong, independent, inverse predictor of the risk of coronary heart disease. High plasma levels of the major apolipoprotein of HDL, APOA-I, have been also shown to predict decreased risk of coronary heart disease. One major atheroprotective mechanism by which HDL/APOA-I may protect against atherosclerosis involves the transport of excess cholesterol from peripheral tissues, including macrophages, to the liver, bile, and eventually feces for excretion, a process known as reverse cholesterol transport.The scavenger receptor SR-BI is an 82-kDa glycosylated plasma membrane protein that binds HDL/APOA-I with high affinity and stimulates the bi-directional flux of cholesterol between cells and extracellular HDL particles. In mice, SR-BI, encodeed by the Scarb1 gene, is a major determinant of HDL metabolism in mice and is protective against atherosclerosis. Indeed, hepatic overexpression of SR-BI markedly reduces plasma HDL-C levels, increases biliary secretion of cholesterol, and decreases atherosclerosis (1-3), whereas deficiency of this receptor resu...

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“…212 The treatment of hamsters with torcetrapib increased the mobilization of radiolabeled cholesterol from peritoneal macrophages into plasma HDL and subsequent excretion into stool. 213,214 Dalcetrapib: Results of a phase IIb study comparing different doses of dalcetrapib in dyslipidemic patients treated with pravastatin (40 mg/day) indicated a positive effect of dalcetrapib on ABCA1-and SR-BI-mediated cellular cholesterol removal. 215 Likewise, in the dal-ACUTE study that enrolled 300 patients who had a recent ACS, dalcetrapib at a daily dose of 600 mg enhanced the capacity of apoB-depleted plasma to elicit non-ABCA1-specific cholesterol efflux from macrophage foam cells, which was related to changes in apoA-I and HDL-cholesterol levels.…”

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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The effect of cholesteryl ester transfer protein overexpression and inhibition on reverse cholesterol transport

Abstract: Both increased (mice study) and decreased (hamster study) CETP activity could result in enhanced RCT.

Cited by 69 publications

References 29 publications

Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters

Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters

Cholesteryl Ester Transfer Protein Expression Partially Attenuates the Adverse Effects of SR-BI Receptor Deficiency on Cholesterol Metabolism and Atherosclerosis

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

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