Low levels of plasma high density lipoproteins (HDL) constitute an important risk factor for the development of atherosclerotic cardiovascular disease. The levels of human HDL are largely controlled by the activities of lipases and lipid transfer proteins. The goal of this proposal is to understand on a molecular level the regulation of the activity of the plasma cholesteryl ester transfer protein (CETP), and to investigate the impact of CETP expression on plasma lipoproteins and atherosclerosis. Recently developed human CETP transgenic mice display increased CETP gene transcription, increased CETP mRNA in liver and other organs, increased plasma CETP activity and potentially pro-atherogenic plasma lipoprotein changes, when placed on a high cholesterol, high fat diet. The data indicate that the human CETP gene contains a cholesterol response element in its flanking DNA sequences. This element will be mapped by preparing transgenic mice with different amounts of the flanking sequence of the CETP gene, as well as by cell transfection of promoter-reporter gene constructions and by other in vivo techniques based on 'gene therapy' approaches. A transgenesis approach will also be used to study the regulation and function of alternative splicing of the human CETP mRNA. The impact of CETP expression on plasma lipoproteins and early atherosclerotic lesions will be determined in mice of different genetic backgrounds which are known to influence plasma lipoprotein profiles and development of atherosclerosis. In collaborative studies, the interaction of CETP with human apolipoproteins will be examined by cross-breeding human CETP transgenic mice with other transgenic mice expressing human apoA-I, apoA-II and mutant forms of apoE that result in human dysbetalipoproteinemia. Overall, the proposed research will increase the understanding of the regulation of human HDL levels, by elucidation of the molecular basis of the regulation of CETP gene expression, and will investigate the factors determining how CETP expression may lead to an atherogenic lipoprotein profile (reduced HDL cholesterol, increased VLDL cholesterol). This may lead to therapeutic strategies to control CETP expression and HDL levels, with a possible beneficial effect on human coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043165-06
Application #
2220901
Study Section
Nutrition Study Section (NTN)
Project Start
1989-08-01
Project End
1995-06-30
Budget Start
1994-08-01
Budget End
1995-06-30
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Masucci-Magoulas, L; Plump, A; Jiang, X C et al. (1996) Profound induction of hepatic cholesteryl ester transfer protein transgene expression in apolipoprotein E and low density lipoprotein receptor gene knockout mice. A novel mechanism signals changes in plasma cholesterol levels. J Clin Invest 97:154-61
Jiang, X C; Bruce, C (1995) Regulation of murine plasma phospholipid transfer protein activity and mRNA levels by lipopolysaccharide and high cholesterol diet. J Biol Chem 270:17133-8
Masucci-Magoulas, L; Moulin, P; Jiang, X C et al. (1995) Decreased cholesteryl ester transfer protein (CETP) mRNA and protein and increased high density lipoprotein following lipopolysaccharide administration in human CETP transgenic mice. J Clin Invest 95:1587-94
Quinet, E; Yang, T P; Marinos, C et al. (1993) Inhibition of the cellular secretion of cholesteryl ester transfer protein by a variant protein formed by alternative splicing of mRNA. J Biol Chem 268:16891-4
Jiang, X C; Masucci-Magoulas, L; Mar, J et al. (1993) Down-regulation of mRNA for the low density lipoprotein receptor in transgenic mice containing the gene for human cholesteryl ester transfer protein. Mechanism to explain accumulation of lipoprotein B particles. J Biol Chem 268:27406-12
Jiang, X C; Agellon, L B; Walsh, A et al. (1992) Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences. J Clin Invest 90:1290-5
Inazu, A; Quinet, E M; Wang, S et al. (1992) Alternative splicing of the mRNA encoding the human cholesteryl ester transfer protein. Biochemistry 31:2352-8
Agellon, L B; Zhang, P; Jiang, X C et al. (1992) The CCAAT/enhancer-binding protein trans-activates the human cholesteryl ester transfer protein gene promoter. J Biol Chem 267:22336-9
Hayek, T; Chajek-Shaul, T; Walsh, A et al. (1992) An interaction between the human cholesteryl ester transfer protein (CETP) and apolipoprotein A-I genes in transgenic mice results in a profound CETP-mediated depression of high density lipoprotein cholesterol levels. J Clin Invest 90:505-10
Jiang, X C; Moulin, P; Quinet, E et al. (1991) Mammalian adipose tissue and muscle are major sources of lipid transfer protein mRNA. J Biol Chem 266:4631-9

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