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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