© 1997 American Heart Association, Inc.
Articles |
Cholesteryl Ester Transfer Protein Activity Enhances Plasma Cholesteryl Ester Formation
Studies in CETP Transgenic Mice and Human Genetic CETP Deficiency
From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (H.C.F.O., L.M., A.R.T.); the University of Ottawa Heart Institute, Ottawa, Canada (R.M.); the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle (S.M.M.); and the Second Department of Internal Medicine, Kanazawa University, Japan (A.I., H.M.).
Correspondence to Dr Alan R. Tall, Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032.
Abstract The plasma cholesteryl ester transfer protein (CETP) promotes the removal of HDL cholesteryl esters and is thought to stimulate reverse cholesterol transport (RCT). However, mechanisms by which CETP may stimulate RCT are poorly understood. Thus, we examined the relationship between plasma CETP expression and plasma cholesteryl ester formation in CETP transgenic (Tg) mice, hamsters, and human subjects with genetic CETP deficiency. Incubation of CETP Tg mouse plasma showed a 20% to 40% increase in plasma cholesterol esterification rate (CER, P<.05) compared with control mice. Injection of a neutralizing CETP monoclonal antibody (MAb) (TP2) into natural flanking region CETP Tg mice resulted in an increase in plasma free cholesterol (FC) concentration, FC/CE ratio, FC/phosphatidylcholine ratio, and hepatic CETP mRNA. In hamsters, CETP inhibition also resulted in an increase in plasma FC/phosphatidylcholine ratio and increased CETP mRNA in adipose tissue. In humans with two common CETP gene mutations (an intron 14 splicing defect and a D442G missense mutation), mean plasma CERs were 39 and 60, respectively, compared with 89 nmol·mL-1·h-1 in normal subjects. By contrast, lecithin:cholesterol acyltransferase (LCAT) mass was normal in CETP-deficient subjects. MAb neutralization of CETP activity in incubated human plasma did not alter the LCAT reaction, even after supplementation with discoidal HDL and VLDL. Thus, genetic alterations in CETP levels lead to secondary changes in the plasma LCAT reaction, possibly because of remodeling of HDL by CETP acting in concert with other factors in vivo. In human genetic CETP deficiency, a moderate impairment in the plasma LCAT reaction may contribute to a defect in RCT, providing a potential mechanism to explain the recently observed excess of coronary heart disease in these subjects.
Key Words: cholesteryl ester transfer protein • transgenic mice • reverse cholesterol transport • cholesterol esterification rate
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