Increased prebeta-HDL levels, cholesterol efflux, and LCAT-mediated esterification in mice expressing the human cholesteryl ester transfer protein (CETP) and human apolipoprotein A-I (apoA-I) transgenes.
The effects of cholesteryl ester transfer protein (CETP) on the distribution of apolipoprotein (apo) A-I between high density lipoprotein (HDL) subspecies and its impact on efflux and esterification of cell-derived cholesterol was studied in transgenic mice expressing either the human apoA-I (HuAITg) or both the human apoA-I and CETP (HuAICETPTg) transgenes. The simultaneous expression of the human CETP and apoA-I transgenes induced a 2-fold increase in the proportion of human apoA-I in the prebeta-HDL fraction and 1.4- and 2.2-fold increases in the HDL3a and HDL3c fractions, respectively, at the expense of the larger HDL2b population. HuAICETPTg mouse plasma has a greater ability to cause efflux of cholesterol from 3H-labeled fibroblasts than plasma from HuAITg mice. Furthermore, the LCAT-mediated esterification of cell-derived cholesterol is increased 1.7-fold in mice expressing the human apoA-I and CETP transgenes compared to HuAITg mouse plasma. LCAT activity (measured with an exogenous substrate) was increased 1.4-fold and LCAT mRNA levels were increased 1.3-fold as a result of CETP expression. Taken together, these data indicate that in vivo, the expression of CETP resulted in an increase in the proportion of apoA-I in the prebeta-HDL fraction and a stimulation of the efflux and esterification of cell-derived cholesterol.
Francone
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Department of Cardiovascular and Metabolic Diseases, Pfizer Inc., Groton, CT 06340, USA.
Royer
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Haghpassand
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D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D005347:Fibroblasts; D006023:Glycoproteins; D053442:High-Density Lipoproteins, Pre-beta; D006801:Humans; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000097:blood*; D051379:Mice; D008822:Mice, Transgenic; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000096:biosynthesis / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D012867:Skin / Q000378:metabolism; D014158:Transcription, Genetic
D016632:Apolipoprotein A-I; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase