|
|
J Clin Invest. 1992 October; 90(4): 1290–1295. doi: 10.1172/JCI115993. | PMCID: PMC443172 |
Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences. X C Jiang, L B Agellon, A Walsh, J L Breslow, and A Tall Department of Medicine, Columbia University, New York 10032. Abstract To investigate the regulation of expression of the human cholesteryl ester transfer protein (CETP) gene, transgenic mice were prepared using a CETP minigene linked to the natural flanking sequences of the human CETP gene. By using a transgene containing 3.2 kb of upstream and 2.0 kb of downstream flanking sequence, five different lines of transgenic mice were generated. The abundance of CETP mRNA in various tissues was determined on standard laboratory diet or high fat, high cholesterol diets. In three lines of transgenic mice the tissues expressing the human CETP mRNA were similar to those in humans (liver, spleen, small intestine, kidney, and adipose tissue); in two lines expression was more restricted. There was a marked (4-10-fold) induction of liver CETP mRNA in response to a high fat, high cholesterol diet. The increase in hepatic CETP mRNA was accompanied by a fivefold increase in transcription rate of the CETP transgene, and a 2.5-fold increase in plasma CETP mass and activity. In contrast, CETP transgenic mice, in which the CETP minigene was linked to a metallothionein promoter rather than to its own flanking sequences, showed no change in liver CETP mRNA in response to a high cholesterol diet. Thus (a) the CETP minigene or natural flanking sequences contain elements directing authentic tissue-specific expression; (b) a high cholesterol diet induces CETP transgene transcription, causing increased hepatic CETP mRNA and plasma CETP; (c) this cholesterol response requires DNA sequences contained in the natural flanking regions of the human CETP gene. Full text Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References. Images in this article Click on the image to see a larger version. These references are in PubMed. This may not be the complete list of references from this article. - Hesler CB, Swenson TL, Tall AR. Purification and characterization of a human plasma cholesteryl ester transfer protein. J Biol Chem. 1987 Feb 15;262(5):2275–2282. [PubMed]
- Quinet EM, Agellon LB, Kroon PA, Marcel YL, Lee YC, Whitlock ME, Tall AR. Atherogenic diet increases cholesteryl ester transfer protein messenger RNA levels in rabbit liver. J Clin Invest. 1990 Feb;85(2):357–363. [PubMed]
- Ha YC, Barter PJ. Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species. Comp Biochem Physiol B. 1982;71(2):265–269. [PubMed]
- Jiang XC, Moulin P, Quinet E, Goldberg IJ, Yacoub LK, Agellon LB, Compton D, Schnitzer-Polokoff R, Tall AR. Mammalian adipose tissue and muscle are major sources of lipid transfer protein mRNA. J Biol Chem. 1991 Mar 5;266(7):4631–4639. [PubMed]
- Agellon LB, Walsh A, Hayek T, Moulin P, Jiang XC, Shelanski SA, Breslow JL, Tall AR. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J Biol Chem. 1991 Jun 15;266(17):10796–10801. [PubMed]
- Drayna D, Jarnagin AS, McLean J, Henzel W, Kohr W, Fielding C, Lawn R. Cloning and sequencing of human cholesteryl ester transfer protein cDNA. Nature. 327(6123):632–634. [PubMed]
- Quinet E, Tall A, Ramakrishnan R, Rudel L. Plasma lipid transfer protein as a determinant of the atherogenicity of monkey plasma lipoproteins. J Clin Invest. 1991 May;87(5):1559–1566. [PubMed]
- Son YS, Zilversmit DB. Increased lipid transfer activities in hyperlipidemic rabbit plasma. Arteriosclerosis. 1986 May–Jun;6(3):345–351. [PubMed]
- Pape ME, Rehberg EF, Marotti KR, Melchior GW. Molecular cloning, sequence, and expression of cynomolgus monkey cholesteryl ester transfer protein. Inverse correlation between hepatic cholesteryl ester transfer protein mRNA levels and plasma high density lipoprotein levels. Arterioscler Thromb. 1991 Nov–Dec;11(6):1759–1771. [PubMed]
- Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990 Feb 1;343(6257):425–430. [PubMed]
- Ryan TM, Behringer RR, Martin NC, Townes TM, Palmiter RD, Brinster RL. A single erythroid-specific DNase I super-hypersensitive site activates high levels of human beta-globin gene expression in transgenic mice. Genes Dev. 1989 Mar;3(3):314–323. [PubMed]
- Caterina JJ, Ryan TM, Pawlik KM, Palmiter RD, Brinster RL, Behringer RR, Townes TM. Human beta-globin locus control region: analysis of the 5' DNase I hypersensitive site HS 2 in transgenic mice. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1626–1630. [PubMed]
- Simonet WS, Bucay N, Lauer SJ, Wirak DO, Stevens ME, Weisgraber KH, Pitas RE, Taylor JM. In the absence of a downstream element, the apolipoprotein E gene is expressed at high levels in kidneys of transgenic mice. J Biol Chem. 1990 Jul 5;265(19):10809–10812. [PubMed]
- Walsh A, Ito Y, Breslow JL. High levels of human apolipoprotein A-I in transgenic mice result in increased plasma levels of small high density lipoprotein (HDL) particles comparable to human HDL3. J Biol Chem. 1989 Apr 15;264(11):6488–6494. [PubMed]
- Schibler U, Hagenbüchle O, Wellauer PK, Pittet AC. Two promoters of different strengths control the transcription of the mouse alpha-amylase gene Amy-1a in the parotid gland and the liver. Cell. 1983 Jun;33(2):501–508. [PubMed]
- Goldman MJ, Back DW, Goodridge AG. Nutritional regulation of the synthesis and degradation of malic enzyme messenger RNA in duck liver. J Biol Chem. 1985 Apr 10;260(7):4404–4408. [PubMed]
- Marcel YL, McPherson R, Hogue M, Czarnecka H, Zawadzki Z, Weech PK, Whitlock ME, Tall AR, Milne RW. Distribution and concentration of cholesteryl ester transfer protein in plasma of normolipemic subjects. J Clin Invest. 1990 Jan;85(1):10–17. [PubMed]
- Tall A, Granot E, Brocia R, Tabas I, Hesler C, Williams K, Denke M. Accelerated transfer of cholesteryl esters in dyslipidemic plasma. Role of cholesteryl ester transfer protein. J Clin Invest. 1987 Apr;79(4):1217–1225. [PubMed]
- Nishina PM, Verstuyft J, Paigen B. Synthetic low and high fat diets for the study of atherosclerosis in the mouse. J Lipid Res. 1990 May;31(5):859–869. [PubMed]
- Ptashne M, Gann AA. Activators and targets. Nature. 1990 Jul 26;346(6282):329–331. [PubMed]
- Quig DW, Zilversmit DB. Plasma lipid transfer activities. Annu Rev Nutr. 1990;10:169–193. [PubMed]
- Mazzone T, Gump H, Diller P, Getz GS. Macrophage free cholesterol content regulates apolipoprotein E synthesis. J Biol Chem. 1987 Aug 25;262(24):11657–11662. [PubMed]
- Chao YS, Yamin TT, Thompson GM, Kroon PA. Tissue-specific expression of genes encoding apolipoprotein E and apolipoprotein A-I in rabbits. J Biol Chem. 1984 Apr 25;259(8):5306–5309. [PubMed]
- Li YC, Wang DP, Chiang JY. Regulation of cholesterol 7 alpha-hydroxylase in the liver. Cloning, sequencing, and regulation of cholesterol 7 alpha-hydroxylase mRNA. J Biol Chem. 1990 Jul 15;265(20):12012–12019. [PubMed]
- Pandak WM, Li YC, Chiang JY, Studer EJ, Gurley EC, Heuman DM, Vlahcevic ZR, Hylemon PB. Regulation of cholesterol 7 alpha-hydroxylase mRNA and transcriptional activity by taurocholate and cholesterol in the chronic biliary diverted rat. J Biol Chem. 1991 Feb 25;266(6):3416–3421. [PubMed]
- Jelinek DF, Andersson S, Slaughter CA, Russell DW. Cloning and regulation of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis. J Biol Chem. 1990 May 15;265(14):8190–8197. [PubMed]
- Jelinek DF, Russell DW. Structure of the rat gene encoding cholesterol 7 alpha-hydroxylase. Biochemistry. 1990 Aug 28;29(34):7781–7785. [PubMed]
- Agellon LB, Quinet EM, Gillette TG, Drayna DT, Brown ML, Tall AR. Organization of the human cholesteryl ester transfer protein gene. Biochemistry. 1990 Feb 13;29(6):1372–1376. [PubMed]
- Tall AR. Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. J Clin Invest. 1990 Aug;86(2):379–384. [PubMed]
|
This article has been 
