Plasma high density lipoproteins (HDL) are a negative risk factor for atherosclerosis. Increased HDL is sometimes clustered in families, but a genetic basis has never been clearly documented. The plasma cholesteryl ester transfer protein (CETP) catalyses the transfer of cholesteryl ester from HDL to other lipoproteins and therefore might influence HDL levels. Using monoclonal antibodies, we show that CETP is absent in two Japanese siblings who have markedly increased and enlarged HDL. Furthermore, they are homozygous for a point mutation in the 5'-splice donor site of intron 14 of the gene for CETP, a change that is incompatible with normal splicing of pre-messenger RNA. The results indicate that the family has an inherited deficiency of CETP due to a gene splicing defect, and illustrate the key role that CETP has in human HDL metabolism.
A MAb (TP-2) directed against human cholesteryl ester transfer protein (CETP) has been applied to the development of a competitive solid-phase RIA. Experiments with immobilized CETP have shown that upon incubation with plasma or HDL in the presence of Tween (0.05%) apo A-I (but not apo A-II) binds to CETP while TP-2 binding to CETP is concomitantly decreased. With high detergent concentration (0.5% Triton), the interference is eliminated and a specific RIA in which all plasma CETP fractions have the same affinity can be obtained. Plasma levels of CETP, apo A-I, lipids, and lipoproteins were measured in 50 normolipemic, healthy subjects of both sexes. CETP levels varied nearly fourfold with a mean value of 1.7 gg/ml. CETP was positively correlated only with apo A-I (r = 0.38) and HDL-triglyceride (r = 0.39). In 29 other normolipemic subjects, where several apolipoproteins were also measured, significant correlations of CETP with apo A-I (0.41), apo E (0.43), and HDL-cholesterol (0.41) were observed, but there was no significant relationship between CETP and either apo A-II, B, or D. In other experiments CETP was shown to be present mostly in HDL3 and VHDL, to display exclusively an a2-electrophoretic migration, and to occur within discrete particles ranging in size from 129 to 154 kD. In conclusion, the association of CETP with apo A-I-containing lipoproteins probably explains the correlation between CETP and apo A-I levels. The relationship between CETP and apo E suggests either a common metabolism or a specific cooperative role in cholesterol ester transport for these proteins. (J. Clin. Invest. 1990. 85:10-17.) cholesterol * cholesteryl ester transfer protein-high-density lipoprotein-lipoprotein
Cholesteryl ester transfer activity is increased in plasma of cholesterol-fed rabbits. To investigate the mechanisms leading to changes in activity, we measured cholesteryl ester transfer protein (CETP) mass by RIA and CETP mRNA abundance by Northern and slot blot analysis using a human CETP cDNA probe in control (n = 8) and cholesterol-fed rabbits (n = 10). Cholesterol feeding (chow plus 0.5% cholesterol, 10% corn oil) for 30 d increased CETP mass in plasma 3.2-fold in the cholesterol-fed rabbits (12.45±0.82 ;g/ml) compared with controls (3.86±038 pg/ml). In the hypercholesterolemic rabbit, liver CETP mRNA levels were increased 2.8 times control mRNA levels. Actin, apo E, lecithin-cholesterol acyltransferase, and albumin mRNA abundances were unchanged. In contrast to the widespread tissue distribution in humans, CETP mRNA was not detected in extrahepatic tissues of either control or cholesterol-fed animals. Using a sensitive RNase protection assay, the increase in liver CETP mRNA was detectable within 3 d of beginning the high cholesterol diet. Thus, in response to the atherogenic diet there is an early increase in liver CETP mRNA, probably causing increased CETP synthesis and secretion, and increased plasma CETP.
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