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.
Highlights
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
Hamster CETP, which has a markedly higher preference for TG as a substrate compared with all other CETP species, 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 examined the lipid transfer properties of human CETP mutants that have markedly higher preference for TG, or CE, as a substrate compared with wild-type
Summary
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. Hamster CETP, which has a markedly higher preference for TG as a substrate compared with all other CETP species, 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
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