Skip to main content
SpringerLink
Log in

Identification of Branched Chain Amino Acids; Underlying Molecular Pathways Using Transcriptomic Analysis: Application to Cirrhosis

  • Chapter
  • First Online:
Branched Chain Amino Acids in Clinical Nutrition

Part of the book series: Nutrition and Health ((NH))

  • 1374 Accesses

Abstract

Oral administration of branched-chain amino acids (BCAA) is important in improving the prognosis of patients with chronic liver disease. BCAA can improve albumin synthesis, hepatic encephalopathy, insulin resistance, and suppress hepatocarcinoma, leading to higher event-free survival rate and better quality of life. We addressed the effects of BCAA dietary supplementation on global gene expression in liver and skeletal muscle and the molecular mechanisms underlying the improvement in liver cirrhosis using DNA microarray analysis combined with RNase protection assay. We established, for the first time, the regulatory gene pathways of processes involved in hepatic fibrosis and energy metabolism (hypoalbuminemia, hyperammonemia, and carbohydrate catabolism, and their relationships) under BCAA supplementation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Tsuchiya M, Sakaida I, Okamoto M, Okita K. The effect of a late evening snack in patients with liver cirrhosis. Hepatol Res. 2005;31:95–103.

    Article  PubMed  Google Scholar 

  2. Urata Y, Okita K, Korenaga K, et al. The effect of supplementation with branched-chain amino acids in patients with liver cirrhosis. Hepatol Res. 2007;37:510–6.

    Article  CAS  PubMed  Google Scholar 

  3. Parker PJ, Randle PJ. Partial purification and properties of branched-chain 2-oxo acid dehydrogenase of Ox liver. Biochem J. 1978;171:751–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Ohno T, Tanaka Y, Sugauchi F, et al. Suppressive effect of oral administration of branched-chain amino acid granules on oxidative stress and inflammation in HCV-positive patients with liver cirrhosis. Hepatol Res. 2008;38:683–8.

    Article  CAS  PubMed  Google Scholar 

  5. Moriwaki H, Shiraki M, Fukushima H, et al. Long-term outcome of branched-chain amino acid treatment in patients with liver cirrhosis. Hepatol Res. 2008;38:S102–6.

    Article  PubMed  Google Scholar 

  6. Kajiwara K, Okuno M, Kobayashi T, et al. Oral supplementation with branched chain amino acids improves survival rate of rats with carbon tetrachloride-induced liver cirrhosis. Dig Dis Sci. 1998;43:1572–9.

    Article  CAS  PubMed  Google Scholar 

  7. Muto Y, Sato S, Watanabe A, et al. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res. 2006;35:204–14.

    CAS  PubMed  Google Scholar 

  8. Kato M, Moriwaki H, Muto Y. Impaired metabolism of amino acid and protein in patients with liver cirrhosis. Nihon Rinsho. 1994;52:145–9.

    CAS  PubMed  Google Scholar 

  9. Michitaka K, Hiraoka A, Kume M, et al. Amino acid imbalance in patients with chronic liver diseases. Hepatol Res. 2010;40:393–8.

    Article  CAS  PubMed  Google Scholar 

  10. Kato M, Miwa Y, Tajika M, et al. Preferential use of branched-chain amino acids an energy substrate in patients with liver cirrhosis. Intern Med. 1998;37:429–34.

    Article  CAS  PubMed  Google Scholar 

  11. Yamato M, Muto M, Yoshida T, et al. Clearance rate of plasma branched-chain amino acids correlates significantly with blood ammonia level in patient with liver cirrhosis. Int Hepatol Commun. 1995;3:91–6.

    Article  Google Scholar 

  12. Yamauchi M, Takeda K, Sakamoto K, et al. Effect of oral branched chain amino acid supplementation in the late evening on the nutritional state of patients with liver cirrhosis. Hepatol Res. 2001;21:199–204.

    Article  CAS  PubMed  Google Scholar 

  13. Nakaya Y, Okita K, Suzuki K, et al. BCAA-enriched snack improves nutritional state of cirrhosis. Nutrition. 2007;23:113–20.

    Article  CAS  PubMed  Google Scholar 

  14. Iwasa J, Shimizu M, Shiraki M, et al. Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/dbmice. Cancer Sci. 2010;101:460–7.

    Article  CAS  PubMed  Google Scholar 

  15. Laviano A, Meguid MM, Inui A, Rossi-Fanelli F. Role of leucine in regulating food intake. Science. 2006;313:1236–8.

    Article  CAS  PubMed  Google Scholar 

  16. Dennis PB, Jaeschke A, Saitoh M, et al. Mammalian TOR, a homeostatic ATP sensor. Science. 2001;294:1102–5.

    Article  CAS  PubMed  Google Scholar 

  17. Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110:177–89.

    Article  CAS  PubMed  Google Scholar 

  18. Matsumura T, Morinaga Y, Fujitani S, et al. Oral administration of branched-chain amino acids activates the mTOR signal in cirrhotic rat liver. Hepatol Res. 2005;33:27–32.

    Article  CAS  PubMed  Google Scholar 

  19. Holecek M, Simek J, Palicka V, Zadak Z. Effect of glucose and branched chain amino acid (BCAA) infusion on onset of liver regeneration and plasma amino acid pattern in partially hepatectomized rats. J Hepatol. 1991;13:14–20.

    Article  CAS  PubMed  Google Scholar 

  20. Rigotti P, Peters JC, Tranberg KG, Fischer JE. Effects of amino acid infusions on liver regeneration after partial hepatectomy in the rat. JPEN J Parenter Enteral Nutr. 1986;10:17–20.

    Article  CAS  PubMed  Google Scholar 

  21. Kakazu E, Kanno N, Ueno Y, Shimosegawa T. Extracellular branched-chain amino acids, especially valine, regulate maturation and function of monocyte-derived dendritic cells. J Immunol. 2007;179:137–46.

    Article  Google Scholar 

  22. Suzuki K, Kato A, Iwai M. Branched-chain amino acid treatment in patients with liver cirrhosis. Hepatol Res. 2004;30S:25–9.

    Article  PubMed  Google Scholar 

  23. Yoshizawa F. Regulation of protein synthesis by branched-chain amino acids in vivo. Biochem Biophys Res Commun. 2004;313:417–22.

    Article  CAS  PubMed  Google Scholar 

  24. Desikan V, Mileva I, Garlick J, et al. The effect of oral leucine on protein metabolism in adolescents with type 1 diabetes mellitus. Int J Pediatr Endocrinol. 2010;2010:493258.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Doi M, Yamaoka I, Nakayama M, et al. Hypoglycemic effect of isoleucine involves increased muscle glucose uptake and whole body glucose oxidation and decreased hepatic gluconeogenesis. Am J Physiol Endocrinol Metab. 2007;292:E1683–93.

    Article  CAS  PubMed  Google Scholar 

  26. Sakaida I, Tsuchiya M, Okamoto M, et al. Late evening snack and the change of blood glucose level in patients with liver cirrhosis. Hepatol Res. 2004;30:67–72.

    Article  Google Scholar 

  27. Miyake T, Abe M, Furukawa S, et al. Long-term branched-chain amino acid supplementation improves glucose tolerance in patients with nonalcoholic steatohepatitis-related cirrhosis. Intern Med. 2012;51:2151–5.

    Article  CAS  PubMed  Google Scholar 

  28. Takeshita Y, Takamura T, Kita Y, et al. Beneficial effect of branched-chain amino acid supplementation on glycemic control in chronic hepatitis C patients with insulin resistance: implications for type 2 diabetes. Metabolism. 2012;61:1388–94.

    Article  CAS  PubMed  Google Scholar 

  29. Singh B, Saxena A. Surrogate markers of insulin resistance: a review. World J Diabetes. 2010;1:36–47.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Nkontchou G, Bastard JP, Ziol M, et al. Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis. J Hepatol. 2010;53:827–33.

    Article  CAS  PubMed  Google Scholar 

  31. Yoshiji H, Noguchi R, Kitade M, et al. Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol. 2009;44:483–91.

    Article  CAS  PubMed  Google Scholar 

  32. Poon RT, Yu WC, Fan ST, et al. Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a randomized trial. Aliment Pharmacol Ther. 2004;19:779–88.

    Article  CAS  PubMed  Google Scholar 

  33. Nishikawa H, Osaki Y, Inuzuka T, et al. Branched-chain amino acid treatment before transcatheter arterial chemoembolization for hepatocellular carcinoma. World J Gastroenterol. 2012;18:1379–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Morihara D, Iwata K, Hanano T, et al. Late-evening snack with branched-chain amino acids improves liver function after radiofrequency ablation for hepatocellular carcinoma. Hepatol Res. 2012;42:658–67.

    Article  CAS  PubMed  Google Scholar 

  35. Togo S, Tanaka K, Morioka D, et al. Usefulness of granular BCAA after hepatectomy for liver cancer complicated with liver cirrhosis. Nutrition. 2005;21:480–6.

    Article  CAS  PubMed  Google Scholar 

  36. Muto Y, Sato S, Watanabe A, et al. Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol. 2005;3:705–13.

    Article  CAS  PubMed  Google Scholar 

  37. Hayaishi S, Chung H, Kudo M, et al. Oral branched-chain amino acid granules reduce the incidence of hepatocellular carcinoma and improve event-free survival in patients with liver cirrhosis. Dig Dis. 2011;29:326–32.

    Article  PubMed  Google Scholar 

  38. Nagao Y, Kawaguchi T, Ide T, et al. Effect of branched-chain amino acid-enriched nutritional supplementation on interferon therapy in Japanese patients with chronic hepatitis C virus infection: a retrospective study. Virol J. 2012;9:282–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Kawaguchi T, Torimura T, Takata A, et al. Valine, a branched-chain amino acid, reduced HCV viral load and led to eradication of HCV by interferon therapy in a decompensated cirrhotic patient. Case Rep Gastroenterol. 2012;6:660–7.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Park SH, Choi MS, Park T. Changes in the hepatic gene expression profile in a rat model of chronic ethanol treatment. Food Chem Toxicol. 2008;46:1378–88.

    Article  CAS  PubMed  Google Scholar 

  41. Zindy PJ, L’Helgoualc’h A, Bonnier D, et al. Upregulation of the tumor suppressor gene menin in hepatocellular carcinomas and its significance in fibrogenesis. Hepatology. 2006;44:1296–307.

    Article  CAS  PubMed  Google Scholar 

  42. Shackel NA, McGuinness PH, Abbott CA, et al. Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression. Gut. 2001;49:565–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW. Novel differential gene expression in human cirrhosis detected by suppression subtractive hybridization. Hepatology. 2003;38:577–88.

    Article  CAS  PubMed  Google Scholar 

  44. Jia H, Takahashi S, Saito K, Kato H. DNA microarray analysis identified molecular pathways mediating the effect of the supplementation of branched amino acids on CCl4-induced cirrhosis in rats. Mol Nutr Food Res. 2013;57:291–306.

    Article  CAS  PubMed  Google Scholar 

  45. Okuno M, Moriwaki H, Kato M, Muto Y, Kojima S. Changes in the ratio of branched-chain to aromatic amino acids affect the secretion of albumin in cultured rat hepatocytes. Biochem Biophys Res Commun. 1995;214:1045–50.

    Article  CAS  PubMed  Google Scholar 

  46. Hara K, Yonezawa K, Weng QP, et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem. 1998;273:14484–94.

    Article  CAS  PubMed  Google Scholar 

  47. Chávez E, Reyes-Gordillo K, Segovia J, et al. Resveratrol prevents fibrosis, NF-κB activation and TGF-β increases induced by chronic CCl4 treatment in rats. J Appl Toxicol. 2008;28:35–43.

    Article  PubMed  Google Scholar 

  48. Gribilas G, Zarros A, Zira A, et al. Involvement of hepatic stimulator substance in experimentally induced fibrosis and cirrhosis in the rat. Dig Dis Sci. 2008;54:2367–76.

    Article  PubMed  Google Scholar 

  49. Arthur MJ. Degradation of matrix proteins in liver fibrosis. Pathol Res Pract. 1994;190:825–33.

    Article  CAS  PubMed  Google Scholar 

  50. Chávez E, Segovia J, Shibayama M, et al. Antifibrotic and fibrolytic properties of celecoxib in liver damage induced by carbon tetrachloride in the rat. Liver Int. 2010;30:969–78.

    Article  PubMed  Google Scholar 

  51. Hazell AS, Butterworth RF. Hepatic encephalopathy: an update of pathophysiologic mechanisms. Proc Soc Exp Biol Med. 2000;222:99–112.

    Article  Google Scholar 

  52. Fujii T, Kohno M, Hirayama C. Metabolism of 15N-ammonia in patients with cirrhosis. Hepatology. 1992;16:347–52.

    Article  CAS  PubMed  Google Scholar 

  53. Holeček M, Šprongl L, Tichý M. Effect of hyperammonemia on leucine and protein metabolism in rats. Metabolism. 2000;49:1330–4.

    Article  PubMed  Google Scholar 

  54. Krahenbuhl S, Weber Jr FL, Brass EP. Decreased hepatic glycogen content and accelerated response to starvation in rats with carbon tetrachloride-induced cirrhosis. Hepatology. 1991;14:1189–95.

    CAS  PubMed  Google Scholar 

  55. Romijn JA, Endert E, Sauerwein HP. Glucose and fat metabolism during short-term starvation in cirrhosis. Gastroenterology. 1991;100:731–7.

    CAS  PubMed  Google Scholar 

  56. Nishitani S, Matsumura T, Fujitani S, et al. Leucine promotes glucose uptake in skeletal muscles of rats. Biochem Biophys Res Commun. 2002;299:693–6.

    Article  CAS  PubMed  Google Scholar 

  57. Svegliati Baroni G, D’Ambrosio L, Ferreti G, et al. Fibrogenic effect of oxidative stress on rat hepatic stellate cells. Hepatology. 1998;27:720–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Corporate Sponsored Research Program ‘Food for Life’, Organization for Interdisciplinary Research Projects, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan

    Huijuan Jia Ph.D., Wanping Aw Ph.D. & Hisanori Kato Ph.D.

  2. Naruto Research Institute, Research and Development Center, Otsuka Pharmaceutical Factory, Inc., 115 Kuguhara, Tateiwa, Muya-cho, Naruto, Tokushima, Japan

    Nozomi Tamura M.S. & Masako Doi Ph.D.

Authors
  1. Huijuan Jia Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nozomi Tamura M.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wanping Aw Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masako Doi Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hisanori Kato Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hisanori Kato Ph.D. .

Editor information

Editors and Affiliations

  1. Intensive Care, Barnet and Chase Farm Hospitals, Royal Free London NHS Foundation Trust, London, United Kingdom

    Rajkumar Rajendram

  2. Diabetes and Nutritional Sciences, Kings College London, London, United Kingdom

    Victor R. Preedy

  3. Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this chapter

Cite this chapter

Jia, H., Tamura, N., Aw, W., Doi, M., Kato, H. (2015). Identification of Branched Chain Amino Acids; Underlying Molecular Pathways Using Transcriptomic Analysis: Application to Cirrhosis. In: Rajendram, R., Preedy, V., Patel, V. (eds) Branched Chain Amino Acids in Clinical Nutrition. Nutrition and Health. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1914-7_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-1914-7_11

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-1913-0

  • Online ISBN: 978-1-4939-1914-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation