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Journal of Lipid Research, Vol. 44, 2287-2296, December 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

CETP and lipid transfer inhibitor protein are uniquely affected by the negative charge density of the lipid and protein domains of LDL

Richard E. Morton¹ and Diane J. Greene

Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH

¹ To whom correspondence should be addressed. e-mail: mortonr{at}ccf.org

Lipoprotein surface charge influences cholesteryl ester transfer protein (CETP) activity and its association with lipoproteins; however, the relationship between these events is not clear. Additionally, although CETP and its regulator, lipid transfer inhibitor protein (LTIP), bind to lipoproteins, it is not known how the charge density of lipoprotein protein and lipid domains influences these factors. Here, the electronegativity of the protein (by acetylation) and surface lipid (oleate addition) domains of LDL were modified. LDL-only lipid transfer assays measured changes in CETP and LTIP activities. CETP activity was stimulated by <10 µM oleate but completely suppressed by >20 µM. The same electronegative potential induced by acetylation mildly stimulated CETP. Modification-induced enhanced binding of CETP did not correlate with CETP activity. LTIP activity was completely blocked by 10 µM oleate but only mildly suppressed by acetylation. LTIP binding to LDL was not decreased by oleate.

Thus, the negative charge of LDL surface lipids, but not protein, is an important regulator of CETP and LTIP activity. Altered binding could not explain changes in CETP activity, suggesting that the extent of CETP binding is not normally rate limiting to its activity. Physiologic and pathophysiologic conditions that modify the negative charge of lipoprotein surface lipids will suppress LTIP activity first, followed by CETP.

Abbreviations: CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; LTIP, lipid transfer inhibitor protein; REM, relative electrophoretic mobility

Supplementary key words surface charge • binding kinetics • cholesteryl ester transfer protein

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