Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Nov 15;98(10):2373–2380. doi: 10.1172/JCI119050

Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes.

X Jiang 1, O L Francone 1, C Bruce 1, R Milne 1, J Mar 1, A Walsh 1, J L Breslow 1, A R Tall 1
PMCID: PMC507689  PMID: 8941656

Abstract

Human plasma phospholipid transfer protein (PLTP) circulates bound to high density lipoprotein (HDL) and mediates both net transfer and exchange of phospholipids between different lipoproteins. However, its overall function in lipoprotein metabolism is unknown. To assess the effects of increased plasma levels of PLTP, human PLTP transgenic mice were established using the human PLTP gene driven by its natural promoter. One line of PLTP transgenic mice with moderate expression of PLTP mRNA and protein was obtained. The order of human PLTP mRNA expression in tissues was: liver, kidney, brain, small intestine > lung > spleen > heart, adipose tissue. Western blotting using a human PLTP monoclonal antibody revealed authentic human PLTP (Mr 80 kD) in plasma. Plasma PLTP activity was increased by 29% in PLTP transgenic mice. However, plasma lipoprotein analysis, comparing PLTP transgenic mice to control littermates, revealed no significant changes in the plasma lipoprotein lipids or apolipoproteins. Since previous studies have shown that human cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase only function optimally in human apoAI transgenic mice, the human PLTP transgenic mice were cross-bred with human apoAI transgenic mice. In the human apoAI transgenic background, PLTP expression resulted in increased PLTP activity (47%), HDL phospholipid (26%), cholesteryl ester (24%), free cholesterol (37%), and apoAI (22%). There was a major increase of apoAI in prebeta-HDL (56%) and a small increase in alpha-HDL (14%). The size distribution of HDL particles within alpha- and prebeta-migrating species was not changed. The results suggest that PLTP increases the influx of phospholipid and secondarily cholesterol into HDL, leading to an increase in potentially antiatherogenic prebeta-HDL particles.

Full Text

The Full Text of this article is available as a PDF (252.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agellon L. B., Walsh A., Hayek T., Moulin P., Jiang X. C., Shelanski S. A., Breslow J. L., Tall A. R. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J Biol Chem. 1991 Jun 15;266(17):10796–10801. [PubMed] [Google Scholar]
  2. Albers J. J., Wolfbauer G., Cheung M. C., Day J. R., Ching A. F., Lok S., Tu A. Y. Functional expression of human and mouse plasma phospholipid transfer protein: effect of recombinant and plasma PLTP on HDL subspecies. Biochim Biophys Acta. 1995 Aug 24;1258(1):27–34. doi: 10.1016/0005-2760(95)00091-p. [DOI] [PubMed] [Google Scholar]
  3. Barrans A., Collet X., Barbaras R., Jaspard B., Manent J., Vieu C., Chap H., Perret B. Hepatic lipase induces the formation of pre-beta 1 high density lipoprotein (HDL) from triacylglycerol-rich HDL2. A study comparing liver perfusion to in vitro incubation with lipases. J Biol Chem. 1994 Apr 15;269(15):11572–11577. [PubMed] [Google Scholar]
  4. Castle C. K., Pape M. E., Marotti K. R., Melchior G. W. Secretion of pre-beta-migrating apoA-I by cynomolgus monkey hepatocytes in culture. J Lipid Res. 1991 Mar;32(3):439–447. [PubMed] [Google Scholar]
  5. Clay M. A., Newnham H. H., Barter P. J. Hepatic lipase promotes a loss of apolipoprotein A-I from triglyceride-enriched human high density lipoproteins during incubation in vitro. Arterioscler Thromb. 1991 Mar-Apr;11(2):415–422. doi: 10.1161/01.atv.11.2.415. [DOI] [PubMed] [Google Scholar]
  6. Day J. R., Albers J. J., Lofton-Day C. E., Gilbert T. L., Ching A. F., Grant F. J., O'Hara P. J., Marcovina S. M., Adolphson J. L. Complete cDNA encoding human phospholipid transfer protein from human endothelial cells. J Biol Chem. 1994 Mar 25;269(12):9388–9391. [PubMed] [Google Scholar]
  7. Fisher W. R., Venkatakrishnan V., Zech L. A., Hall C. M., Kilgore L. L., Stacpoole P. W., Diffenderfer M. R., Friday K. E., Sumner A. E., Marsh J. B. Kinetic evidence for both a fast and a slow secretory pathway for apolipoprotein A-I in humans. J Lipid Res. 1995 Jul;36(7):1618–1628. [PubMed] [Google Scholar]
  8. Francone O. L., Gong E. L., Ng D. S., Fielding C. J., Rubin E. M. Expression of human lecithin-cholesterol acyltransferase in transgenic mice. Effect of human apolipoprotein AI and human apolipoprotein all on plasma lipoprotein cholesterol metabolism. J Clin Invest. 1995 Sep;96(3):1440–1448. doi: 10.1172/JCI118180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Galjart N. J., Morreau H., Willemsen R., Gillemans N., Bonten E. J., d'Azzo A. Human lysosomal protective protein has cathepsin A-like activity distinct from its protective function. J Biol Chem. 1991 Aug 5;266(22):14754–14762. [PubMed] [Google Scholar]
  10. Glomset J. A. The plasma lecithins:cholesterol acyltransferase reaction. J Lipid Res. 1968 Mar;9(2):155–167. [PubMed] [Google Scholar]
  11. Hara H., Yokoyama S. Role of apolipoproteins in cholesterol efflux from macrophages to lipid microemulsion: proposal of a putative model for the pre-beta high-density lipoprotein pathway. Biochemistry. 1992 Feb 25;31(7):2040–2046. doi: 10.1021/bi00122a021. [DOI] [PubMed] [Google Scholar]
  12. Hayek T., Chajek-Shaul T., Walsh A., Agellon L. B., Moulin P., Tall A. R., Breslow J. L. 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. 1992 Aug;90(2):505–510. doi: 10.1172/JCI115887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Huang Y., von Eckardstein A., Assmann G. Cell-derived unesterified cholesterol cycles between different HDLs and LDL for its effective esterification in plasma. Arterioscler Thromb. 1993 Mar;13(3):445–458. doi: 10.1161/01.atv.13.3.445. [DOI] [PubMed] [Google Scholar]
  14. Ishida B. Y., Albee D., Paigen B. Interconversion of prebeta-migrating lipoproteins containing apolipoprotein A-I and HDL. J Lipid Res. 1990 Feb;31(2):227–236. [PubMed] [Google Scholar]
  15. Ishida B. Y., Frolich J., Fielding C. J. Prebeta-migrating high density lipoprotein: quantitation in normal and hyperlipidemic plasma by solid phase radioimmunoassay following electrophoretic transfer. J Lipid Res. 1987 Jul;28(7):778–786. [PubMed] [Google Scholar]
  16. Itoh K., Takiyama N., Kase R., Kondoh K., Sano A., Oshima A., Sakuraba H., Suzuki Y. Purification and characterization of human lysosomal protective protein expressed in stably transformed Chinese hamster ovary cells. J Biol Chem. 1993 Jan 15;268(2):1180–1186. [PubMed] [Google Scholar]
  17. Jauhiainen M., Metso J., Pahlman R., Blomqvist S., van Tol A., Ehnholm C. Human plasma phospholipid transfer protein causes high density lipoprotein conversion. J Biol Chem. 1993 Feb 25;268(6):4032–4036. [PubMed] [Google Scholar]
  18. Jiang X. C., Bruce C. Regulation of murine plasma phospholipid transfer protein activity and mRNA levels by lipopolysaccharide and high cholesterol diet. J Biol Chem. 1995 Jul 21;270(29):17133–17138. doi: 10.1074/jbc.270.29.17133. [DOI] [PubMed] [Google Scholar]
  19. Jiang X. C., Masucci-Magoulas L., Mar J., Lin M., Walsh A., Breslow J. L., Tall A. 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. 1993 Dec 25;268(36):27406–27412. [PubMed] [Google Scholar]
  20. Kunitake S. T., Mendel C. M., Hennessy L. K. Interconversion between apolipoprotein A-I-containing lipoproteins of pre-beta and alpha electrophoretic mobilities. J Lipid Res. 1992 Dec;33(12):1807–1816. [PubMed] [Google Scholar]
  21. Lefevre M., Sloop C. H., Roheim P. S. Characterization of dog prenodal peripheral lymph lipoproteins. Evidence for the peripheral formation of lipoprotein-unassociated apoA-I with slow pre-beta electrophoretic mobility. J Lipid Res. 1988 Sep;29(9):1139–1148. [PubMed] [Google Scholar]
  22. Lusa S., Jauhiainen M., Metso J., Somerharju P., Ehnholm C. The mechanism of human plasma phospholipid transfer protein-induced enlargement of high-density lipoprotein particles: evidence for particle fusion. Biochem J. 1996 Jan 1;313(Pt 1):275–282. doi: 10.1042/bj3130275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Miller G. J., Miller N. E. Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease. Lancet. 1975 Jan 4;1(7897):16–19. doi: 10.1016/s0140-6736(75)92376-4. [DOI] [PubMed] [Google Scholar]
  25. Neary R. H., Gowland E. Stability of free apolipoprotein A-1 concentration in serum, and its measurement in normal and hyperlipidemic subjects. Clin Chem. 1987 Jul;33(7):1163–1169. [PubMed] [Google Scholar]
  26. Nichols A. V., Gong E. L., Blanche P. J., Forte T. M., Shore V. G. Pathways in the formation of human plasma high density lipoprotein subpopulations containing apolipoprotein A-I without apolipoprotein A-II. J Lipid Res. 1987 Jun;28(6):719–732. [PubMed] [Google Scholar]
  27. Reichl D., Hathaway C. B., Sterchi J. M., Miller N. E. Lipoproteins of human peripheral lymph. Apolipoprotein AI-containing lipoprotein with alpha-2 electrophoretic mobility. Eur J Clin Invest. 1991 Dec;21(6):638–643. doi: 10.1111/j.1365-2362.1991.tb01421.x. [DOI] [PubMed] [Google Scholar]
  28. Rubin E. M., Ishida B. Y., Clift S. M., Krauss R. M. Expression of human apolipoprotein A-I in transgenic mice results in reduced plasma levels of murine apolipoprotein A-I and the appearance of two new high density lipoprotein size subclasses. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):434–438. doi: 10.1073/pnas.88.2.434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tall A. R., Abreu E., Shuman J. Separation of a plasma phospholipid transfer protein from cholesterol ester/phospholipid exchange protein. J Biol Chem. 1983 Feb 25;258(4):2174–2180. [PubMed] [Google Scholar]
  30. Tall A. R., Krumholz S., Olivecrona T., Deckelbaum R. J. Plasma phospholipid transfer protein enhances transfer and exchange of phospholipids between very low density lipoproteins and high density lipoproteins during lipolysis. J Lipid Res. 1985 Jul;26(7):842–851. [PubMed] [Google Scholar]
  31. Tollefson J. H., Ravnik S., Albers J. J. Isolation and characterization of a phospholipid transfer protein (LTP-II) from human plasma. J Lipid Res. 1988 Dec;29(12):1593–1602. [PubMed] [Google Scholar]
  32. Tu A. Y., Nishida H. I., Nishida T. High density lipoprotein conversion mediated by human plasma phospholipid transfer protein. J Biol Chem. 1993 Nov 5;268(31):23098–23105. [PubMed] [Google Scholar]
  33. Verheijen F. W., Palmeri S., Hoogeveen A. T., Galjaard H. Human placental neuraminidase. Activation, stabilization and association with beta-galactosidase and its protective protein. Eur J Biochem. 1985 Jun 3;149(2):315–321. doi: 10.1111/j.1432-1033.1985.tb08928.x. [DOI] [PubMed] [Google Scholar]
  34. Walsh A., Ito Y., Breslow J. L. 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] [Google Scholar]
  35. Whitmore T. E., Day J. R., Albers J. J. Localization of the human phospholipid transfer protein gene to chromosome 20q12-q13.1. Genomics. 1995 Aug 10;28(3):599–600. doi: 10.1006/geno.1995.1198. [DOI] [PubMed] [Google Scholar]
  36. Wiegant J., Galjart N. J., Raap A. K., d'Azzo A. The gene encoding human protective protein (PPGB) is on chromosome 20. Genomics. 1991 Jun;10(2):345–349. doi: 10.1016/0888-7543(91)90318-9. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES