The plasma cholesteryl ester transfer protein (CETP) promotes the transfer of neutral lipids between the plasma lipoproteins and may play a role in determining the susceptibility of different species to atherosclerosis. The objectives are to investigate nutritional influences on the expression of the CETP gene, to elucidate the structure of the human CETP gene and its regulatory elements, and to explore the role of CETP in lipoprotein physiology and atherosclerosis. Recent studies have shown that rabbits fed an atherogenic diet develop increased levels of CETP mRNA in their livers and an increased mass of CETP in plasma. In the proposed studies the effects of dietary cholesterol and saturated fat on CETP mRNA levels in liver and other tissues, and the relationship of CETP levels to atherosclerosis, will be investigated in Cynomolgus and African green monkeys. The transcription start site, intron/exon organization and flanking DNA sequences of the human CETP gene will be elucidated, and the gene will be transfected into cultured cells. Regulatory elements of the CETP gene, required for basal or lipoprotein-stimulated expression, will be defined in tissue culture. Mice lack an endogenous gene homologous to CETP, and are resistant to dietary atherosclerosis. In collaboration with Dr. J. Breslow, the human CETP gene, containing an inducible promoter, will be introduced into mice, and the effects of CETP induction on lipoprotein profiles and atherosclerosis will be determined. CETP transgenic mice will also be inbred with transgenic mice expressing high levels of human apoA-I or with other strains susceptible or resistant to dietary atherosclerosis. Finally, transgenic mice will be prepared using the natural promoter and enhancers of the CETP gene, in order to elucidate tissue-specific and diet-responsive elements of the CETP gene in vivo. These experiments will provide new information on the CETP gene and its regulation, especially by nutritional factors, and should help to elucidate the impact of CETP gene expression on lipoprotein physiology and atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043165-03
Application #
3361681
Study Section
Nutrition Study Section (NTN)
Project Start
1989-08-01
Project End
1992-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
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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