HDL biologyLandmark
The Morton lab introduces substrate-preference modification as a new paradigm for engineering CETP-targeting drugs (J Lipid Res 2015)
Original title: Modification of CETP function by changing its substrate preference: a new paradigm for CETP drug design
Building on the discovery that hamster cholesteryl ester transfer protein (CETP), unlike human CETP, promotes a novel one-way transfer of triglyceride from VLDL to HDL, this study tested whether this nonreciprocal transfer arises from the unusually high triglyceride-to-cholesteryl-ester substrate preference of hamster CETP. Approximately 25% of total lipid transfer by the human Q199A CETP mutant, which prefers triglyceride as substrate, was nonreciprocal, and other human CETP mutants with higher or lower triglyceride-to-cholesteryl-ester preference than wild type also showed nonreciprocal transfer, moving triglyceride from VLDL to HDL when preference was high and cholesteryl ester in reverse, from HDL to VLDL, when preference was low. The anti-CETP TP2 antibody altered the substrate preference of CETP and the extent of nonreciprocal transfer, showing that external agents can modify the transfer properties of CETP, establishing substrate-preference modification as a novel paradigm for CETP-targeting drug design.
Original abstract
We previously determined that hamster cholesteryl ester transfer protein (CETP), unlike human CETP, promotes a novel one-way transfer of TG from VLDL to HDL, causing HDL to gain lipid. We hypothesize that this nonreciprocal lipid transfer activity arises from the usually high TG/cholesteryl ester (CE) substrate preference of hamster CETP. Consistent with this, we report here that ∼25% of the total lipid transfer promoted by the human Q199A CETP mutant, which prefers TG as substrate, is nonreciprocal transfer. Other human CETP mutants with TG/CE substrate preferences higher or lower than wild-type also possess nonreciprocal lipid transfer activity. Mutants with high TG/CE substrate preference promote the nonreciprocal lipid transfer of TG from VLDL to HDL, but mutants with low TG/CE substrate preference promote the nonreciprocal lipid transfer of CE, not TG, and this lipid flow is in the reverse direction (from HDL to VLDL). Anti-CETP TP2 antibody alters the TG/CE substrate preference of CETP and also changes the extent of nonreciprocal lipid transfer, showing the potential for externally acting agents to modify the transfer properties of CETP. Overall, these data show that the lipid transfer properties of CETP can be manipulated. Function-altering pharmaceuticals may offer a novel approach to modify CETP activity and achieve specific modifications in lipoprotein metabolism.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.