HDL biology
ApoCI blocks CETP by disrupting CETP-HDL binding through its electrostatic C-terminal helix (J Biol Chem 2005)
Original title: Molecular mechanism of the blockade of plasma cholesteryl ester transfer protein by its physiological inhibitor apolipoprotein CI
Building on evidence that apolipoprotein CI (apoCI) is a potent physiological inhibitor of CETP, researchers investigated the molecular mechanism of this blockade. The inhibitory effect of apoCI depended on the amount of HDL present, not on the amount of active CETP, and increasing apoCI progressively altered the electrostatic charge of HDL, its main plasma carrier; neutralizing apoCI lysine residues by acetylation markedly reduced its inhibitory potency. The C-terminal alpha-helix of apoCI, which carries significant electrostatic properties, reproduced the inhibitory activity of the full-length protein, while the N-terminal helix, which does not alter HDL electronegativity, had no CETP-inhibitory effect; binding experiments showed apoCI and its C-terminal helix disrupt CETP-lipoprotein complexes in a concentration-dependent manner. The authors conclude apoCI inhibits CETP through electrostatic modification of HDL that weakens CETP-HDL binding and reduces cholesteryl ester transfer.
Original abstract
Genetically engineered mice demonstrated that apolipoprotein (apo) CI is a potent, physiological inhibitor of plasma cholesteryl ester transfer protein (CETP) activity. The goal of this study was to determine the molecular mechanism of the apoCI-mediated blockade of CETP activity. Kinetic analyses revealed that the inhibitory property of apoCI is independent of the amount of active CETP, but it is tightly dependent on the amount of high density lipoproteins (HDL) in the incubation mixtures. The electrostatic charge of HDL, i.e. the main carrier of apoCI in human plasma, is gradually modified with increasing amounts of apoCI, and the neutralization of apoCI lysine residues by acetylation produces a marked reduction in its inhibitory potential. The inhibitory property of full-length apoCI is shared by its C-terminal alpha-helix with significant electrostratic properties, whereas its N-terminal alpha-helix with no CETP inhibitory property has no effect on HDL electronegativity. Finally, binding experiments demonstrated that apoCI and to a lower extent its C-terminal alpha-helix are able to disrupt CETP-lipoprotein complexes in a concentration-dependent manner. It was concluded that the inhibition of CETP activity by apoCI is in direct link with its specific electrostatic properties, and the apoCI-mediated reduction in the binding properties of lipoproteins results in weaker CETP-HDL interactions and fewer cholesteryl ester transfers.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.