Abstract-Cholesteryl ester transfer protein (CETP) catalyzes the net transfer of cholesteryl ester (CE) between lipoproteins in exchange for triglyceride (heteroexchange). It is generally held that CETP primarily associates with HDL and preferentially transfers lipids from this lipoprotein fraction. This is illustrated in normal plasma where HDL is the primary donor of the CE transferred to VLDL by CETP. However, in plasma deficient in lipid transfer inhibitor protein (LTIP) activity, HDL and LDL are equivalent donors of CE to VLDL (Arterioscler Thromb Vasc Biol. 1997;17:1716 -1724. Thus, we have hypothesized that the preferential transfer of CE from HDL in normal plasma is a consequence of LTIP activity and not caused by a preferential CETP-HDL interaction. We have tested this hypothesis in lipid mass transfer assays with partially purified CETP and LTIP, and isolated lipoproteins. With a physiological mixture of lipoproteins, the preference ratio (PR, ratio of CE mass transferred from a lipoprotein to VLDL versus its CE content) for HDL and LDL in the presence of CETP alone was Ϸ1 (ie, no preference). Fourfold variations in the LDL/HDL ratio or in the levels of HDL in the assay did not result in significant preferential transfer from any lipoprotein. On addition of LTIP, the PR for HDL was increased up to 2-fold and that for LDL decreased in a concentration-dependent manner.Under all conditions where LDL and HDL levels were varied, LTIP consistently resulted in a PR Ͼ1 for CE transfer from HDL. Short-term experiments with radiolabeled lipoproteins and either partially purified or homogenous CETP confirmed these observations and further demonstrated that CETP has a strong predilection to mediate homoexchange (bidirectional transfer of the same lipid) rather than heteroexchange (CE for TG); LTIP had no effect on the selection of CE or TG by CETP or its mechanism of action. The ability of CETP to facilitate the remodeling of lipoprotein composition endows an important role to this protein in the intravascular metabolism of lipoproteins. CETP participates in determining the ratio of HDL 2 to HDL 3 , 3-5 facilitates the loss of apo A-I from ␣-migrating HDL resulting in an increase of pre␤ HDL, 6 and enhances reverse cholesterol transport. 2,7,8 CETP also affects the level of LDL subfractions and their interaction with the LDL receptor, 9 -13 and facilitates the conversion of VLDL to LDL. 1,14 Many of these observations have been verified and extended through studies of humans who are genetically deficient in CETP 15,16 and in transgenic mice bearing the CETP transgene. 17,18 Overall, CETP activity significantly influences the structure and function of the lipoproteins with which it interacts.We and others have suggested that the function of CETP, that is, its capacity to affect changes in the composition of individual lipoprotein fractions, is modulated by a second plasma protein, lipid transfer inhibitor protein (LTIP). 19 -24 LTIP is a LDL-associated protein of ϳ30 kd that preferentially reduces the action of C...

We previously demonstrated that lipid transfer inhibitor protein (LTIP) is a potent modifier of lipid transfer protein (LTP) function in vitro. Based on these studies, we proposed that LTIP activity is an important determinant of lipoprotein size and composition, which leads to a stimulation of reverse cholesterol transport. To further evaluate this hypothesis, we have studied a normolipidemic, uremic patient population undergoing continuous ambulatory peritoneal dialysis (CAPD) that is deficient in LTIP activity (< 18% of control). LDL from CAPD plasma was triglyceride enriched; the diameters of both CAPD LDL and HDL were increased and CAPD HDL was dominated by the largest subfraction, HDL2b. In CAPD patients, the plasma cholesterol esterification rate was only 61% of control; this decrease was due mainly to the poor reactivity of CAPD lipoproteins. CAPD lipoprotein-deficient plasma promoted twofold greater transfer of radiolabeled cholesteryl ester (CE) between standard lipoproteins than control, although LTP itself was increased only 39%. This twofold increase was not equally expressed among individual lipoprotein classes; CE transfers involving LDL were increased 2.4-fold, whereas those not involving LDL were increased only 50%. In whole plasma, CE net mass transfer to VLDL was slightly increased in CAPD plasma; relative to their CE content, control HDL contributed twofold more CE mass to VLDL than control LDL, but in CAPD plasma this preferential transfer of CE from HDL was absent. Collectively, the aberrations in CAPD lipoprotein composition and metabolism are consistent with the hypothesized role of LTIP. The data further support the role of LTIP in modulating the participation of HDL in CE mass transfers to VLDL. This is the first report of LTIP activity deficiency in humans.

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We analyzed subfraction composition of HDL and cholesterol-acceptor properties of the plasma in Russian men with high and low HDL cholesterol. HDL were subfractionated by two-dimensional electrophoresis in agarose-polyacrylamide gel. The content of pre-beta1 HDL increased in individuals with high concentration of HDL cholesterol and strictly correlated with acception of cellular cholesterol in both groups.