Determination of lipid transfer inhibitor protein activity in human lipoprotein-deficient plasma.

Morton, Richard E.; Steinbrunner, Jeffrey V.

doi:10.1161/01.atv.13.12.1843

Cited by 82 publications

(119 citation statements)

References 33 publications

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“…The decrease observed in CET could result from a reduction in the free cholesterol content of lipoproteins, which has been shown to be a major regulator of CET, 13 or an increase in the activity of a CETP inhibitory protein. 50 Further studies are required to assess these possibilities. Preliminary observations showing that the same abnormalities in CET and lipoprotein core lipids in IDDM patients 14 -15 persist following successful pancreas transplantation, 51 when the patients are no longer diabetic but continue to be hyperinsulinemic, 52 are consistent with the present findings.…”

Section: Discussionmentioning

confidence: 99%

Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus.

Bagdade

Dunn

Eckel

et al. 1994

Arterioscler Thromb

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Patients with insulin-dependent diabetes mellitus (IDDM) have proatherogenic disturbances in cholesteryl ester transfer (GET) despite intensive subcutaneous insulin therapy (ISC). Since CET is activated by insulin-sensitive lipoprotein lipase (LPL), which normally increases postprandially, we queried whether iatrogenic hyperinsulinism from ISC stimulated LPL and CET by studying well-controlled IDDM patients after ISC and then 6 months after lowering systemic insulin levels by intraperitoneal (IP) insulin delivery. Although glycemic control (HbA,c IDDM, 6.9±1.7%; control, 4.5% to 8%) was excellent during ISC, CET was accelerated (P<.001) and both systemic insulin levels and LPL specific activity were increased (P< .05). Following IP, basal systemic insulin levels declined by more than one half (ISC, 8.22±6.5 versus IP, 2.77±2.4 ^iU/mL; mean±SD; P<.025), and both LPL and CET activities returned to normal. Plasma triglyceride, cholesterol, high-density lipoprotein-2 (HDL 2 ) cholesterol, HDL, cholesterol, cholesteryl ester transfer protein mass, and glyce-A ssiduous diabetic management can reduce the /\ prevalence of the renal and retinal microvascu-.Z \-lar and neuropathic complications of insulindependent diabetes mellitus (IDDM) 12 but not the premature morbidity and mortality attributable to cardiovascular disease. The failure of rigorous glycemic control achieved with multiple daily injections of insulin to slow the development of diabetic macrovascular disease has led to the suspicion that the hyperinsulinemia that inevitably results from insulin therapy might actually promote atherogenesis. C 1994 American Heart Association, Inc.mic control (HbA,c, 6.3±0.8%) were unchanged and remained normal. These findings indicate that ISC is associated with high levels of basal CET and LPL. These alterations both appear to be closely linked to iatrogenic hyperinsulinemia resulting from ISC. The fact that they are both reversed when systemic insulin levels are reduced by IP suggests that insulin, acting through LPL, influences the nature of the interaction of the lipoproteins engaged in CET. Since accelerated CET is believed to result in the enrichment of certain subpopulations of apolipoprotein B-containing lipoproteins with cholesteryl ester, an alteration presumed to enhance their atherogenicity, its correction by IP therapy suggests that this more physiological mode of insulin delivery may reduce cardiovascular risk in IDDM. (Arterioscler Thromb. 1994;14:1933-1939

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Section: Discussionmentioning

confidence: 99%

Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus.

Bagdade

Dunn

Eckel

et al. 1994

Arterioscler Thromb

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“…Lipoproteins were extensively dialyzed against 0.9% NaCl, 0.01% EDTA, 0.02% NaN 3 , pH 7.4, and stored at 4°C. Radiolabeled lipoproteins were prepared by CETP-induced transfer (15) of [1␣,2␣(n)-3 H]cholesteryl oleate (48.0 Ci/mmol, Amersham Biosciences) from phosphatidylcholine cholesterol-[ 3 H]CE liposomes prepared as previously described (36). After the labeling procedure, VLDL and LDL were isolated by affinity chromatography on heparin-Sepharose (15), whereas HDL 2 and HDL 3 were re-isolated within their original density intervals by ultracentrifugation.…”

Section: Methodsmentioning

confidence: 99%

“…Consequently, in the absence of other factors, LDL is the most active donor of CE to VLDL due to the relative abundance of CE in this lipoprotein in normal plasma. However, CETP activity is controlled by several apolipoproteins including lipid transfer inhibitor protein (LTIP) (15)(16)(17)(18)(19). LTIP has been purified and characterized as an acidic glycoprotein with a molecular mass of 33 kDa (17,20).…”

mentioning

confidence: 99%

Lipid Transfer Inhibitor Protein Defines the Participation of High Density Lipoprotein Subfractions in Lipid Transfer Reactions Mediated by Cholesterol Ester Transfer Protein (CETP)

Paromov

Morton

2003

Journal of Biological Chemistry

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Cholesterol ester transfer protein (CETP) moves triglyceride (TG) and cholesteryl ester (CE) between lipoproteins. CETP has no apparent preference for high (HDL) or low (LDL) density lipoprotein as lipid donor to very low density lipoprotein (VLDL), and the preference for HDL observed in plasma is due to suppression of LDL transfers by lipid transfer inhibitor protein (LTIP).Given the heterogeneity of HDL, and a demonstrated ability of HDL subfractions to bind LTIP, we examined whether LTIP might also control CETP-facilitated lipid flux among HDL subfractions. CETP-mediated CE transfers from [ 3 H]CE VLDL to various lipoproteins, combined on an equal phospholipid basis, ranged 2-fold and followed the order: HDL 3 > LDL > HDL 2 . LTIP inhibited VLDL to HDL 2 transfer at one-half the rate of VLDL to LDL. In contrast, VLDL to HDL 3 transfer was stimulated, resulting in a CETP preference for HDL 3 that was 3-fold greater than that for LDL or HDL 2 . Long-term mass transfer experiments confirmed these findings and further established that the previously observed stimulation of CETP activity on HDL by LTIP is due solely to its stimulation of transfer activity on HDL 3 . TG enrichment of HDL 2 , which occurs during the HDL cycle, inhibited CETP activity by ϳ2-fold and LTIP activity was blocked almost completely. This suggests that LTIP keeps lipid transfer activity on HDL 2 low and constant regardless of its TG enrichment status. Overall, these results show that LTIP tailors CETP-mediated remodeling of HDL 3 and HDL 2 particles in subclass-specific ways, strongly implicating LTIP as a regulator of HDL metabolism.Cholesteryl ester transfer protein (CETP) 1 promotes the net transfer of lipids among lipoproteins (1, 2). Because of its unique capacity to mediate net exchange of triglyceride (TG) and cholesteryl ester (CE) between TG-rich VLDL and CE-rich lipoproteins, such as LDL and HDL, CETP plays an essential role in regulating plasma cholesterol levels. By altering lipoprotein core lipid composition, CETP participates in the catabolism of VLDL to LDL (1, 3, 4) and affects the level of LDL subfractions (5-7). Additionally, CETP facilitates HDL metabolism by promoting the formation of larger TG-rich HDL 2 from smaller HDL 3 subspecies (8, 9), stimulating LCAT activity (10, 11), and enhancing the formation of pre␤-HDL (12). These processes influence the reverse transport of peripheral tissue cholesterol to the liver (2,13,14).In a previous study (15), we demonstrated that CETP possesses no functional preference for HDL over LDL. Consequently, in the absence of other factors, LDL is the most active donor of CE to VLDL due to the relative abundance of CE in this lipoprotein in normal plasma. However, CETP activity is controlled by several apolipoproteins including lipid transfer inhibitor protein (LTIP) (15-19). LTIP has been purified and characterized as an acidic glycoprotein with a molecular mass of 33 kDa (17,20). Molecular cloning of LTIP had determined its identity with apolipoprotein F (20). LTIP prevents CETP activi...

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“…Partially purified CETP was isolated from lipoprotein-deficient human plasma by hydrophobic and ion-exchange chromatography as previously described 40 and stored in 0.27 mmol/L EDTA, pH 7.4. These preparations typically contained 4.1 g CETP protein/mL based on immunoassay of CETP mass with TP2 monoclonal antibody.…”

Section: Isolation Of Cetp and Ltipmentioning

confidence: 99%

Lipid Transfer Inhibitor Protein Defines the Participation of Lipoproteins in Lipid Transfer Reactions

Serdyuk

Morton

1999

ATVB

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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...

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Determination of lipid transfer inhibitor protein activity in human lipoprotein-deficient plasma.

Cited by 82 publications

References 33 publications

Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus.

Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus.

Lipid Transfer Inhibitor Protein Defines the Participation of High Density Lipoprotein Subfractions in Lipid Transfer Reactions Mediated by Cholesterol Ester Transfer Protein (CETP)

Lipid Transfer Inhibitor Protein Defines the Participation of Lipoproteins in Lipid Transfer Reactions

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