Abstract
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.
Highlights
The effects of cholesteryl ester transfer protein (CETP) on the distribution of apolipoprotein 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 mechanism by which HDL prevents atherosclerosis remains poorly understood, several lines of evidence suggest that HDL plays a pivotal role in the transport of cholesterol in Abbreviations: VLDL, very low density lipoproteins; LDL, low density lipoproteins; HDL, high density lipoproteins; lecithin:cholesterol acyltransferase (LCAT), 1ecithin:cholesterolacyltransferase;CETP, cholesteryl ester transfer protein; human apoA-I transgene (HuAITg), transgenic mice expressing human apoA-I; HuAICETPg, transgenic mice expressing human apoA-I and CETP transgenes; MAb, monoclonal antibody; RCT, reverse cholesterol transport; PLTP, phospholipid transfer protein
We have used transgenic mice expressing the human apoA-I and CETP transgenes to show that, in vivo, human CETP promotes the formation of small HDL with a prep electrophoretic mobility, and increases cell-derived cholesterol efflux and esterification
Summary
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 LCAT-mediated esterification of cell-derived cholesterol is increased 1.7-foldin mice expressing the human apoA-I and CETP transgenes compared to HuAITg mouse plasma. Increased prep-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 mechanism by which HDL prevents atherosclerosis remains poorly understood, several lines of evidence suggest that HDL plays a pivotal role in the transport of cholesterol in Abbreviations: VLDL, very low density lipoproteins; LDL, low density lipoproteins; HDL, high density lipoproteins; LCAT, 1ecithin:cholesterolacyltransferase;CETP, cholesteryl ester transfer protein; HuAITg, transgenic mice expressing human apoA-I; HuAICETPg, transgenic mice expressing human apoA-I and CETP transgenes; MAb, monoclonal antibody; RCT, reverse cholesterol transport; PLTP, phospholipid transfer protein. Studies in vitro [6,7]and in transgenic mice [8]demonstrated that the conversion of prePHDL to a-HDL is mediated by LCAT
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