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.
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