Skip to main content

Advertisement

SpringerLink
Log in

Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non-alcoholic fatty liver disease development

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

We aim to investigate the preventive and therapeutic effects of ghrelin on a rat NAFLD model and possible underlying mechanism. Sprague–Dawley rats were fed with high-fat diet for 8 weeks to induce NAFLD. A group of rats were also treated with ghrelin throughout the NAFLD induction. After 8 weeks, rats were sacrificed for liver injury measurements. Rats with NAFLD showed obvious histological changes including necrosis and inflammation foci, elevated serum enzyme (ALT and AST) levels, dysregulated hepatic lipid metabolism, increased formation of oxidative stress, and lipid peroxidation markers, up-regulated levels of pro-inflammatory cytokines and apoptotic cells in the liver. Treatment of ghrelin improved liver injury through counter-acting those events. The improvement of ghrelin was accompanied with a restoration of LKB1/AMPK and PI3 K/Akt pathways. Ghrelin treatment alone did not influence the healthy rat liver. In addition, “therapeutic” ghrelin administration (2 weeks) after the establishment of early NAFLD symptoms (4 weeks) in rats further proved the beneficial effects of ghrelin. In conclusion, administration of ghrelin could attenuate NAFLD-induced liver injury, oxidative stress, inflammation, and apoptosis partly through the action of LKB1/AMPK and PI3 K/Akt pathways.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

ALT:

Alanine aminotransferase

AMPK:

AMP-activated protein kinase

AST:

Aspartate aminotransferase

CYP2E1:

Cytochrome P450 2E1

ELISA:

Enzyme-linked immunosorbent assay

GH:

Growth hormone

IL:

Interleukin

MDA:

Malondialdehyde

NAFLD:

Non-alcoholic fatty liver disease

PNPLA3:

Patatin-like phospholipase domain-containing protein 3

TNF-α:

Tumor necrosis factor alpha

TUNEL:

Terminal deoxynucleotidyl transferase dUTP-nick end labeling

References

  1. A.E. Reid, Nonalcoholic steatohepatitis. Gastroenterology 121, 710–723 (2001)

    Article  PubMed  CAS  Google Scholar 

  2. J.K. Dowman, J.W. Tomlinson, P.N. Newsome, Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 33, 525–540 (2011)

    Article  PubMed  CAS  Google Scholar 

  3. E.E. Powell, W.G. Cooksley, R. Hanson, J. Searle, J.W. Halliday, L.W. Powell, The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 11, 74–80 (1990)

    Article  PubMed  Google Scholar 

  4. M.R. Teli, O.F. James, A.D. Burt, M.K. Bennett, C.P. Day, The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 22, 1714–1719 (1995)

    Article  PubMed  CAS  Google Scholar 

  5. R.C. Harmon, D.G. Tiniakos, C.K. Argo, Inflammation in nonalcoholic steatohepatitis. Expert. Rev. Gastroenterol. Hepatol. 5, 189–200 (2011)

    Article  PubMed  Google Scholar 

  6. N. Alkhouri, C. Carter-Kent, A.E. Feldstein, Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert. Rev. Gastroenterol. Hepatol. 5, 201–212 (2011)

    Article  PubMed  Google Scholar 

  7. G.H. Koek, P.R. Liedorp, A. Bast, The role of oxidative stress in non-alcoholic steatohepatitis. Clin. Chim. Acta 412, 1297–1305 (2011)

    Article  PubMed  CAS  Google Scholar 

  8. M. Pan, Y.L. Song, J.M. Xu, H.Z. Gan, Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in rats. J. Pineal Res. 41, 79–84 (2006)

    Article  PubMed  CAS  Google Scholar 

  9. A. Inui, A. Asakawa, C.Y. Bowers, G. Mantovani, A. Laviano, M.M. Meguid, M. Fujimiya, Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J. 18, 439–456 (2004)

    Article  PubMed  CAS  Google Scholar 

  10. M. Kojima, H. Hosoda, Y. Date, M. Nakazato, H. Matsuo, K. Kangawa, Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999)

    Article  PubMed  CAS  Google Scholar 

  11. T.R. Castañeda, J. Tong, R. Datta, M. Culler, M.H. Tschöp, Ghrelin in the regulation of body weight and metabolism. Front. Neuroendocrinol. 31, 44–60 (2010)

    Article  PubMed  Google Scholar 

  12. D.E. Cummings, D.S. Weigle, R.S. Frayo, P.A. Breen, M.K. Ma, E.P. Dellinger, J.Q. Purnell, Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N. Engl. J. Med. 346, 1623–1630 (2002)

    Article  PubMed  Google Scholar 

  13. S.M. Pöykkö, E. Kellokoski, S. Hörkkö, H. Kauma, Y.A. Kesäniemi, O. Ukkola, Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes 52, 2546–2553 (2003)

    Article  PubMed  Google Scholar 

  14. J. Tong, R.L. Prigeon, H.W. Davis, M. Bidlingmaier, S.E. Kahn, D.E. Cummings, M.H. Tschöp, D. D’Alessio, Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Diabetes 59, 2145–2151 (2010)

    Article  PubMed  CAS  Google Scholar 

  15. T. Waseem, M. Duxbury, H. Ito, Ghrelin ameliorates TNF-α induced antiproliferative and pro-apoptotic effects and promotes intestinal epithelial restitution. J. Am. Coll. Surg. 199, 16 (2004)

    Article  Google Scholar 

  16. T. Waseem, M. Duxbury, H. Ito, S.W. Ashley, M.K. Robinson, Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways. Surgery 143, 334–342 (2008)

    Article  PubMed  Google Scholar 

  17. E. Gonzalez-Rey, A. Chorny, M. Delgado, Therapeutic action of ghrelin in a mouse model of colitis. Gastroenterology 130, 1707–1720 (2006)

    Article  PubMed  CAS  Google Scholar 

  18. R. Wu, W. Dong, Y. Ji, M. Zhou, C.P. Marini, T.S. Ravikumar, P. Wang, Orexigenic hormone ghrelin attenuates local and remote organ injury after intestinal ischemia-reperfusion. PLoS ONE 3, e2026 (2008)

    Article  PubMed  Google Scholar 

  19. S.O. Işeri, G. Sener, B. Saglam, F. Ercan, N. Gedik, B.C. Yeğen, Ghrelin alleviates biliary obstruction-induced chronic hepatic injury in rats. Regul Pept 146, 73–79 (2008)

    Article  PubMed  Google Scholar 

  20. D.E. Kleiner, E.M. Brunt, M. Van Natta, C. Behling, M.J. Contos, O.W. Cummings, L.D. Ferrell, Y.C. Liu, M.S. Torbenson, A. Unalp-Arida, M. Yeh, A.J. McCullough, A.J. Sanyal, Nonalcoholic Steatohepatitis Clinical Research Network, Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005)

    Article  PubMed  Google Scholar 

  21. J. Aubert, K. Begriche, L. Knockaert, M.A. Robin, B. Fromenty, Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin. Res. Hepatol. Gastroenterol. 35, 630–637 (2011)

    Article  PubMed  CAS  Google Scholar 

  22. G.S. Salvesen, Caspases: opening the boxes and interpreting the arrows. Cell Death Differ. 9, 3–5 (2002)

    Article  PubMed  Google Scholar 

  23. S. Ghavami, M. Hashemi, S.R. Ande, B. Yeganeh, W. Xiao, M. Eshraghi, C.J. Bus, K. Kadkhoda, E. Wiechec, A.J. Halayko, M. Los, Apoptosis and cancer: mutations within caspase genes. J. Med. Genet. 46, 497–510 (2009)

    Article  PubMed  CAS  Google Scholar 

  24. W.W. Winder, D.G. Hardie, AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am. J. Physiol. 277, E1–E10 (1999)

    PubMed  CAS  Google Scholar 

  25. J.W. Han, X.R. Zhan, X.Y. Li, B. Xia, Y.Y. Wang, J. Zhang, B.X. Li, Impaired PI3 K/Akt signal pathway and hepatocellular injury in high-fat fed rats. World J. Gastroenterol. 28, 6111–6118 (2010)

    Article  Google Scholar 

  26. S.K. Panchal, H. Poudyal, T.V. Arumugam, L. Brown, Rutin attenuates metabolic changes, nonalcoholic steatohepatitis, and cardiovascular remodeling in high-carbohydrate, high-fat diet-fed rats. J. Nutr. 141, 1062–1069 (2011)

    Article  PubMed  CAS  Google Scholar 

  27. Z. Song, I. Deaciuc, Z. Zhou, M. Song, T. Chen, D. Hill, C.J. McClain, Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G894–G902 (2007)

    Article  PubMed  CAS  Google Scholar 

  28. H.J. Park, D.A. DiNatale, M.Y. Chung, Y.K. Park, J.Y. Lee, S.I. Koo, M. O’Connor, J.E. Manautou, R.S. Bruno, Green tea extract attenuates hepatic steatosis by decreasing adipose lipogenesis and enhancing hepatic antioxidant defenses in ob/ob mice. J. Nutr. Biochem. 22, 393–400 (2011)

    Article  PubMed  CAS  Google Scholar 

  29. J. Ozer, M. Ratner, M. Shaw, W. Bailey, S. Schomaker, The current state of serum biomarkers of hepatotoxicity. Toxicology 245, 194–205 (2008)

    Article  PubMed  CAS  Google Scholar 

  30. S. Seki, T. Kitada, T. Yamada, H. Sakaguchi, K. Nakatani, K. Wakasa, In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J. Hepatol. 37, 56–62 (2002)

    Article  PubMed  CAS  Google Scholar 

  31. N. Chalasani, M.A. Deeg, D.W. Crabb, Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am. J. Gastroenterol. 99, 1497–1502 (2004)

    Article  PubMed  CAS  Google Scholar 

  32. M.D. Weltman, G.C. Farrell, C. Liddle, Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology 111, 1645–1653 (1996)

    Article  PubMed  CAS  Google Scholar 

  33. C.P. Day, From fat to inflammation. Gastroenterology 2006(130), 207–210 (2006)

    Article  Google Scholar 

  34. A.E. Feldstein, A. Canbay, P. Angulo, M. Taniai, L.J. Burgart, K.D. Lindor, G.J. Gores, Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125, 437–443 (2003)

    Article  PubMed  Google Scholar 

  35. M. Moreno, J.F. Chaves, P. Sancho-Bru, F. Ramalho, L.N. Ramalho, M.L. Mansego, C. Ivorra, M. Dominguez, L. Conde, C. Millán, M. Marí, J. Colmenero, J.J. Lozano, P. Jares, J. Vidal, X. Forns, V. Arroyo, J. Caballería, P. Ginès, R. Bataller, Ghrelin attenuates hepatocellular injury and liver fibrogenesis in rodents and influences fibrosis progression in humans. Hepatology 51, 974–985 (2010)

    Article  PubMed  CAS  Google Scholar 

  36. M.J. Sanders, P.O. Grondin, B.D. Hegarty, M.A. Snowden, D. Carling, Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem. J. 403, 139–148 (2007)

    Article  PubMed  CAS  Google Scholar 

  37. M.S. Lee, D. Kim, K. Jo, J.K. Hwang, Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice. Biochem. Biophys. Res. Commun. 401, 92–97 (2010)

    Article  PubMed  CAS  Google Scholar 

  38. J. Dufour, P. Clavien, Signaling pathways in liver diseases, 2nd edn. (Springer, Heidelberg, 2010)

    Book  Google Scholar 

  39. A. Chorny, P. Anderson, E. Gonzalez-Rey, M. Delgado, Ghrelin protects against experimental sepsis by inhibiting high-mobility group box 1 release and by killing bacteria. J. Immunol. 2008(180), 8369–8377 (2008)

    Google Scholar 

  40. O. Kasımay, S.O. Işeri, A. Barlas, D. Bangir, C. Yeğen, S. Arbak, B.C. Yeğen, Ghrelin ameliorates pancreaticobiliary inflammation and associated remote organ injury in rats. Hepatol. Res. 36, 11–19 (2006)

    Article  PubMed  Google Scholar 

  41. C.X. Huang, M.J. Yuan, H. Huang, G. Wu, Y. Liu, S.B. Yu, H.T. Li, T. Wang, Ghrelin inhibits post-infarct myocardial remodeling and improves cardiac function through anti-inflammation effect. Peptides 30, 2286–2291 (2009)

    Article  PubMed  CAS  Google Scholar 

  42. E. Cetin, M. Kanbur, N. Cetin, G. Eraslan, A. Atasever, Hepatoprotective effect of ghrelin on carbon tetrachloride-induced acute liver injury in rats. Regul Pept 171, 1–5 (2011)

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Endocrinology, First Affiliated Hospital, Xinxiang Medical University, Jiankang Road, Xinxiang City, Henan, China

    Yan Li, Jie Hai, Lake Li, Xuehui Chen, Hua Peng, Meng Cao & Qinggui Zhang

Authors
  1. Yan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Hai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lake Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuehui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hua Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Meng Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qinggui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qinggui Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Y., Hai, J., Li, L. et al. Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non-alcoholic fatty liver disease development. Endocrine 43, 376–386 (2013). https://doi.org/10.1007/s12020-012-9761-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-012-9761-5

Keywords

Search

Navigation