Alpha-Tocopherol Transfer Protein (${\alpha}$-TTP): Insights from Alpha-Tocopherol Transfer Protein Knockout Mice

  • Lim, Yun-Sook (Department of Food and Nutrition, Kyung Hee University) ;
  • Traber, Maret G. (Department of Nutrition and Food Management, Linus Pauling Institute, Oregon State University)
  • Published : 2007.12.31

Abstract

Alpha-tocopherol transfer protein (${\alpha}$-TTP) is a liver cytosolic transport protein that faciliates ${\alpha}$-tocopherol (${\alpha}$-T) transfer into liver secreted plasma lipoproteins. Genetic defects in ${\alpha}$-TTP, like dietary vitamin E deficiency, are associated with infertility, muscular weakness and neurological disorders. Both human and ${\alpha}$-TTP deficient (${\alpha}-TTP^{-/-}$) mice exhibit severe plasma and tissue vitamin E deficiency that can be attenuated by sufficient dietary ${\alpha}$-T supplementations. In this review, we summarize the literature concerning studies utilizing the ${\alpha}-TTP^{-/-}$ mice. Levels of vitamin E in the ${\alpha}-TTP^{-/-}$ mice do not appear to be directly related to the amounts of dietary ${\alpha}$-T or to the levels of ${\alpha}$-TTP protein in tissues. The ${\alpha}-TTP^{-/-}$ mice appear to present a good model for investigating the specific role of ${\alpha}$-T in tissue vitamin E metabolism. Furthermore, ${\alpha}-TTP^{-/-}$ mice appear to be useful to elucidate functions of ${\alpha}$-TTP beyond its well recognized functions of transferring ${\alpha}$-T from liver to plasma lipoprotein fractions.

Keywords

References

  1. Arita M, Sato Y, Miyata A, Tanabe T, Takahashi E, Kayden HJ, Arai H & Inoue K (1995). Human alpha-tocopherol transfer protein: cDNA cloning, expression and chromosomal localization. Biochem J 306:437-443 https://doi.org/10.1042/bj3060437
  2. Ban R, Takitani K, Kim HS, Murata T, Morinobu T, Ogihara T & Tamai H (2002). alpha-Tocopherol transfer protein expression in rat liver exposed to hyperoxia. Free Radic Res 36:933-938 https://doi.org/10.1080/107156021000006644
  3. Beharka A, Redican S, Leka L & Meydani SN (1997). Vitamin E status and immune function. Methods Enzymol 282:247-263 https://doi.org/10.1016/S0076-6879(97)82112-X
  4. Boscoboinik D, Szewczyk A & Azzi A (1991a). Alpha-tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch Biochem Biophys 286:264-269 https://doi.org/10.1016/0003-9861(91)90039-L
  5. Boscoboinik D, Szewczyk A, Hensey C & Azzi A (1991b). Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C. J Biol Chem 266:6188-6194
  6. Catignani GL (1975). An alpha-tocopherol binding protein in rat river cytoplasm. Biochem Biophys Acta 497:349-357
  7. Copp RP, Wisniewski T, Hentati F, Larnaout A, Ben Hamida M & Kayden HJ (1999). Localization of alpha-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders. Brain Res 822:80-87 https://doi.org/10.1016/S0006-8993(99)01090-2
  8. Cuddihy SL, Musiek ES, Morrow JD & Dugan LL (2004). Long-term vitamin e deficiency in mice decreases superoxide radical production in brain. Ann N Y Acad Sci 1031:428-431 https://doi.org/10.1196/annals.1331.064
  9. Das P & Chowdhury M (1999). Vitamin E-deficiency induced changes in ovary and uterus. Mol Cell Biochem 198:151-156 https://doi.org/10.1023/A:1006954032164
  10. Desrumaux C, Risold PY, Schroeder H, Deckert V, Masson D, Athias A, Laplanche H, Le Guern N, Blache D, Jiang XC, Tall AR, Desor D & Lagrost L (2005). Phospholipid transfer protein (PLTP) deficiency reduces brain vitamin E content and increases anxiety in mice. Faseb J 19:296-297 https://doi.org/10.1096/fj.04-2400fje
  11. Doerflinger N, Linder C, Ouahchi K, Gyapay G, Weissenbach J, Le Paslier D, Rigault P, Belal S, Ben Hamida C & Hentati F et al. (1995). Ataxia with vitamin E deficiency: refinement of genetic localization and analysis of linkage disequilibrium by using new markers in 14 families. Am J Hum Genet 56:1116-1124
  12. Evans HM & Bishop KS (1922). On the existence of a hitherto unrecognizd dietary factor essential for reproduction. Science 56:650 https://doi.org/10.1126/science.56.1458.650
  13. Food and Nutrition Board & Institute of Medicine (2000). Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. National Academy Press, Washington. USA
  14. Gohil K, Godzdanker R, O'Roark E, Schock BC, Kaini RR, Packer L, Cross CE & Traber MG (2004). {alpha}-Tocopherol Transfer Protein Deficiency in Mice Causes Multi-Organ Deregulation of Gene Networks and Behavioral Deficits with Age. Ann N Y Acad Sci 1031:109-126 https://doi.org/10.1196/annals.1331.012
  15. Gohil K, Oommen S, Vasu VT, Aung HH & Cross CE (2007). Tocopherol transfer protein deficiency modifies nuclear receptor transcriptional networks in lungs: Modulation by cigarette smoke in vivo. Mol Aspects Med
  16. Gohil K, Schock BC, Chakraborty AA, Terasawa Y, Raber J, Farese RV, Jr., Packer L, Cross CE & Traber MG (2003). Gene expression profile of oxidant stress and neurodegeneration in transgenic mice deficient in alpha-tocopherol transfer protein. Free Radic Biol Med 35:1343-1354 https://doi.org/10.1016/S0891-5849(03)00509-4
  17. Goodwin B, Redinbo MR & Kliewer SA (2002). Regulation of cyp3a gene transcription by the pregnane x receptor. Annu Rev Pharmacol Toxicol 42:1-23 https://doi.org/10.1146/annurev.pharmtox.42.111901.111051
  18. Hoshino M, Masuda N, Ito Y, Murata M, Goto J, Sakurai M & Kanazawa I (1999). Ataxia with isolated vitamin E deficiency: a Japanese family carrying a novel mutation in the alpha-tocopherol transfer protein gene. Ann Neurol 45:809-812 https://doi.org/10.1002/1531-8249(199906)45:6<809::AID-ANA19>3.0.CO;2-9
  19. Hosomi A, Arita M, Sato Y, Kiyose C, Ueda T, Igarashi O, Arai H & Inoue K (1997). Affinity for alpha-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Lett 409:105-108 https://doi.org/10.1016/S0014-5793(97)00499-7
  20. Hosomi A, Goto K, Kondo H, Iwatsubo T, Yokota T, Ogawa M, Arita M, Aoki J, Arai H & Inoue K (1998). Localization of alpha-tocopherol transfer protein in rat brain. Neurosci Lett 256:159-162 https://doi.org/10.1016/S0304-3940(98)00785-X
  21. Jishage K, Arita M, Igarashi K, Iwata T, Watanabe M, Ogawa M, Ueda O, Kamada N, Inoue K, Arai H & Suzuki H (2001). Alpha-tocopherol transfer protein is important for the normal development of placental labyrinthine trophoblasts in mice. J Biol Chem 276:1669-1672 https://doi.org/10.1074/jbc.C000676200
  22. Kaempf-Rotzoll DE, Horiguchi M, Hashiguchi K, Aoki J, Tamai H, Linderkamp O & Arai H (2003). Human placental trophoblast cells express alpha-tocopherol transfer protein. Placenta 24:439-444 https://doi.org/10.1053/plac.2002.0966
  23. Kaempf-Rotzoll DE, Igarashi K, Aoki J, Jishage K, Suzuki H, Tamai H, Linderkamp O & Arai H (2002). Alpha-tocopherol transfer protein is specifically localized at the implantation site of pregnant mouse uterus. Biol Reprod 67:599-604 https://doi.org/10.1095/biolreprod67.2.599
  24. Leonard SW, Terasawa Y, Farese RV, Jr. & Traber MG (2002). Incorporation of deuterated RRR- or all-rac-alpha-tocopherol in plasma and tissues of alpha-tocopherol transfer protein--null mice. Am J Clin Nutr 75:555-560 https://doi.org/10.1093/ajcn/75.3.555
  25. Mardones P, Strobel P, Miranda S, Leighton F, Quinones V, Amigo L, Rozowski J, Krieger M & Rigotti A (2002). Alpha-tocopherol metabolism is abnormal in scavenger receptor class B type I (SR-BI)-deficient mice. J Nutr 132:443-449
  26. Mariotti C, Gellera C, Rimoldi M, Mineri R, Uziel G, Zorzi G, Pareyson D, Piccolo G, Gambi D, Piacentini S, Squitieri F, Capra R, Castellotti B & Di Donato S (2004). Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci 25:130-137 https://doi.org/10.1007/s10072-004-0246-z
  27. Meier R, Tomizaki T, Schulze-Briese C, Baumann U & Stocker A (2003). The molecular basis of vitamin E retention: structure of human alpha-tocopherol transfer protein. J Mol Biol 331:725-734 https://doi.org/10.1016/S0022-2836(03)00724-1
  28. Min KC, Kovall RA & Hendrickson WA (2003). Crystal structure of human alpha-tocopherol transfer protein bound to its ligand: implications for ataxia with vitamin E deficiency. Proc Natl Acad Sci USA 100:14713-14718
  29. Morley S, Panagabko C, Shineman D, Mani B, Stocker A, Atkinson J & Manor D (2004). Molecular determinants of heritable vitamin E deficiency. Biochemistry 43:4143-4149 https://doi.org/10.1021/bi0363073
  30. Muller-Schmehl K, Beninde J, Finckh B, Florian S, Dudenhausen JW, Brigelius-Flohe R & Schuelke M (2004). Localization of alphatocopherol transfer protein in trophoblast, fetal capillaries' endothelium and amnion epithelium of human term placenta. Free Radic Res 38:413-420 https://doi.org/10.1080/10715760310001659611
  31. Mustacich DJ, Leonard SW, Devereaux MW, Sokol RJ & Traber MG (2006). Alpha-tocopherol regulation of hepatic cytochrome P450s and ABC transporters in rats. Free Radic Biol Med 41:1069-1078 https://doi.org/10.1016/j.freeradbiomed.2006.06.022
  32. Oommen S, Vasu VT, Leonard SW, Traber MG, Cross CE & Gohil K (2007). Genome wide responses of murine lungs to dietary alpha-tocopherol. Free Radic Res 41:98-109 https://doi.org/10.1080/10715760600935567
  33. Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, Arai H, Inoue K, Mandel JL & Koenig M (1995). Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 9:141-145 https://doi.org/10.1038/ng0295-141
  34. Packer L (1991). Protective role of vitamin E in biological systems. Am J Clin Nutr 53:1050S-1055S https://doi.org/10.1093/ajcn/53.4.1050S
  35. Panagabko C, Morley S, Hernandez M, Cassolato P, Gordon H, Parsons R, Manor D & Atkinson J (2003). Ligand specificity in the CRAL-TRIO protein family. Biochemistry 42:6467-6474 https://doi.org/10.1021/bi034086v
  36. Panagabko C, Morley S, Neely S, Lei H, Manor D, & Atkinson J (2002). Expression and refolding of recombinant human alphatocopherol transfer protein capable of specific alpha-tocopherol binding. Protein Expr Purif 24:395-403 https://doi.org/10.1006/prep.2001.1576
  37. Qanungo S, Sen A & Mukherjea M (1999). Antioxidant status and lipid peroxidation in human feto-placental unit. Clin Chim Acta 285:1-12 https://doi.org/10.1016/S0009-8981(99)00051-0
  38. Ricciarelli R, Tasinato A, Clement S, Ozer NK, Boscoboinik D & Azzi A (1998). alpha-Tocopherol specifically inactivates cellular protein kinase C alpha by changing its phosphorylation state. Biochem J 334:243-249 https://doi.org/10.1042/bj3340243
  39. Schock BC, Van der Vliet A, Corbacho AM, Leonard SW, Finkelstein E, Valacchi G, Obermueller-Jevic U, Cross CE & Traber MG (2004). Enhanced inflammatory responses in alpha-tocopherol transfer protein null mice. Arch Biochem Biophys 423:162-169 https://doi.org/10.1016/j.abb.2003.12.009
  40. Schuelke M, Elsner A, Finckh B, Kohlschutter A, Hubner C & Brigelius-Flohe R (2000). Urinary alpha-tocopherol metabolites in alpha-tocopherol transfer protein-deficient patients. J Lipid Res 41:1543-1551
  41. Sen A & Mukherjea M (1998). Modulation of bilayer fluidity by lipid peroxidation of human placental syncytiotrophoblast membranes during embryogenesis. Indian J Biochem Biophys 35:216-223
  42. Tanito M, Yoshida Y, Kaidzu S, Chen ZH, Cynshi O, Jishage K, Niki E & Ohira A (2007). Acceleration of age-related changes in the retina in alpha-tocopherol transfer protein null mice fed a Vitamin E-deficient diet. Invest Ophthalmol Vis Sci 48:396-404 https://doi.org/10.1167/iovs.06-0872
  43. Terasawa Y, Ladha Z, Leonard SW, Morrow JD, Newland D, Sanan D, Packer L, Traber MG & Farese RV, Jr. (2000). Increased atherosclerosis in hyperlipidemic mice deficient in alpha -tocopherol transfer protein and vitamin E. Proc Natl Acad Sci U S A 97:13830-13834
  44. Traber MG (1999). Vitamin E. p. 347-361 in ME Shils, Olson, J.A., Shike, M. & Ross, A.C., eds, ed. Modern Nutrition in Health and Disease. Williams & Willkins, Baltimore
  45. Traber MG & Arai H (1999). Molecular mechanisms of vitamin E transport. Annu Rev Nutr 19:343-355 https://doi.org/10.1146/annurev.nutr.19.1.343
  46. Traber MG, Lane JC, Lagmay NR & Kayden HJ (1992). Studies on the transfer of tocopherol between lipoproteins. Lipids 27:657-663 https://doi.org/10.1007/BF02536020
  47. Traber MG, Siddens LK, Leonard SW, Schock B, Gohil K, Krueger SK, Cross CE & Williams DE (2005). Alpha-tocopherol modulates Cyp3a expression, increases gamma-CEHC production, and limits tissue gamma-tocopherol accumulation in mice fed high gammatocopherol diets. Free Radic Biol Med 38:773-785 https://doi.org/10.1016/j.freeradbiomed.2004.11.027
  48. Traber MG, Sokol RJ, Burton GW, Ingold KU, Papas AM, Huffaker JE & Kayden HJ (1990). Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver. J Clin Invest 85:397-407 https://doi.org/10.1172/JCI114452
  49. Trigatti B, Rigotti A & Krieger M (2000). The role of the highdensity lipoprotein receptor SR-BI in cholesterol metabolism. Curr Opin Lipidol 11:123-131 https://doi.org/10.1097/00041433-200004000-00004
  50. Vasu VT, Hobson B, Gohil K & Cross CE (2007). Genome-wide screening of alpha-tocopherol sensitive genes in heart tissue from alpha-tocopherol transfer protein null mice (ATTP (-/-)). FEBS Lett 581:1572-1578 https://doi.org/10.1016/j.febslet.2007.03.017
  51. Yokota T, Igarashi K, Uchihara T, Jishage K, Tomita H, Inaba A, Li Y, Arita M, Suzuki H, Mizusawa H & Arai H (2001). Delayed-onset ataxia in mice lacking alpha -tocopherol transfer protein: model for neuronal degeneration caused by chronic oxidative stress. Proc Natl Acad Sci USA 98:15185-15190
  52. Yokota T, Shiojiri T, Gotoda T, Arita M, Arai H, Ohga T, Kanda T, Suzuki J, Imai T, Matsumoto H, Harino S, Kiyosawa M, Mizusawa H & Inoue K (1997). Friedreich-like ataxia with retinitis pigmentosa caused by the His101Gln mutation of the alphatocopherol transfer protein gene. Ann Neurol 41:826-832 https://doi.org/10.1002/ana.410410621
  53. Yokota T, Uchihara T, Kumagai J, Shiojiri T, Pang JJ, Arita M, Arai H, Hayashi M, Kiyosawa M, Okeda R & Mizusawa H (2000). Postmortem study of ataxia with retinitis pigmentosa by mutation of the alpha-tocopherol transfer protein gene. J Neurol Neurosurg Psychiatry 68:521-525 https://doi.org/10.1136/jnnp.68.4.521