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Apolipoprotein CI deficiency markedly augments plasma lipoprotein changes mediated by human cholesteryl ester transfer protein (CETP) in CETP transgenic/apoCI-knocked out mice

Author: Gautier, T. · Masson, D. · Jong, M.C. · Duverneuil, L. · Guern, N.L. · Deckert, V. · Barros, J.-P.P.de · Dumont, L. · Bataille, A. · Zak, Z. · Jiang, X.-C. · Tall, A.R. · Havekes, L.M. · Lagrost, L.
Type:article
Date:2002
Institution: Gaubius Instituut TNO
Source:Journal of Biological Chemistry, 35, 277, 31354-31363
Identifier: 236662
doi: doi:10.1074/jbc.M203151200
Keywords: Biology · Cholesterol · Chromatographic analysis · Esters · Proteins · Apolipoproteins · Biochemistry · High density lipoprotein · Very low density lipoprotein · Animal experiment · Concentration response · Controlled study · Gel permeation chromatography · Knockout mouse · Lipoprotein blood level · Mouse · Nonhuman · Protein deficiency · Protein expression · Transgenic mouse · Animals · Apolipoprotein C-I · Apolipoproteins C · Carrier Proteins · Cholesterol Ester Transfer Proteins · Glycoproteins · Humans · Kinetics · Lipoproteins · Mice · Mice, Inbred C57BL · Mice, Knockout · Mice, Transgenic · Animalia · Mus musculus

Abstract

Transgenic mice expressing human cholesteryl ester transfer protein (HuCETPTg mice) were crossed with apolipoprotein CI-knocked out (apoCI-KO) mice. Although total cholesterol levels tended to be reduced as the result of CETP expression in HuCETPTg heterozygotes compared with C57BL6 control mice (-13%, not significant), a more pronounced decrease (-28%, p < 0.05) was observed when human CETP was expressed in an apoCI-deficient background (HuCETPTg/apoCI-KO mice). Gel permeation chromatography analysis revealed a significant, 6.1-fold rise (p < 0.05) in the cholesteryl ester content of very low density lipoproteins in HuCETPTg/apoCI-KO mice compared with control mice, whereas the 2.7-fold increase in HuCETPTg mice did not reach the significance level in these experiments. Approximately 50% decreases in the cholesteryl ester content and cholesteryl ester to triglyceride ratio of high density lipoproteins (HDL) were observed in HuCETPTg/apoCI-KO mice compared with controls (p < 0.05 in both cases), with intermediate -20% changes in HuCETPTg mice. The cholesteryl ester depletion of HDL was accompanied with a significant reduction in their mean apparent diameter (8.68 ± 0.04 nm in HuCETPTg/apoCI-KO mice versus 8.83 ± 0.02 nm in control mice; p < 0.05), again with intermediate values in HuCETPTg mice (8.77 ± 0.04 nm). In vitro purified apoCI was able to inhibit cholesteryl ester exchange when added to either total plasma or reconstituted HDL-free mixtures, and coincidently, the specific activity of CETP was significantly increased in the apoCI-deficient state (173 ± 75 pmol/μg/h in HuCETPTg/apoCI-KO mice versus 72 ± 19 pmol/μg/h in HuCETPTg, p < 0.05). Finally, HDL from apoCI-KO mice were shown to interact more readily with purified CETP than control HDL that differ only by their apoCI content. Overall, the present observations provide direct support for a potent specific inhibition of CETP by plasma apoCI in vivo. Chemicals/CAS: Apolipoprotein C-I; Apolipoproteins C; Carrier Proteins; CETP protein, human; Cholesterol Ester Transfer Proteins; Glycoproteins; Lipoproteins