Biochemical characterization of cholesteryl ester transfer protein inhibitors

Ranalletta, Mollie; Bierilo, Kathleen K.; Chen, Ying; Milot, Denise P.; Chen, Qing; Tung, Elaine C.; Houde, Caroline; Elowe, Nadine H.; García‐Calvo, Margarita; Porter, Gene; Eveland, Suzanne S.; Frantz-Wattley, Betsy; Kavana, Mike; Addona, George H.; Sinclair, Peter J.; Sparrow, Carl P.; O’Neill, Edward A.; Koblan, Ken S.; Sitlani, Ayesha; Hubbard, Brian K.; Fisher, Timothy S.

doi:10.1194/jlr.m007468

Cited by 95 publications

(98 citation statements)

References 78 publications

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“…3). This is in excellent agreement with reported IC 50 values: ‫ف‬ 17 nM (isolated lipoproteins) and ‫ف‬ 50 nM (95% human serum) ( 26 ), which convert to from VLDL to HDL (blue) is generally 4-fold greater than TG fl ux from LDL to HDL (red), consistent with the estimate that f c VLDL > f c LDL ( 29 ). Furthermore, the dominance of VLDL-TG transfer is abolished in the presence of anacetrapib ( Fig.…”

Section: The Mean Forsupporting

confidence: 81%

Evaluation of CETP activity in vivo under non-steady-state conditions: influence of anacetrapib on HDL-TG flux

McLaren

Previs

Phair³

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org ( 3,4 ) identifi ed a single lipid transfer protein in human plasma that was capable of carrying out this apparent heterolipid exchange and that is known today as cholesteryl ester transfer protein (CETP). In these and other reports, the exchange of HDL-CE for apoB-lipoprotein-TG was evaluated in vitro using lipoproteins containing radiolabeled CE and/or TG. Using this approach, the effects of donor and acceptor lipid composition ( 4 ), hypercholesterolemia ( 5 ), and many other parameters on CETP-mediated neutral lipid exchange have been assessed. The CETPmediated exchange of neutral lipids between lipoproteins in vivo has also been studied ( 6-9 ). In such cases, the experimental protocol typically involves injection of lipoprotein particles, radiolabeled with CE either in vitro or in vivo, into subjects followed by collection of blood samples for further analysis. Transfer activity is then evaluated by measuring the loss of enrichment from the donor particle and increase in enrichment of acceptor particles that were isolated from the postinjection blood samples.We hypothesized that the movement of TG from apoB lipoproteins to HDL could serve as a quantifi able activity measurement in vivo that would not require prior isolation and reinjection of donor particles. As noted, although the protein is commonly referred to as "cholesteryl ester transfer protein," the transfer of TG also occurs; this should allow an experimental protocol to be designed based on well-characterized methods for labeling TGs in free-living subjects. Lipoprotein TG kinetics have been studied for at least 30 years using both radioisotopes and stable isotopes to label the fatty acid precursors or the glycerol backbone. In the majority of cases, the goals of such studies have been determination of the fl ux (mass per unit Nichols and Smith ( 1 ) were the fi rst to observe that cholesteryl esters (CEs) could be transferred from HDL to apoB-containing lipoproteins in exchange for TG in incubated human serum, a fi nding later confi rmed by Hopkins and Barter ( 2 ). Subsequent investigations by Morton et al.

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Section: The Mean Forsupporting

confidence: 81%

Evaluation of CETP activity in vivo under non-steady-state conditions: influence of anacetrapib on HDL-TG flux

McLaren

Previs

Phair³

et al. 2016

Journal of Lipid Research

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“…Because CETP defi ciency increases HDL levels, there has been much interest in developing pharmacologic CETP inhibitors. Thus far, CETP inhibitors studied in clinical trials equally inhibit the CETP-mediated transfer of both TG and CE ( 37 ). To date, this approach has not shown any clinical benefi t ( 38 ), suggesting that global suppression of CETP activity may not be a…”

Section: Discussionmentioning

confidence: 99%

Modification of CETP function by changing its substrate preference: a new paradigm for CETP drug design

Morton

Izem

2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org lipoproteins is altered, but the amount of this lipid in a lipoprotein particle is unchanged. Changes in core lipid composition alter the biological properties of lipoproteins and modify their catabolism ( 3,(6)(7)(8)(9).We recently compared the lipid transfer properties of human CETP with CETP from three other species ( 10 ). Compared with human CETP, the relative preference for TG as a transfer substrate instead of CE was higher in monkey, rabbit, and hamster CETPs. Like human CETP, these CETP species promoted both lipid homoexchange, where the same lipid species is transferred between two lipoproteins, and the heteroexchange of lipids as described above. However, hamster CETP, which has a markedly higher preference for TG as a substrate compared with all other CETP species, also facilitated a unique lipid transfer event where the transfer of TG from VLDL to HDL was not coupled to the return of lipid to VLDL, causing HDL to have a net gain in core lipid. We refer to this as nonreciprocal lipid transfer.Hamster CETP has ‫ف‬ 80% amino acid homology with human CETP ( 10 ). It seems reasonable that the capacity of hamster CETP to promote nonreciprocal lipid transfer arises from a different molecular structure due to the 66 nonconservative amino acid substitutions between these species. However, Qiu et al. ( 11 ) demonstrated that a Q199A mutation in human CETP signifi cantly alters its relative preference for TG versus CE as substrate, resulting in a TG/CE preference ratio similar to that of hamster CETP ( 10, 11 ). Because it is unlikely that this glutamine to alanine substitution induces global changes in the CETP structure, this observation provides an opportunity to test the hypothesis that human CETP can be induced to promote nonreciprocal lipid transfer activity if its lipid substrate preference is altered to mirror that of hamster CETP . Hence, we propose that nonreciprocal lipid transfer occurs in hamster CETP because of its high preference for TG over CE, not because its many amino acid differences have induced large-scale structural changes that endow it with the unique ability to promote nonreciprocal transfer. Cholesteryl ester transfer protein (CETP) plays an important role in human lipoprotein metabolism ( 1-4 ). CETP alters lipoprotein composition by its ability to promote lipid heteroexchange. This involves the transfer of TG from TG-rich lipoproteins, such as VLDL, to cholesteryl ester (CE)-rich lipoproteins, such as HDL, in return for an equimolar transfer of CE in the opposite direction ( 5 ). As a result, the core lipid (CE and TG) composition of

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“…The precise mechanism by which anacetrapib inhibits CETP is not known, although, like torcetrapib, it promotes a tight binding of CETP to HDL particles ( 85 ). This immobilizes CETP, making it unavailable to shuttle cholesteryl esters between lipoprotein particles.…”

Section: Anacetrapibmentioning

confidence: 99%

“…This immobilizes CETP, making it unavailable to shuttle cholesteryl esters between lipoprotein particles. Anacetrapib, torcetrapib, and dalcetrapib compete with one another for binding CETP ( 85 ), although it remains uncertain how this relates to the mechanism of action of any of these agents.…”

Section: Anacetrapibmentioning

confidence: 99%

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

Barter

Rye

2012

Journal of Lipid Research

133

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Biochemical characterization of cholesteryl ester transfer protein inhibitors

Cited by 95 publications

References 78 publications

Evaluation of CETP activity in vivo under non-steady-state conditions: influence of anacetrapib on HDL-TG flux

Evaluation of CETP activity in vivo under non-steady-state conditions: influence of anacetrapib on HDL-TG flux

Modification of CETP function by changing its substrate preference: a new paradigm for CETP drug design

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

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