Submitted on February 19, 2008
Revised on March 20, 2008
Accepted on March 20, 2008
Control of cholesteryl ester transfer protein activity by sequestration of lipid transfer inhibitor protein in an inactive complex
Yubin He, Diane J Greene, Michael Kinter, and Richard E Morton
Cell Biology, Cleveland Clinic Foundation, Cleveland, OH 44195
Corresponding Author: 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 co-eluting with LDL, and another of ~470kDa. The 470kDa LTIP complex had a density of 1.134 g/ml, indicating ~50% lipid content, and contained apolipoprotein A-I. By mass spectrometry, partially purified 470kDa LTIP also contains apolipoproteins C-II, D, E, J, and paraoxonase 1. Unlike LDL-associated LTIP, the 470kDa LTIP complex does not inhibit CETP activity. In normolipidemic subjects, ~25% of LTIP is in the LDL-associated, active form. In hypercholesterolemia, this increased 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.
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