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Proline supplementation mitigates the early stage of liver injury in bile duct ligated rats

  • Reza Heidari EMAIL logo , Hamidreza Mohammadi , Vahid Ghanbarinejad , Asrin Ahmadi , Mohammad Mehdi Ommati , Hossein Niknahad , Akram Jamshidzadeh , Negar Azarpira and Narges Abdoli EMAIL logo
Published/Copyright: September 6, 2018

Abstract

Background

Proline is a proteinogenic amino acid with multiple biological functions. Several investigations have been supposed that cellular proline accumulation is a stress response mechanism. This amino acid acts as an osmoregulator, scavenges free radical species, boosts cellular antioxidant defense mechanisms, protects mitochondria, and promotes energy production. The current study was designed to investigate the effect of proline treatment on the liver in bile duct ligated (BDL) rats as an animal model of cholestasis/cirrhosis.

Methods

BDL rats were supplemented with proline-containing drinking water (0.25% and 0.5% w:v), and samples were collected at scheduled time intervals (3, 7, 14, 28, and 42 days after BDL surgery).

Results

Drastic elevation in the serum level of liver injury biomarkers and significant tissue histopathological changes were evident in BDL rats. Markers of oxidative stress were also higher in the liver of BDL animals. It was found that proline supplementation attenuated BDL-induced alteration in serum biomarkers of liver injury, mitigated liver histopathological changes, and alleviated markers of oxidative stress at the early stage of BDL operation (3, 7, and 14 days after BDL surgery).

Conclusions

The hepatoprotection provided by proline in BDL animals might be associated with its ability to attenuate oxidative stress and its consequences.

Acknowledgments

The instrumental facility provided from Pharmaceutical Sciences Research Center of Shiraz University of Medical Sciences is gratefully acknowledged. The current investigation was financially supported by the Vice-Chancellor for Research Affairs of Shiraz University of Medical Sciences (Funder Id: 10.13039/501100004320, Grant number: 95-01-36-13555).

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: Shiraz University of Medical Sciences (95-01-36-13555).

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Szabados L, Savoure A. Proline: a multifunctional amino acid. Trends Plant Sci 2010;15:89–97.10.1016/j.tplants.2009.11.009Search in Google Scholar PubMed

2. Banu MN, Hoque MA, Watanabe-Sugimoto M, Matsuoka K, Nakamura Y, Shimoishi Y, et al. Proline and glycinebetaine induce antioxidant defense gene expression and suppress cell death in cultured tobacco cells under salt stress. J Plant Physiol 2009;166:146–56.10.1016/j.jplph.2008.03.002Search in Google Scholar PubMed

3. Kaul S, Sharma SS, Mehta IK. Free radical scavenging potential of L-proline: evidence from in vitro assays. Amino Acids 2008;34:315–20.10.1007/s00726-006-0407-xSearch in Google Scholar PubMed

4. Krishnan N, Dickman MB, Becker DF. Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress. Free Radical Biol Med 2008;44:671–81.10.1016/j.freeradbiomed.2007.10.054Search in Google Scholar PubMed PubMed Central

5. Obayashi Y, Arisaka H, Yoshida S, Mori M, Takahashi M. Proline protects liver from d-galactosamine hepatitis by activating the IL-6/STAT3 survival signaling pathway. Amino Acids 2012;43:2371–80.10.1007/s00726-012-1317-8Search in Google Scholar PubMed

6. Obayashi Y, Arisaka H, Yoshida S, Mori M, Takahashi M. The protection mechanism of proline from D-galactosamine hepatitis involves the early activation of ROS-eliminating pathway in the liver. SpringerPlus 2015;4:199.10.1186/s40064-015-0969-8Search in Google Scholar PubMed PubMed Central

7. Ashraf M, Foolad M. Roles of glycine betaine and proline in improving plant abiotic stress resistance. Environ Exp Bot 2007;59:206–16.10.1016/j.envexpbot.2005.12.006Search in Google Scholar

8. Su J, Wu R. Stress-inducible synthesis of proline in transgenic rice confers faster growth under stress conditions than that with constitutive synthesis. Plant Sci 2004;166:941–8.10.1016/j.plantsci.2003.12.004Search in Google Scholar

9. Karimzadeh Toosi AE. Liver fibrosis: causes and methods of assessment, a review. Roman J Int Med 2015;53:304–14.10.1515/rjim-2015-0039Search in Google Scholar PubMed

10. Wang P, Koyama Y, Liu X, Xu J, Ma H-Y, Liang S, et al. Promising therapy candidates for liver fibrosis. Front Physiol 2016;7:47.10.3389/fphys.2016.00047Search in Google Scholar PubMed PubMed Central

11. Kim DY, Chung SI, Ro SW, Paik YH, Lee JI, Jung MK, et al. Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats. Apoptosis 2013;18:1481–91.10.1007/s10495-013-0896-5Search in Google Scholar PubMed

12. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134:1655–69.10.1053/j.gastro.2008.03.003Search in Google Scholar PubMed

13. Sánchez-Valle V, Chavez-Tapia NC, Uribe M, Méndez-Sánchez N. Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr Med Chem 2012;19:4850–60.10.2174/092986712803341520Search in Google Scholar PubMed

14. Tsukamoto H, Rippe R, Niemelä O, Lin M. Roles of oxidative stress in activation of Kupffer and Ito cells in liver fibrogenesis. J Gastroenterol Hepatol 1995;10:S50–3.10.1111/j.1440-1746.1995.tb01798.xSearch in Google Scholar

15. Ahmadian E, Pennefather PS, Eftekhari A, Heidari R, Eghbal MA. Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention. Expert Rev Gastroenterol Hepatol 2016;10:1279–88.10.1080/17474124.2016.1207523Search in Google Scholar PubMed

16. Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med 2000;21:49–98.10.1016/S0098-2997(00)00004-2Search in Google Scholar PubMed

17. Parola M, Robino G. Oxidative stress-related molecules and liver fibrosis. J Hepatol 2001;35:297–306.10.1016/S0168-8278(01)00142-8Search in Google Scholar PubMed

18. Luckey SW, Petersen DR. Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp Mol Pathol 2001;71:226–40.10.1006/exmp.2001.2399Search in Google Scholar PubMed

19. Copple BL, Jaeschke H, Klaassen CD. Oxidative stress and the pathogenesis of cholestasis. Semin Liver Dis 2010;30:195–204.10.1055/s-0030-1253228Search in Google Scholar PubMed

20. Krähenbühl S, Talos C, Lauterburg BH, Reichen J. Reduced antioxidative capacity in liver mitochondria from bile duct ligated rats. Hepatology 1995;22:607–12.10.1002/hep.1840220234Search in Google Scholar PubMed

21. Butterworth RF, Norenberg MD, Felipo V, Ferenci P, Albrecht J, Blei AT. Experimental models of hepatic encephalopathy: ISHEN guidelines. Liver Int 2009;29:783–8.10.1111/j.1478-3231.2009.02034.xSearch in Google Scholar PubMed

22. Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 2010;51:1062–9.10.1002/hep.23367Search in Google Scholar PubMed

23. Moezi L, Heidari R, Amirghofran Z, Nekooeian AA, Monabati A, Dehpour AR. Enhanced anti-ulcer effect of pioglitazone on gastric ulcers in cirrhotic rats: the role of nitric oxide and IL-1b. Pharmacol Rep 2013;65:134–43.10.1016/S1734-1140(13)70971-XSearch in Google Scholar PubMed

24. Kountouras J, Billing BH, Scheuer PJ. Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Brit J Exp Pathol 1984;65:305–11.Search in Google Scholar

25. Heidari R, Jamshidzadeh A, Keshavarz N, Azarpira N. Mitigation of methimazole-induced hepatic injury by taurine in mice. Sci Pharm 2014;83:143–58.10.3797/scipharm.1408-04Search in Google Scholar PubMed PubMed Central

26. Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol 2007;47: 598–607.10.1016/j.jhep.2007.07.006Search in Google Scholar PubMed

27. Gupta R, Dubey DK, Kannan GM, Flora SJ. Concomitant administration of Moringa oleifera seed powder in the remediation of arsenic-induced oxidative stress in mouse. Cell Biol Int 2007;31:44–56.10.1016/j.cellbi.2006.09.007Search in Google Scholar PubMed

28. Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Ommati MM, Abdoli N, et al. Mitochondria protection as a mechanism underlying the hepatoprotective effects of glycine in cholestatic mice. Biomed Pharmacother 2018;97:1086–95.10.1016/j.biopha.2017.10.166Search in Google Scholar PubMed

29. Heidari R, Taheri V, Rahimi HR, Shirazi Yeganeh B, Niknahad H, Najibi A. Sulfasalazine-induced renal injury in rats and the protective role of thiol-reductants. Ren Fail 2016;16: 137–41.10.3109/0886022X.2015.1096731Search in Google Scholar PubMed

30. Heidari R, Niknahad H, Jamshidzadeh A, Azarpira N, Bazyari M, Najibi A. Carbonyl traps as potential protective agents against methimazole-induced liver injury. J Biochem Mol Toxicol 2014;29:173–81.10.1002/jbt.21682Search in Google Scholar PubMed

31. Jamshidzadeh A, Abdoli N, Niknahad H, Azarpira N, Mardani E, Mousavi S, et al. Taurine alleviates brain tissue markers of oxidative stress in a rat model of hepatic encephalopathy. Trends Pharm Sci 2017;3:181–92.Search in Google Scholar

32. Heidari R, Babaei H, Roshangar L, Eghbal MA. Effects of enzyme induction and/or glutathione depletion on methimazole-induced hepatotoxicity in mice and the protective role of N-acetylcysteine. Adv Pharm Bull 2014;4:21–8.Search in Google Scholar PubMed

33. Heidari R, Jafari F, Khodaei F, Shirazi Yeganeh B, Niknahad H. The mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrology 2018;23:351–61.10.1111/nep.13012Search in Google Scholar PubMed

34. Ommati MM, Jamshidzadeh A, Niknahad H, Mohammadi H, Sabouri S, Heidari R, et al. N-acetylcysteine treatment blunts liver failure-associated impairment of locomotor activity. PharmaNutrition 2017;5:141–7.10.1016/j.phanu.2017.10.003Search in Google Scholar

35. Jamshidzadeh A, Heidari R, Abasvali M, Zarei M, Ommati MM, Abdoli N, et al. Taurine treatment preserves brain and liver mitochondrial function in a rat model of fulminant hepatic failure and hyperammonemia. Biomed Pharmacother 2017;86:514–20.10.1016/j.biopha.2016.11.095Search in Google Scholar

36. Ommati MM, Heidari R, Jamshidzadeh A, Zamiri MJ, Sun Z, Sabouri S, et al. Dual effects of sulfasalazine on rat sperm characteristics, spermatogenesis, and steroidogenesis in two experimental models. Toxicol Lett 2018;284:46–55.10.1016/j.toxlet.2017.11.034Search in Google Scholar PubMed

37. Alía M, Horcajo C, Bravo L, Goya L. Effect of grape antioxidant dietary fiber on the total antioxidant capacity and the activity of liver antioxidant enzymes in rats. Nut Res 2003;23:1251–67.10.1016/S0271-5317(03)00131-3Search in Google Scholar

38. Saradhi PP, AliaArora S, Prasad K. Proline accumulates in plants exposed to UV radiation and protects them against UV-induced peroxidation. Biochem Biophys Res Commun 1995;209:1–5.10.1006/bbrc.1995.1461Search in Google Scholar PubMed

39. Tanaka T, Takahashi K, Iwamoto N, Agawa Y, Sawada Y, Yoshimura Y, et al. Hepatoprotective action of dietary bluefin tuna skin proteins on CCl4-intoxicated mice. Fish Sci 2012;78:911–21.10.1007/s12562-012-0499-zSearch in Google Scholar

40. Verbruggen N, Hermans C. Proline accumulation in plants: a review. Amino Acids 2008;35:753–9.10.1007/s00726-008-0061-6Search in Google Scholar PubMed

41. Orellana M, Rodrigo R, Thielemann L, Guajardo V. Bile duct ligation and oxidative stress in the rat: effects in liver and kidney. Comp Biochem Physiol 2000;126:105–11.10.1016/S0742-8413(00)00102-XSearch in Google Scholar

42. Sokol RJ, Devereaux M, Dahl R, Gumpricht E. “Let there be bile” – understanding hepatic injury in cholestasis. J Pediatr Gastroenterol Nutr 2006;43(suppl 1):S4–9.10.1097/01.mpg.0000226384.71859.16Search in Google Scholar PubMed

43. Ara C, Kirimlioglu H, Karabulut AB, Coban S, Ay S, Harputluoglu M, et al. Protective effect of resveratrol against oxidative stress in cholestasis. J Surg Res 2005;127:112–7.10.1016/j.jss.2005.01.024Search in Google Scholar PubMed

44. Tahan G, Akin H, Aydogan F, Ramadan SS, Yapicier O, Tarcin O, et al. Melatonin ameliorates liver fibrosis induced by bile-duct ligation in rats. Can J Surg 2010;53:313.Search in Google Scholar PubMed

45. Heidari R, Jamshidzadeh A, Niknahad H, Mardani E, Ommati MM, Azarpira N, et al. Effect of taurine on chronic and acute liver injury: focus on blood and brain ammonia. Toxicol Report 2016;3:870–9.10.1016/j.toxrep.2016.04.002Search in Google Scholar

46. Heidari R, Moezi L, Asadi B, Ommati MM, Azarpira N. Hepatoprotective effect of boldine in a bile duct ligated rat model of cholestasis/cirrhosis. PharmaNutrition 2017;5:109–17.10.1016/j.phanu.2017.07.001Search in Google Scholar

47. Jamshidzadeh A, Heidari R, Latifpour Z, Ommati MM, Abdoli N, Mousavi S, et al. Carnosine ameliorates liver fibrosis and hyperammonemia in cirrhotic rats. Clin Res Hepatol Gastroenterol 2017;41:424–34.10.1016/j.clinre.2016.12.010Search in Google Scholar PubMed

48. Alia, Pardha Saradhi P, Mohanty P. Involvement of proline in protecting thylakoid membranes against free radical-induced photodamage. J Photochem Photobiol B: Biol 1997;38:253–7.10.1016/S1011-1344(96)07470-2Search in Google Scholar

49. Alia, Mohanty P, Matysik J. Effect of proline on the production of singlet oxygen. Amino Acids 2001;21:195–200.10.1007/s007260170026Search in Google Scholar PubMed

50. Matysik J, Alia, Bhalu B, Mohanty P. Molecular mechanisms of quenching of reactive oxygen species by proline under stress in plants. Curr Sci 2002;82:525–32.Search in Google Scholar

51. Ozden M, Demirel U, Kahraman A. Effects of proline on antioxidant system in leaves of grapevine (Vitis vinifera L.) exposed to oxidative stress by H2O2. Sci Horticult 2009;119:163–8.10.1016/j.scienta.2008.07.031Search in Google Scholar

52. Ben Rejeb K, Abdelly C, Savouré A. How reactive oxygen species and proline face stress together. Plant Physiol Biochem 2014;80:278–84.10.1016/j.plaphy.2014.04.007Search in Google Scholar PubMed

53. Kaushal N, Gupta K, Bhandhari K, Kumar S, Thakur P, Nayyar H. Proline induces heat tolerance in chickpea (Cicer arietinum L.) plants by protecting vital enzymes of carbon and antioxidative metabolism. Physiol Mol Biol Plants 2011;17:203.10.1007/s12298-011-0078-2Search in Google Scholar PubMed PubMed Central

54. Chen C, Dickman MB. Proline suppresses apoptosis in the fungal pathogen Colletotrichum trifolii. Proc Natl Acad Sci 2005;102:3459–64.10.1073/pnas.0407960102Search in Google Scholar PubMed PubMed Central

55. Rolo AP, Oliveira PJ, Moreno AJ, Palmeira CM. Bile acids affect liver mitochondrial bioenergetics: possible relevance for cholestasis therapy. Toxicol Sci 2000;57:177–85.10.1093/toxsci/57.1.177Search in Google Scholar PubMed

56. Arduini A, Serviddio G, Tormos AM, Monsalve M, Sastre J. Mitochondrial dysfunction in cholestatic liver diseases. Front Biosci 2012;4:2233–52.10.2741/e539Search in Google Scholar

57. Rolo AP, Palmeira CM, Wallace KB. Mitochondrially mediated synergistic cell killing by bile acids. Biochim Biophys Acta 2003;1637:127–32.10.1016/S0925-4439(02)00224-7Search in Google Scholar PubMed

58. Palmeira CM, Rolo AP. Mitochondrially-mediated toxicity of bile acids. Toxicology 2004;203:1–15.10.1016/j.tox.2004.06.001Search in Google Scholar PubMed

59. Krähenbühl S, Talos C, Fischer S, Reichen J. Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology 1994;19:471–9.10.1002/hep.1840190228Search in Google Scholar PubMed

60. Alptekin N, Mehmetçik G, Uysal M, Aykaç-Toker G. Evidence for oxidative stress in the hepatic mitochondria of bile duct ligated rats. Pharmacol Res 1997;36:243–7.10.1006/phrs.1997.0225Search in Google Scholar PubMed

61. Atlante A, Passarella S, Pierro P, Quagliariello E. Proline transport in rat kidney mitochondria. Arch Biochem Biophys 1994;309:139–48.10.1006/abbi.1994.1096Search in Google Scholar PubMed

62. Cybulski RL, Fisher RR. Mitochondrial neutral amino acid transport: evidence for a carrier mediated mechanism. Biochemistry 1977;16:5116–20.10.1021/bi00642a026Search in Google Scholar PubMed

63. Natarajan SK, Zhu W, Liang X, Zhang L, Demers AJ, Zimmerman MC, et al. Proline dehydrogenase is essential for proline protection against hydrogen peroxide-induced cell death. Free Radical Biol Med 2012;53:1181–91.10.1016/j.freeradbiomed.2012.07.002Search in Google Scholar

64. Meyer J. Proline transport in rat liver mitochondria. Arch Biochem Biophys 1977;178:387–95.10.1016/0003-9861(77)90208-9Search in Google Scholar PubMed

65. Pinzani M, Rombouts K. Liver fibrosis: from the bench to clinical targets. Dig Liver Dis 2004;36:231–42.10.1016/j.dld.2004.01.003Search in Google Scholar PubMed

66. Stalnikowitz DK, Weissbrod AB. Liver fibrosis and inflammation. A review. Ann Hepatol 2003;2:159–63.10.1016/S1665-2681(19)32127-1Search in Google Scholar PubMed

67. Tag CG, Sauer-Lehnen S, Weiskirchen S, Borkham-Kamphorst E, Tolba RH, Tacke F, et al. Bile duct ligation in mice: induction of inflammatory liver injury and fibrosis by obstructive cholestasis. J Vis Exp 2015;96:52438.10.3791/52438Search in Google Scholar PubMed PubMed Central

Received: 2018-01-05
Accepted: 2018-07-11
Published Online: 2018-09-06
Published in Print: 2018-12-19

©2019 Walter de Gruyter GmbH, Berlin/Boston

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