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Total Parenteral Nutrition Leads to Alteration of Hepatocyte Cell Cycle Gene Expression and Proliferation in the Mouse

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Abstract

Total parenteral nutrition (TPN) is correlated with progressive liver injury. Such injury may be associated with either an increase or decrease in hepatocyte growth. The goal of these experiments was to determine TPN-related alterations in intrahepatic genes, as they relate with the cell cycle, using microarray techniques. After 7 days of infusion of saline or TPN-solution, hepatocyte gene expression was examined with a 5000-cDNA microarray chip. TPN was associated with an up-regulation of the cyclin kinase Cdc25B mRNA, which controls the cell cycle at the G2/M phase. Based on this, our studies were directed at alterations in genes related to mitosis in this phase of the cell cycle. mRNA expression of mitotic phase inducers and inhibitors were examined. Cdc25B1 mRNA expression increased with TPN. TPN also led to additional significant alterations in the expression of other factors which mediate proliferation in this phase of mitosis. Histologically, TPN resulted in a significant decline in hepatocyte proliferation. Coincident with the alteration in cyclin expression was a significant decrease in hepatocytes in the G2/M phase with TPN administration. This study demonstrates significant alterations in cell cycle gene expression with TPN. The findings correlate with a loss of hepatocyte proliferation and may give insight into the potential mechanism of TPN-induced hepatocyte injury.

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References

  1. Teitelbaum DH (1997) Parenteral nutrition-associated cholestasis. Curr Opin Pediatr 9:270–275

    Article  PubMed  CAS  Google Scholar 

  2. Karrer F, Bensard D (2000) Neonatal cholestasis. Semin Pediatr Surg 9:166–169

    Article  PubMed  CAS  Google Scholar 

  3. Angelico M, Della Guardia P (2000) Hepatobiliary complications associated with total parenteral nutrition. Aliment Pharmacol Ther 14(Suppl 2):54–57

    Article  PubMed  Google Scholar 

  4. Chou YH, Yau KI, Hsu HC, Chang MH (1993) Total parenteral nutrition-associated cholestasis in infants: clinical and liver histologic studies. Acta Paediatr Sin 34(4):264–271

    PubMed  CAS  Google Scholar 

  5. Beath SV, Davies P, Papadopoulou A, et al. (1996) Parenteral nutrition-related cholestasis in postsurgical neonates: multivariate analysis of risk factors. J Pediatr Surg 31(4):604–606

    Article  PubMed  CAS  Google Scholar 

  6. Mullick FG, Moran CA, Ishak KG (1994) Total parenteral nutrition: a histopathologic analysis of the liver changes in 20 children. Mod Pathol 7(2):190–194

    PubMed  CAS  Google Scholar 

  7. Benjamin DR (1981) Hepatobiliary dysfunction in infants and children associated with long-term total parenteral nutrition. A clinico-pathologic study. Am J Clin Pathol 76(3):276–283

    CAS  Google Scholar 

  8. Drongowski RA, Coran AG (1989) An analysis of factors contributing to the development of total parenteral nutrition-induced cholestasis. J Parent Enter Nutr 13(6):586–589

    CAS  Google Scholar 

  9. Btaiche IF, Khalidi N (2002) Parenteral nutrition-associated liver complications in children. Pharmacotherapy 22:188– 211

    Article  PubMed  Google Scholar 

  10. Heubi JE, Daugherty CC (1990) Neonatal cholestasis: an approach for the practicing pediatrician. Curr Probl Pediatr 20(5):233–295

    Article  PubMed  CAS  Google Scholar 

  11. Iyer K, Spitz L, Clayton P (1998) New insight into mechanims of parenteral nutrition - associated cholestasis: role of plant sterols. J Pediatr Surg 33(1):1–6

    Article  PubMed  CAS  Google Scholar 

  12. Aitman T (2001) DNA microarrays in medical practice. Br Med J 323:611

    Article  CAS  Google Scholar 

  13. Lockhart D, Winzeler E (2000) Genomics, gene expression and DNA arrays. Nature 405:827–836

    Article  PubMed  CAS  Google Scholar 

  14. Bulera S, Eddy S, Ferguson E, et al. (2001) RNA expression in the early characterization of hepatotoxicants in Wistar rats by high-density DNA microarrays. Hepatology 33:1239–1258

    Article  PubMed  CAS  Google Scholar 

  15. McGaughan G, Shackel N, Gorrell M (2001) Discussion on differential gene expression between chronic hepatitis B and C hepatic lesion. Gastroenterology 121:1263–1269

    Article  PubMed  CAS  Google Scholar 

  16. Shackel N, McGuinness P, Abbott C, et al. (2001) Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression. Gut 49:565–570

    Article  PubMed  CAS  Google Scholar 

  17. Kiristioglu I, Teitelbaum DH (1998) Alteration of the intestinal intraepithelial lymphocytes during total parenteral nutrition. J Surg Res 79(2):91–96

    Article  PubMed  CAS  Google Scholar 

  18. Russo T, Zambrano N, Esposito F, et al. (1995) A p53-independent pathway for activation of WAF1/CIP1 expression following oxidative stress. J Biol Chem 270:29386–19391

    Article  PubMed  CAS  Google Scholar 

  19. Yang H, Fan Y, Teitelbaum DH (2003) Intraepithelial lymphocyte-derived interferon-gamma evokes enterocyte apoptosis with parenteral nutrition in mice. Am J Physiol Gastrointest Liver Physiol 284(4):G629–G637

    PubMed  CAS  Google Scholar 

  20. Evans W (1970) Fractionation of liver plasma membranes prepared by zonal centrifugation. Biochem J 166:833–842

    Google Scholar 

  21. Doucet J, Trifaro J (1988) A discontinuous and highly porous sodium dodecyl sulfate polyacrylamide slab gel system of high resolution. Anal Biochem 168:265–271

    Article  PubMed  CAS  Google Scholar 

  22. Fraker P, King L, Lill-Elghanian D, Telford W (1995) Quantification of apoptotic events in pure and heterogeneous populations of cells using the flow cytometer. Methods Cell Biol 46:57–76

    PubMed  CAS  Google Scholar 

  23. Goldstein D, Dudoit S, Speed T (2000) Power of a score test for quantitative trait linkage analysis of relative pairs. Genet Epidemiol 19(Suppl 1):S85–S91

    Article  PubMed  Google Scholar 

  24. Peden V, Witzleben C, Skelton M (1971) Total parenteral nutrition [Letter]. J Pediatr 78:180–181

    PubMed  CAS  Google Scholar 

  25. Sax HC, Bower RH (1988) Hepatic complications of total parenteral nutrition. J Parent and Enter Nutr 12(6):615– 618

    CAS  Google Scholar 

  26. Bell R, Ferry G, Smith E (1986) Total parenteral nutrition-associated cholestasis in infants. J Parent Enter Nutr 10:356– 359

    CAS  Google Scholar 

  27. Merritt R (1986) Cholestasis associated with total parenteral nutrition. J Pediatr Gastroenterol Nutr 5:9–22

    Article  PubMed  CAS  Google Scholar 

  28. Pines J (1999) Cell cycle. Checkpoint on the nuclear frontier. Nature 397:104–105

    CAS  Google Scholar 

  29. Pines J (1999) Four-dimensional control of the cell cycle. Nat Cell Biol 1:E3–E9

    Article  CAS  Google Scholar 

  30. Gould K, Nurse P (1989) Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 342:39–40

    Article  PubMed  CAS  Google Scholar 

  31. Lammer C, Wagerer S, Saffrich R, et al. (1998) The cdc25B phosphatase is essential for the G2/M phase transition in human cells. J Cell Sci 111:2445–2453

    PubMed  CAS  Google Scholar 

  32. Miyata H, Doki Y, Yamamoto H, et al. (2001) Overexpression of CDC25B overrides radiation-induced G2-M arrest and results in increased apoptosis in esophageal cancer cells. Cancer Res 61:3188–3193

    PubMed  CAS  Google Scholar 

  33. Gasparotto D, Maestro R, Piccinin S, et al. (1997) Overexpression of CDC25A and CDC25B in head and neck cancers. Cancer Res 57:2366–2369

    PubMed  CAS  Google Scholar 

  34. Forrest A, McCormack A, DeSouza C, et al. (1999) Multiple splicing variants of cdc25B regulate G2/M progression. Biochem Biophys Res Commun 260:510–515

    Article  PubMed  CAS  Google Scholar 

  35. Pasternack M Jr, Liu X, Goodman RA, Rannels DE (1997) Regulated stimulation of epithelial cell DNA synthesis by fibroblast-derived mediators. Am J Physiol 272(4, Pt 1):L619–L630

    PubMed  CAS  Google Scholar 

  36. Weinert T (1997) A DNA damage checkpoint meets the cell cycle engine. Science 277:1450–1451

    Article  PubMed  CAS  Google Scholar 

  37. Buchman AL (2003) Choline deficiency during parenteral nutrition in humans. Nutr Clin Pract 18:353–358

    Article  PubMed  Google Scholar 

  38. Spencer AU, Tracy T, Auothmany M, et al. (2005) Neonatal risk of parenteral nutrition-associated cholestasis: A multivariate analysis of the effect of taurine. J Parent Enter Nutr 29(5):337–344

    Google Scholar 

  39. Staunton M, Phelan DM (1995) Manganese toxicity in a patient with cholestasis receiving total parenteral nutrition [letter; comment]. Anaesthesia 50(7):665

    PubMed  CAS  Google Scholar 

  40. Moss RL, Haynes AL, Pastuszyn A, Glew RH (1999) Methionine infusion reproduces liver injury of parenteral nutrition cholestasis. Pediatr Res 45(5, Pt 1):664–668

    PubMed  CAS  Google Scholar 

  41. Bunz F, Dutriaux A, Lengauer C, et al. (1998) Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282:1497–1501

    Article  PubMed  CAS  Google Scholar 

  42. Chan T, Hwang P, Hermeking H, et al. (2000) Cooperative effects of genes controlling the G(2)/M checkpoint. Genes Dev 14:1584–1588

    PubMed  CAS  Google Scholar 

  43. De Handt H, Elwi A, Soliman M (1966) Observations of the binucleate cells of the liver. Nature 212:827–829

    Article  PubMed  CAS  Google Scholar 

  44. Chen Y, Wan B (1986) A study on amitosis of the nucleus of the mammalian cell. I. A study under the light and transmission electron microscope. Acta Anat (Basel) 127:69–71

    CAS  Google Scholar 

  45. Hennig A, Elias H (1971) Frequency of binuclear liver cells. Verh Anat Ges 66:475–482

    PubMed  CAS  Google Scholar 

  46. Skladanowski A (2002) Modulation of G2 arrest enhances cell death induced by the antitumor 1-nitroacridine derivative, nitracrine. Apoptosis 7:347–359

    Article  PubMed  CAS  Google Scholar 

  47. Strathdee G, Sansom O, Sim A, et al. (2001) A role for mismatch repair in control of DNA ploidy following DNA damage. Oncogene 20:1923–1927

    Article  PubMed  CAS  Google Scholar 

  48. Yan H, Papadopoulos N, Marra G, et al. (2000) Conversion of diploidy to haploidy. Nature 403:723–724

    Article  PubMed  CAS  Google Scholar 

  49. Alverdy JC, Aoys E, Moss GS (1988) Total parenteral nutrition promotes bacterial translocation from the gut. Surgery 104(2):185–190

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH Grant AI44076-01 and also supported in part by the UM-Comprehensive Cancer Center, NIH 5P30CA46592I.

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Authors and Affiliations

  1. Section of Pediatric Surgery, C. S. Mott Children’s Hospital, Department of Surgery, University of Michigan Medical School, F3970 Mott Children’s Hospital, Box 0245, Ann Arbor, Michigan, 48109, USA

    Yuko Tazuke, Barbara E. Wildhaber, Hua Yang & Daniel H. Teitelbaum

  2. Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Joseph Washburn

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  1. Yuko Tazuke
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  2. Barbara E. Wildhaber
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  3. Hua Yang
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  4. Joseph Washburn
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  5. Daniel H. Teitelbaum
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Correspondence to Daniel H. Teitelbaum.

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Tazuke, Y., Wildhaber, B.E., Yang, H. et al. Total Parenteral Nutrition Leads to Alteration of Hepatocyte Cell Cycle Gene Expression and Proliferation in the Mouse. Dig Dis Sci 52, 920–930 (2007). https://doi.org/10.1007/s10620-006-9364-1

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  • DOI: https://doi.org/10.1007/s10620-006-9364-1

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