Mechanism of inhibition defines CETP activity: a mathematical model for CETP in vitro

• Published in: Journal of lipid research Vol. 50; no. 11; pp. 2222 - 2234
• Main Authors: Potter, Laura K., Sprecher, Dennis L., Walker, Max C., Tobin, Frank L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2009; American Society for Biochemistry and Molecular Biology; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Algorithms; Animals; Anticholesteremic Agents - pharmacology; Binding Sites; CETP inhibitors; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; Cholesterol Ester Transfer Proteins - metabolism; Cholesterol Esters - metabolism; Cholesterol, HDL - metabolism; Cholesterol, LDL - metabolism; Cholesterol, VLDL - metabolism; cholesteryl ester transfer protein; Computer Simulation; Humans; Kinetics; lipemia; lipoprotein metabolism; Models, Biological; Quinolines - pharmacology; reverse cholesterol transport; Sulfhydryl Compounds - pharmacology; Triglycerides - metabolism; reverse cholesterol transport; lipemia; cholesteryl ester transfer protein; lipoprotein metabolism; CETP inhibitors
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M900015-JLR200

Because cholesteryl ester transfer protein (CETP) inhibition is a potential HDL-raising therapy, interest has been raised in the mechanisms and consequences of CETP activity. To explore these mechanisms and the dynamics of CETP in vitro, a mechanistic mathematical model was developed based upon the shuttle mechanism for lipid transfer. Model parameters were estimated from eight published experimental datasets, and the resulting model captures observed dynamics of CETP in vitro. Simulations suggest the shuttle mechanism yields behaviors consistent with experimental observations. Three key findings predicted from model simulations are: 1) net CE transfer activity from HDL to VLDL and LDL can be significantly altered by changing the balance of homoexchange versus heteroexchange of neutral lipids via CETP; 2) lipemia-induced increases in CETP activity are more likely caused by increases in lipoprotein particle size than particle number; and 3) the inhibition mechanisms of the CETP inhibitors torcetrapib and JTT-705 are significantly more potent than a classic competitive inhibition mechanism with the irreversible binding mechanism having the most robust response. In summary, the model provides a plausible representation of CETP activity in vitro, corroborates strong evidence for the shuttle hypothesis, and provides new insights into the consequences of CETP activity and inhibition on lipoproteins.