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

Abstract

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

LDL Receptor Gene-ablated Hamsters: A Rodent Model of Familial Hypercholesterolemia With Dominant Inheritance and Diet-induced Coronary Atherosclerosis

“…However, in contrast to FH patients, the cholesterol concentration in the VLDL fraction is higher in chow diet-fed homozygous Ldlr KO hamsters than in humans. As CETP is highly expressed in hamsters, in which the transfer capacity of TG to CE is highest compared to other species ( Morton and Izem 2015 ), we speculate that the complete loss of Ldlr in the hamster can affect CETP expression and activity through unknown molecular mechanisms, leading to cholesterol accumulation in very large lipoproteins, such as VLDLs.…”

HDL cholesterol: reappraisal of its clinical relevance

“…Future strategies may include the identification of patients who benefit from CETP inhibition. Another alternative approach would be the development of new inhibitors that reduce CETP production or modification of CETP function [ 109 ].…”

The lipid substrate preference of CETP controls the biochemical properties of HDL in fat/cholesterol-fed hamsters

“…Another factor influencing the extent to which CETP modifies lipoproteins is the relative preference of CETP itself for CE versus TG as a substrate. Mutations of single amino acid residues in CETP are sufficient to change its preference for CE versus TG as a substrate ( 4 ), which alters the redistribution of these lipids between TG- and CE-rich lipoproteins ( 5 ). This suggests that the equilibrium point for CETP-dependent redistribution of CE and TG among lipoproteins is, at least in part, controlled by the preference of CETP for its different lipid substrates.…”