Expression of simian cholesteryl ester transfer protein (CETP) in normolipidemic Fisher rats has a profound effect on large-sized, apolipoproteinE-containing high density lipoproteins

doi:10.1194/jlr.M200253-JLR200

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Expression of simian cholesteryl ester transfer protein (CETP) in normolipidemic Fisher rats has a profound effect on large-sized, apolipoproteinE-containing high density lipoproteins

Zoulika Zak, Laurent Lagrost, Thomas Gautier, David Masson, Valerie Deckert, Linda Duverneuil, Jean-Paul Pais de Barros, Naig Le Guern, Laure Dumont, Martina Schneider, Valerie Risson, Philippe Moulin, Delphine Autran, Gillian Brooker, Jean Sassard, and Alain Bataillard

INSERM U498, Faculté de Médecine, Dijon, 21 21079

Corresponding Author: Laurent.Lagrost{at}u-bourgogne.fr

Complete cholesteryl ester transfer protein (CETP) deficiency in human homozygotes is characterized by the appearance of large, apolipoproteinE-containing high density lipoproteins (HDL) that are not present in plasmas from normolipidemic subjects and hyperalphalipoproteinemic subjects with normal or half normal CETP activity. In order to investigate the direct effect of CETP on the structure and composition of HDL in vivo, simian CETP was expressed in Fisher rat that, unlike C57BL/6 mouse and Dahl rats previously used for CETP transgenesis, spontaneously displays high plasma levels of HDL1. In the new CETPTg rat line, the production of active CETP by the liver induced a significant 48% decrease in plasma HDL cholesterol, resulting in a 34% decrease in total cholesterol level (P<0.01 in both cases). Detailed analyses by gel filtration chromatography and polyacrylamide gradient gel electrophoresis revealed that, among the various plasma HDL subpopulations, the largest HDL were those mostly affected by CETP, with a 74% decrease in HDL1 versus a significantly weaker 38% decrease in smaller HDL2 (P<0.0001). ApoE-containing HDL1 were selectively affected by CETP expression, whereas ApoA content of HDL remained unmodified. The reduction in the apoE content of serum HDL observed in CETPTg rats compared to controls (53%, P<0.02) suggests that apoE in HDL may constitute in vivo a major determinant of their ability to interact with CETP. These results bring new insight into the lack of HDL1 in plasma from CETP-deficient heterozygotes despite their 50% decrease in CETP activity. In addition, they indicate that HDL1 constitute reliable and practicable sensors of very low plasma CETP activity in vivo.

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