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Structure and Function of Cholesteryl Ester Transfer Protein in the Tree Shrew

  • Original Article
  • Published:
Lipids

Abstract

Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport (RCT). To study on the structure and function of CETP in the tree shrew, a kind of animal resistant to atherosclerosis, we completed the cloning of the full-length tree-shrew CETP cDNA sequence based on the reported partial sequence. The full-length cDNA of tree shrew CETP was 1,704 bp and the deduced protein of the cDNA showed a sequence identity of 81, 80 and 74%, respectively, with the human, monkey and rabbit CETP. The level of CETP mRNA in the liver was much more abundant than that in the other tissues. A mutant protein with a substitution of Asn at position 110 by Gln was found to possess an impaired secretion property compared with the wild-type tree shrew CETP. The mutant proteins, respectively, with a substitution of Pro at position 344 by Ser and a substitution of Gln at position 452 by Arg displayed similar secretion ability, but a decreased cholesteryl ester transfer capability compared with the wild type (48 and 26% lower, respectively). These findings demonstrate that liver is the main tissue synthesizing CETP in the tree shrew. Asn at position 110 plays an important role in the secretion of tree shrew CETP. The residues at position 344 and 452 play essential roles in cholesteryl ester transferring process.

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Abbreviations

apoB:

Apolipoprotein B

AS:

Atherosclerosis

CE:

Cholesteryl ester

CETP:

Cholesteryl ester transfer protein

CHD:

Coronary heart disease

HDL:

High density lipoprotein

HDL-C:

High density lipoprotein cholesterol

LDL:

Low density lipoprotein

LDL-C:

Low density lipoprotein cholesterol

RCT:

Reverse cholesterol transport

VLDL:

Very low density lipoprotein

References

  1. Cao J, Yang EB, Su JJ et al (2003) The tree shrews: adjuncts and alternatives to primates as models for biomedical research. J Med Primatol 32:123–130

    Article  PubMed  CAS  Google Scholar 

  2. Yang EB, Cao J, Su JJ, Chow P (2005) The tree shrews: useful animal models for the viral hepatitis and hepatocellular carcinoma. Hepatogastroenterology 52:613–616

    PubMed  Google Scholar 

  3. She MP, Lu YZ, Xia RY et al (1982) The role of α-lipoprotein in preventing atheromatous plaques developed in tree shrew associating with induced hypercholesterinemia. Zhong Hua Yao Li Xue Za Zhi 11:23–28

    Google Scholar 

  4. Barter PJ (2002) Hugh sinclair lecture: the regulation and remodelling of HDL by plasma factors. Atheroscler Suppl 3:39–47

    Article  PubMed  CAS  Google Scholar 

  5. Stein O, Stein Y (2005) Lipid transfer proteins (LTP) and atherosclerosis. Atherosclerosis 178:217–230

    Article  PubMed  CAS  Google Scholar 

  6. Masson D, Jiang XC, Lagrost L, Tall AR (2009) The role of plasma lipid transfer proteins in lipoprotein metabolism and atherogenesis. J Lipid Res 50:201–206

    Article  Google Scholar 

  7. Brown ML, Inazu A, Hesler CB et al (1989) Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins. Nature 342:448–451

    Article  PubMed  CAS  Google Scholar 

  8. Inazu A, Brown ML, Hesler CB et al (1990) Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med 323:1234–1238

    Article  PubMed  CAS  Google Scholar 

  9. Thompson A, Di Angelantonio E, Sarwar N et al (2008) Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA 299:2777–2788

    Article  PubMed  CAS  Google Scholar 

  10. Plump AS, Masucci-Magoulas L, Bruce C et al (1999) Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler Thromb Vasc Biol 19:1105–1110

    PubMed  CAS  Google Scholar 

  11. Westerterp M, van der Hoogt CC, de Haan W et al (2006) Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice. Arterioscler Thromb Vasc Biol 26:2552–2559

    Article  PubMed  CAS  Google Scholar 

  12. Tsai MY, Johnson C, Kao WH et al (2008) Cholesteryl ester transfer protein genetic polymorphisms, HDL cholesterol, and subclinical cardiovascular disease in the multi-ethnic study of atherosclerosis. Atherosclerosis 200:359–367

    Article  PubMed  CAS  Google Scholar 

  13. Liu HR, Wu G, Zhou B, Chen BS (2010) Low cholesteryl ester transfer protein and phospholipid transfer protein activities are the factors making tree shrew and Beijing duck resistant to atherosclerosis. Lipids Health Dis 9:114

    PubMed  Google Scholar 

  14. Zeng WW, Zhang J, Chen B (2001) Analysis of cDNA and protein structure of tree shrew cholesterol ester transfer protein. Zhong Hua Yi Xue Za Zhi 81:1316–1320

    CAS  Google Scholar 

  15. Zeng W, Zhang J, Chen B et al (2003) Cloning and characterization of cholesteryl ester transfer protein isolated from the tree shrew. Chin Med J 116:928–931

    PubMed  CAS  Google Scholar 

  16. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108

    Article  PubMed  CAS  Google Scholar 

  17. Liu HR, Zeng WW, Zhou B et al (2008) cDNA cloning and prokaryotic expression of human cholesteryl ester transfer protein and preparation of its antiserum. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 24:471–474

    PubMed  CAS  Google Scholar 

  18. Kotake H, Agellon LB, Yokoyama S (1997) Modification of the N-terminal cysteine of plasma cholesteryl ester transfer protein selectively inhibits triglyceride transfer activity. Biochim Biophys Acta 1347:69–74

    PubMed  CAS  Google Scholar 

  19. Hope HR, Heuvelman D, Duffin K et al (2000) Inhibition of cholesteryl ester transfer protein by substituted dithiobisnicotinic acid dimethyl ester: involvement of a critical cysteine. J Lipid Res 41:1604–1614

    PubMed  CAS  Google Scholar 

  20. Pape ME, Rehberg EF, Marotti KR, Melchior GW (1991) 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 11:1759–1771

    PubMed  CAS  Google Scholar 

  21. Drayna D, Jarnagin AS, Mclean J et al (1987) Cloning and sequencing of human cholesteryl ester transfer protein cDNA. Nature 327:632–634

    Article  PubMed  CAS  Google Scholar 

  22. Nagashima M, Mclean JW, Lawn RM (1988) Cloning and mRNA tissue distribution of rabbit cholesteryl ester transfer protein. J Lipid Res 29:1643–1649

    PubMed  CAS  Google Scholar 

  23. Stevenson SC, Wang S, Deng L, Tall AR (1993) Human plasma cholesteryl ester transfer protein consists of a mixture of two forms reflecting variable glycosylation at asparagines 341. Biochemistry 32:5121–5126

    Article  PubMed  CAS  Google Scholar 

  24. Apweiler R, Hermjakob H, Sharon N (1999) On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta 1473:4–8

    PubMed  CAS  Google Scholar 

  25. Marshall R (1972) Glycoproteins. Annu Rev Biochem 41:673–702

    Article  PubMed  CAS  Google Scholar 

  26. Spiro RG (2002) Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds. Glycobiology 12:43R–56R

    Article  PubMed  CAS  Google Scholar 

  27. Kakko S, Tamminen M, Paivansalo M et al (2000) Cholesteryl ester transfer protein gene polymorphisms are associated with carotid atherosclerosis in men. Eur J Clin Invest 30:18–25

    Article  PubMed  CAS  Google Scholar 

  28. Kakko S, Tamminen M, Kesaniemi YA, Savolainen MJ (1998) R451Q mutation in the cholesteryl ester transfer protein(CETP) gene is associated with high plasma CETP activity. Atherosclerosis 136:233–240

    Article  PubMed  CAS  Google Scholar 

  29. Agerholm-Larsen B, Tybjaerg-Hansen A, Schnohr P et al (2000) Common cholesteryl ester transfer protein mutations decreased HDL cholesterol, and possible decreased risk of ischemic heart disease. Circulation 102:2197–2203

    PubMed  CAS  Google Scholar 

  30. Kaplowitz N (2006) Liver biology and pathobiology. Hepatology 43:S235–S238

    Article  PubMed  CAS  Google Scholar 

  31. Zhou H, Li Z, Silver DL, Jiang XC (2006) Cholesteryl ester transfer protein (CETP) expression enhances HDL cholesteryl ester liver delivery, which is independent of scavenger receptor BI, LDL receptor related protein and possibly LDL receptor. Biochim Biophys Acta 1761:1482–1488

    PubMed  CAS  Google Scholar 

  32. Radeau T, Lau P, Robb M et al (1995) Cholesteryl ester transfer protein (CETP) mRNA abundance in human adipose tissue: relationship to cell size and membrane cholesterol content. J Lipid Res 36:2552–2561

    PubMed  CAS  Google Scholar 

  33. Zhou H, Li Z, Hojjati MR et al (2006) Adipose tissue-specific CETP expression in mice: impact on plasma lipoprotein metabolism. J Lipid Res 47:2011–2019

    Article  PubMed  CAS  Google Scholar 

  34. Welply JK, Shenbagamurthi P, Lennarz WJ, Naider F (1983) Substrate recognition by oligosaccharyl transferase. Studies on glycosylation of modified Asn-X-Thr/Ser tripeptides. J Biol Chem 258:11856–11863

    PubMed  CAS  Google Scholar 

  35. Yan A, Lennarz WJ (2005) Unraveling the mechanism of protein N-glycosylation. J Biol Chem 280:3121–3124

    Article  PubMed  CAS  Google Scholar 

  36. Ben-Dor S, Esterman N, Rubin E, Sharon N (2004) Biases and complex patterns in the residues flanking protein N-glycosylation sites. Glycobiology 14:95–101

    Article  PubMed  CAS  Google Scholar 

  37. Schimmel PR, Flory PJ (1968) Conformational energies and configurational statistics of copolypeptides containing l-proline. J Mol Biol 34:105–120

    Article  PubMed  CAS  Google Scholar 

  38. Macarthur MW, Thornton JM (1991) Influence of proline residues on protein conformation. J Mol Biol 218:397–412

    Article  PubMed  CAS  Google Scholar 

  39. Ho BK, Brasseur R (2005) The Ramachandran plots of glycine and pre-proline. BMC Struct Biol 5:14

    Article  PubMed  Google Scholar 

  40. Barlow DJ, Thornton JM (1988) Helix geometry in proteins. J Mol Biol 201:601–619

    Article  PubMed  CAS  Google Scholar 

  41. Brandl CJ, Deber CM (1986) Hypothesis about the function of membrane-buried proline residues in transport proteins. Proc Natl Acad Sci USA 83:917–921

    Article  PubMed  CAS  Google Scholar 

  42. Qiu X, Mistry A, Ammirati MJ et al (2007) Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat Struct Mol Biol 14:106–113

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Dr. Xue-wei Zhu and Myngan Doung from Department of Pathology/Lipid Sciences, Wake Forest University School of Medicine, USA, for correcting English. This work was supported by the National Natural Science Foundation of China (No. 39770168) and the Doctor Research Fund from Inner Mongolia Agricultural University (No. BJ05-34).

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Authors and Affiliations

  1. College of Life Sciences, Inner Mongolia Agricultural University, Hohhot, 010018, China

    Huirong Liu

  2. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Dong-Dan-San-Tiao 5, Beijing, 100005, China

    Gang Wu & Baosheng Chen

  3. Beijing Center for ADR Monitoring, Beijing, 100011, China

    Bing Zhou

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  1. Huirong Liu
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  2. Gang Wu
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  3. Bing Zhou
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  4. Baosheng Chen
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Correspondence to Huirong Liu or Baosheng Chen.

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Liu, H., Wu, G., Zhou, B. et al. Structure and Function of Cholesteryl Ester Transfer Protein in the Tree Shrew. Lipids 46, 607–616 (2011). https://doi.org/10.1007/s11745-011-3552-2

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  • DOI: https://doi.org/10.1007/s11745-011-3552-2

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