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Journal of Lipid Research, Vol. 49, 1529-1537, July 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Control of cholesteryl ester transfer protein activity by sequestration of lipid transfer inhibitor protein in an inactive complex^*

Yubin He¹, Diane J. Greene, Michael Kinter and Richard E. Morton²

Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195

^* This research was supported in part by Grant HL-60934 from the National Heart, Lung, and Blood Institute, National Institutes of Health.

Published, JLR Papers in Press, March 27, 2008.

¹ Current address of Y. He: Department of Cardiology, General Hospital of B.M.C., No. 5, Nan Men Cang, Dong Cheng District, Beijing, 100700, China.

² To whom correspondence should be addressed. e-mail: mortonr{at}ccf.org

Lipid transfer inhibitor protein (LTIP) is a physiologic regulator of cholesteryl ester transfer protein (CETP) function. We previously reported that LTIP activity is localized to LDL, consistent with its greater inhibitory activity on this lipoprotein. With a recently described immunoassay for LTIP, we investigated whether LTIP mass is similarly distributed. Plasma fractionated by gel filtration chromatography revealed two LTIP protein peaks, one coeluting with LDL, and another of 470 kDa. The 470 kDa LTIP complex had a density of 1.134 g/ml, indicating 50% lipid content, and contained apolipoprotein A-I. By mass spectrometry, partially purified 470 kDa LTIP also contains apolipoproteins C-II, D, E, J, and paraoxonase 1. Unlike LDL-associated LTIP, the 470 kDa LTIP complex does not inhibit CETP activity. In normolipidemic subjects, 25% of LTIP is in the LDL-associated, active form. In hypercholesterolemia,this increases to 50%, suggesting that lipoprotein composition may influence the status of LTIP activity. Incubation (37°C) of normolipidemic plasma increased active, LDL-associated LTIP up to 3-fold at the expense of the inactive pool. Paraoxon inhibited this shift by 50%. Overall, these studies show that LTIP activity is controlled by its reversible incorporation into an inactive complex. This may provide for short-term fine-tuning of lipoprotein remodeling mediated by CETP.

Supplementary key words apolipoprotein F • fast-protein liquid chromatography • gel filtration • apolipoprotein A-I • mass spectrometry • hypercholesterolemia

Abbreviations: CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; FPLC, fast-protein liquid chromatography; LC-tandem MS, liquid chromatography-tandem mass spectrometry; LTIP, lipid transfer inhibitor protein; PLTP, phospholipid transfer protein; TG, triglyceride

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