Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk

Barter, Philip J.; Rye, Kerry Anne

doi:10.1194/jlr.r024075

Cited by 133 publications

(93 citation statements)

References 92 publications

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“…Although many epidemiologic studies have linked elevated levels of HDL-C to a decreased atherosclerotic risk ( 59,60 ), there is evidence in some settings that elevated levels of HDL can in fact be detrimental (61)(62)(63)(64). To date, the mixed results seen in the trials using CETP inhibitors ( 65 ) and niacin ( 66,67 ) also suggest that simply elevating the cholesterol content of HDL does not necessarily improve cardiovascular outcomes ( 65 ). It was previously demonstrated that Scarab ( Ϫ / Ϫ ) mice, which have very high levels of HDL-C, in fact, develop more atherosclerosis ( 27,28,47,52 ).…”

Section: Discussionmentioning

confidence: 99%

Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice

Thacker

Rousset

Esmail

et al. 2015

Journal of Lipid Research

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Section: Discussionmentioning

confidence: 99%

Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice

Thacker

Rousset

Esmail

et al. 2015

Journal of Lipid Research

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“…CETP is also synthesized mainly in the liver and is secreted into plasma where it promotes bidirectional transfers and, thus, equilibration of both cholesteryl esters and triglyceride between plasma lipoprotein particles ( 11 ). Because most of the cholesteryl esters in plasma originate in the HDL fraction, this equilibration results in a net mass transfer of cholesteryl esters from HDL to the VLDL and LDL fractions.…”

mentioning

confidence: 99%

Reduction in PCSK9 levels induced by anacetrapib: an off-target effect?

Barter

Tabet

Rye

2015

Journal of Lipid Research

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“…Most recently, the focus has been on the potential for positive outcomes of CETP inhibition ( 17,19,20 ). Because CETP inhibitors appear to have confl icting biochemical activities with respect to CVD and because two recent large, international clinical trials have failed to show effi cacy, an improved understanding of CETP's molecular interactions could be benefi cial to more defi nitive descriptions of CETP function and drug design.…”

mentioning

confidence: 99%

New molecular insights into CETP structure and function: a review

Charles

Kane

2012

Journal of Lipid Research

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CETP is capable of proatherogenic activities during remodeling through both triglyceride and cholesteryl ester (CE) pathways. CETP mediates transfer of triglycerides from VLDL-1 to HDL and/or LDL in exchange for CE, resulting in larger, relatively triglyceride-enriched HDL and LDL species ( 3,4 ). Hepatic lipase remodels these larger lipoprotein species into i ) smaller and denser HDL remnants destined for removal from the circulation by the hepatic holo receptor and/or by renal clearance ( 5 ) and ii ) smaller, denser LDL destined for the subendothelial space of arteries to initiate plaque formation, as these LDL species react weakly with LDL receptors, thus prolonging their half-lives ( 6-8 ). These pathological endpoints are observed clinically as circulating i ) high normal to moderately elevated triglyceride levels, ii ) low total HDL cholesterol (HDL-C) levels, and iii ) high levels of small, dense LDL. This triad is referred to as the atherogenic lipid profi le, which is observed in ‫ف‬ 25% of the general population in Western countries due to insulin resistance, including type 2 diabetes ( 9, 10 ).Further, but related, proatherogenic activity for CETP involves its redirection of CE to more atherogenic lipoprotein species, rather than to direct CE disposal by the liver via SRB-1 or the LDL receptor ( 4, 6 ). The latter two, in part, mediate reverse cholesterol transport (RCT), in which cholesterol obtained from peripheral tissue is esterifi ed by LCAT. Most CEs derived from LCAT do not return to the liver via the HDL SRB-1 pathway but, rather, through more atherogenic pathways ( 4, 7 ). CETP mediates the transfer of most CE from HDL to VLDL or to other more atherogenic intermediate-density lipoproteins and remnants ( 3 ). Apolipoprotein F may inhibit direct transfer of some, but not all, of CE from HDL to the potentially more atherogenic LDL ( 11 ). Inhibiting the above two proatherogenic remodeling events could be advantageous. Indeed, in vitro studies using human plasma indicate an anti- Recent innovative X-ray crystallographic, electron microscopic (EM), and bioinformatics observations signifi cantly improve our understanding of the physical relationships of cholesteryl ester transfer protein's (CETP) interactions with lipoproteins and lipid transfer processes ( 1, 2 ). Two major observations derived using these novel methods are i ) CETP connects with or forms bridges between two lipoproteins, e.g., HDL and LDL, with resultant neutral lipid transfer, and ii ) CETP appears to contain a hydrophobic tunnel along its entire long axis capable of neutral lipid transfer. Using this new paradigm, prior data regarding CETP and lipoprotein interactions can be reevaluated from current perspectives. Here, we focus on molecular details of CETP that appear relevant to its interactions with lipoproteins, including sensing, penetration, docking, selectivity, ternary complex formation, lipid transfer, and HDL dissociation. Abstract Cholesteryl ester transfer protein (CETP) is im-First, a summary of the biological and ...

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Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk

Cited by 133 publications

References 92 publications

Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice

Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice

Reduction in PCSK9 levels induced by anacetrapib: an off-target effect?

New molecular insights into CETP structure and function: a review

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