Inhibition of cholesteryl ester transfer protein activity by monoclonal antibody. Effects on cholesteryl ester formation and neutral lipid mass transfer in human plasma.

Yen, Frances T.; Deckelbaum, Richard J.; Mann, Christopher; Marcel, Yves L.; Milne, Ross W.; Tall, Alan R.

doi:10.1172/jci114112

Cited by 84 publications

(34 citation statements)

References 38 publications

(18 reference statements)

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“…The percentage of radiolabeled CE transferred to HDL, expressed as %kt, was calculated as described previously (29). In some instances, samples were preincubated for 30 min with 10 g of anti-CETP IgG (TP2) (30) before initiating the transfer assay.…”

Section: Methodsmentioning

confidence: 99%

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Cholesteryl Ester Transfer Protein Biosynthesis and Cellular Cholesterol Homeostasis Are Tightly Interconnected

Izem

Morton

2001

Journal of Biological Chemistry

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Cholesteryl ester transfer protein (CETP) mediates triglyceride and cholesteryl ester (CE) transfer between lipoproteins, and its activity is strongly modulated by dietary cholesterol. To better understand the regulation of CETP synthesis and the relationship between CETP levels and cellular lipid metabolism, we selected the SW872 adipocytic cell line as a model. These cells secrete CETP in a time-dependent manner at levels exceeding those observed for Caco-2 or HepG2 cells. The addition of LDL, 25OH-cholesterol, oleic acid, or acetylated LDL to SW872 cells increased CETP secretion (activity and mass) up to 6-fold. In contrast, CETP production was decreased by almost 60% after treatment with lipoprotein-deficient serum or ␤-cyclodextrin. These effects, which were paralleled by changes in CETP mRNA, show that CETP biosynthesis in SW872 cells directly correlates with cellular lipid status. To investigate a possible, reciprocal relationship between CETP expression and cellular lipid homeostasis, CETP biosynthesis in SW872 cells was suppressed with CETP antisense oligonucleotides. Antisense oligonucleotides reduced CETP secretion (activity and mass) by 60% compared with sensetreated cells. When CETP synthesis was suppressed for 24 h, triglyceride synthesis was unchanged, but cholesterol biosynthesis was reduced by 20%, and acetate incorporation into CE increased 31%. After 3 days of suppressed CETP synthesis, acetate incorporation into the CE pool increased 3-fold over control. This mirrored a similar increase in CE mass. The efflux of free cholesterol to HDL was the same in sense and antisensetreated cells; however, HDL-induced CE hydrolysis in antisense-treated cells was diminished 2-fold even though neutral CE hydrolase activity was unchanged. Thus, CETP-compromised SW872 cells display a phenotype characterized by inefficient mobilization of CE stores leading to CE accumulation. These results strongly suggest that CETP expression levels contribute to normal cholesterol homeostasis in adipocytic cells.Overall, these studies demonstrate that lipid homeostasis and CETP expression are tightly coupled.

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Section: Methodsmentioning

confidence: 99%

“…CETP was eluted from the agarose by adding 50 l of 1 M glycine, pH 2.5, combined with gel-loading buffer, boiled for 5 min, and subjected to 7.5% SDS-polyacrylamide gel electrophoresis. Western blot was accomplished using TP2 anti-CETP antibody (30) and anti-mouse IgG coupled with horseradish peroxidase.…”

Section: Methodsmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein Biosynthesis and Cellular Cholesterol Homeostasis Are Tightly Interconnected

Izem

Morton

2001

Journal of Biological Chemistry

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“…We suggest that there may be several metabolic advantages to the altered lipid flux among HDL subfractions that occurs in the presence of LTIP. LCAT prefers HDL 3 as a substrate (26) and its activity is stimulated by CETP (10,11), presumably because CETP removes CE and minimizes product inhibition of the enzyme (58). Our studies show that LTIP stimulates this function of CETP, and thus would improve the reactivity of these particles with LCAT.…”

Section: Ltip Binding To Ldl Hdlmentioning

confidence: 99%

“…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)(6)(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).…”

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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“…Previous work identified this region as containing a "dominant" B-cell epitope of CETP. 20 Monoclonal antibodies that block human, 21 hamster, 22 and rabbit 11 CETP activity have been shown to bind CETP in this region. This 16-amino-acid sequence has been proposed to assume a conformation as an isolated peptide similar to that in the native CETP molecule.…”

Section: See Page 2029mentioning

confidence: 99%

Vaccine-Induced Antibodies Inhibit CETP Activity In Vivo and Reduce Aortic Lesions in a Rabbit Model of Atherosclerosis

Rittershaus

Miller

Thomas

et al. 2000

ATVB

293

152

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Abstract-Using a vaccine approach, we immunized New Zealand White rabbits with a peptide containing a region of cholesteryl ester transfer protein (CETP) known to be required for neutral lipid transfer function. These rabbits had significantly reduced plasma CETP activity and an altered lipoprotein profile. In a cholesterol-fed rabbit model of atherosclerosis, the fraction of plasma cholesterol in HDL was 42% higher and the fraction of plasma cholesterol in LDL was 24% lower in the CETP-vaccinated group than in the control-vaccinated group. Moreover, the percentage of the aorta surface exhibiting atherosclerotic lesion was 39.6% smaller in the CETP-vaccinated rabbits than in controls. The data reported here demonstrate that CETP activity can be reduced in vivo by vaccination with a peptide derived from CETP and support the concept that inhibition of CETP activity in vivo can be antiatherogenic. In addition, these studies suggest that vaccination against a self-antigen is a viable therapeutic strategy for disease management. (Arterioscler

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Inhibition of cholesteryl ester transfer protein activity by monoclonal antibody. Effects on cholesteryl ester formation and neutral lipid mass transfer in human plasma.

Cited by 84 publications

References 38 publications

Cholesteryl Ester Transfer Protein Biosynthesis and Cellular Cholesterol Homeostasis Are Tightly Interconnected

Cholesteryl Ester Transfer Protein Biosynthesis and Cellular Cholesterol Homeostasis Are Tightly Interconnected

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

Vaccine-Induced Antibodies Inhibit CETP Activity In Vivo and Reduce Aortic Lesions in a Rabbit Model of Atherosclerosis

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