Rola ghreliny i obestatyny w procesach metabolicznych i nowotworowych u ludzi

• Authors: Karolina Jaszczyńska-Nowinka , Anna Markowska

Title variants

EN

Role of ghrelin and obestatin in metabolic processes and in neoplastic conditions in humans

• Languages of publication: EN PL

Abstracts

EN

Both ghrelin and obestatin are peptides derived from the same precursor – preprohormone – encoded on the 3rd chromosome (3p25-26). Both hormones are secreted to the bloodstream. Ghrelin has 28-amino acids with serine at position 3. It is an endogenous ligand of growth hormone receptor (GHS), which has been discovered in hypophysis and hypothalamus. Ghrelin may occur in active and inactive forms. In order to achieve biological activity, ghrelin must contain a N-octa-acetyl group of serine. Total ghrelin is a sum of active and inactive forms. Ghrelin and its receptors GHS-R1a and 1b (growth hormone secretagogue) are widespread in the body, being present mainly in the gastrointestinal tract, central nervous system, reproductive system, heart and kidneys. Obestatin is a recently discovered 23-amino acids long peptide, produced as a result of proteolytic splitting of the preprohormone ghrelin. Systemic distribution of ghrelin is less well known. Both ghrelin and obestatin play a role in energy management (control appetite, body mass, metabolism of fat and glucose, gastrointestinal function), influence cardiovascular, reproductive and immune systems and participate in modulation of central nervous system function. Ghrelin and obestatin regulate processes of cellular proliferation and apoptosis. Variations of ghrelin and obestatin levels, as well as expression of GHS-R in hypophyseal and neuroendocrine tumors, uterine myomas and both benign and malignant ovarian tumors, confirm their role in tumor development and are a promising topic for future studies in oncology.

PL

Ghrelina i obestatyna są peptydami wywodzącymi się z tego samego prekursora – preprohormonu, który kodowany jest na chromosomie 3. (3p25-26); wydzielane są do krwi. Ghrelina to 28-aminokwasowy peptyd, zawierający serynę w pozycji 3. Jest endogennym ligandem receptora wzrostu (GHS), który wykryto w przysadce i podwzgórzu. Występuje ona w formie aktywnej i nieaktywnej. Aby otrzymać aktywność biologiczną, ghrelina musi zawierać N-oktaacetylową grupę seryny. Ghrelina całkowita to suma form aktywnej i nieaktywnej. Ghrelina i jej receptory GHS-R1a i 1b (growth hormone secretagogue) są szeroko rozpowszechnione w organizmie i występują między innymi w przewodzie pokarmowym, ośrodkowym układzie nerwowym, układzie rozrodczym, sercu i nerkach. Obestatyna to ostatnio wykryty 23-aminokwasowy peptyd powstały na skutek proteolitycznego rozszczepienia preprohormonu ghreliny. Dystrybucja obestatyny w organizmie jest mniej znana. Ghrelina i obestatyna biorą udział w kontroli bilansu energii (apetyt, masa ciała, metabolizm tłuszczów i glukozy, funkcje żołądkowo-jelitowe), a także odgrywają rolę w układzie sercowo-naczyniowym, rozrodczym, modulacji immunologicznej i ośrodkowym układzie nerwowym. Regulują procesy proliferacji i apoptozy komórek. Zmiany stężeń ghreliny i obestatyny oraz/lub ekspresja GHS-R w guzach przysadki mózgowej, guzach neuroendokrynnych przewodu pokarmowego (NET), mięśniakach macicy oraz guzach łagodnych i złośliwych jajnika wskazują na ich udział w rozwoju nowotworów i są obiecującym obiektem badań w onkologii.

Keywords

EN

GHS-R; ghrelin; ghrelina; metabolism; metabolizm; nowotwory; obestatin; obestatyna; tumors

Discipline

• MEDICINE: MEDICINE

• Publisher: Medical Communications
• Journal: Current Gynecologic Oncology
• Year: 2010
• Volume: 8
• Issue: 2
• Pages: 132-139

Contributors

author

Karolina Jaszczyńska-Nowinka

• Katedra i Klinika Położnictwa, Chorób Kobiecych i Ginekologii Onkologicznej II Wydziału Lekarskiego Warszawskiego Uniwersytetu Medycznego. Kierownik Kliniki: prof. dr hab. n. med. Jerzy Stelmachów. Oddział Ginekologii Onkologicznej Szpitala Przemienienia Pańskiego, Uniwersytetu Medycznego w Poznaniu, ul. Łąkowa 1/2, 61-848 Poznań, tel.: [phone]

author

Anna Markowska

• Klinika Perinatologii i Chorób Kobiecych Uniwersytetu Medycznego w Poznaniu

References

• 1. Kojima M., Hosoda H., Date Y. i wsp.: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656-660.
• 2. Zhang J.V, Ren P.G., Avsian-Kretchmer O. i wsp.: Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science 2005; 310: 996-999.
• 3. Howard A.D., Feighner S.D., Cully D.F. i wsp.: A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974-977.
• 4. Gnanapavan S., Kola B., Bustin S.A. i wsp.: The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J. Clin. Endocrinol. Metab. 2002: 87: 2988.
• 5. Ariyasu H., Takaya K., Tagami T. i wsp.: Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J. Clin. Endocrinol. Metab. 2001; 86: 4753-4758.
• 6. Smith R.G., Leonard R., Bailey A.R. i wsp.: Growth hormone secretagogue receptor family members and ligands. Endocrine Res. 2001; 14: 9-14.
• 7. Holst B., Egerod K.L., Schild E. i wsp.: GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology 2007; 148: 13-20.
• 8. Tritos N.A., Kokkotou E.G.: The physiology and potential clinical applications of ghrelin, a novel peptide hormone. Review. Mayo Clin. Proc. 2006; 81: 653-660.
• 9. Shimbara T., Mondal M.S., Kawagoe T. i wsp.: Central administration of ghrelin preferentially enhances fat ingestion. Neurosci. Lett. 2004; 369: 75-79.
• 10. Thompson N.M., Gill D.A., Davies R. i wsp.: Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 2004; 145: 234-242.
• 11. Yasuda T., Masaki T., Kakuma T., Yoshimatsu H.: Centrally administered ghrelin suppresses sympathetic nerve activity in brown adipose tissue of rats. Neurosci. Lett. 2003; 349: 75-78.
• 12. Bresciani E., Rapetti D., Dona F. i wsp.: Obestatin inhibits feeding but does not modulate GH and corticosterone secretion in the rat. Endocrinol. Invest. 2006; 29: RC16-RC18.
• 13. Green B.D., Irwin N., Flatt P.R.: Direct and indirect effects of obestatin peptides on food intake and the regulation of glucose homeostasis and insulin secretion in mice. Peptides 2007; 28: 981-987.
• 14. Gourcerol G., St-Pierre D.H., Taché Y.: Lack of obestatin effects on food intake: should obestatin be renamed ghre-lin-associated peptide (GAP)? Review. Regul. Pept. 2007; 141(1-3): 1-7.
• 15. Sibilia V, Bresciani E., Lattuada N. i wsp.: Intracerebroven-tricular acute and chronic administration of obestatin minimally affect food intake but not weight gain in the rat. J. Endocrinol. Invest. 2006; 29: RC31-RC34.
• 16. Pénicaud L., Leloup C., Fioramonti X. i wsp.: Brain glucose sensing: a subtle mechanism. Review. Curr. Opin. Clin. Nutr. Metab. Care 2006; 9: 458-462.
• 17. Heijboer A.C., van den Hoek A.M., Parlevliet E.T. i wsp.: Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice. Diabetologia 2006; 49: 732-738.
• 18. Malagón M.M., Luque R.M., Ruiz-Guerrero E. i wsp.: Intracellular signaling mechanisms mediating ghrelin-stimulated growth hormone release in somatotropes. Endocrinology 2003; 144: 5372-5380.
• 19. Salehi A., Dornonville de la Cour C., Håkanson R., Lundquist I.: Effects of ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice. Regul. Pept. 2004; 118: 143-150.
• 20. Broglio F., Gottero C., Benso A. i wsp.: Effects of ghrelin on the insulin and glycemic responses to glucose, arginine, or free fatty acids load in humans. J. Clin. Endocrinol. Metab. 2003; 88: 4268-4272.
• 21. Granata R., Settanni F., Gallo D. i wsp.: Obestatin promotes survival of pancreatic beta-cells and human islets and induces expression of genes involved in the regulation of beta-cell mass and function. Diabetes 2008; 57: 967-979.
• 22. Barazzoni R., Bosutti A., Stebel M. i wsp.: Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 2005; 288: E228-E235.
• 23. Inui A., Asakawa A., Bowers C.Y. i wsp.: Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J. 2004; 18: 439-456.
• 24. Asakawa A., Inui A., Kaga T. i wsp.: Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 2001; 120: 337-345.
• 25. Peeters T.L.: Central and peripheral mechanisms by which ghrelin regulates gut motility. Review. J. Physiol. Pharmacol. 2003; 54 (supl. 4): 95-103.
• 26. Dass N.B., Munonyara M., Bassil A.K. i wsp.: Growth hormone secretagogue receptors in rat and human gastrointestinal tract and the effects of ghrelin. Neuroscience 2003; 120: 443-453.
• 27. Bassil A.K., Häglund Y., Brown J. i wsp.: Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract. Br. J. Pharmacol. 2007; 150: 58-64.
• 28. Kleinz M.J., Maguire J.J., Skepper J.N., Davenport A.P.: Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. Cardiovasc. Res. 2006, 69: 227-235.
• 29. Nagaya N., Kojima M., Uematsu M. i wsp.: Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001; 280: R1483- R1487.
• 30. Li W.G., Gavrila D., Liu X. i wsp.: Ghrelin inhibits proin-flammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation 2004; 109: 2221-2226.
• 31. Iglesias M.J., Salgado A., Piñeiro R. i wsp.: Lack of effect of the ghrelin gene-derived peptide obestatin on cardiomyocyte viability and metabolism. J. Endocrinol. Invest. 2007; 30: 470-476.
• 32. Koo G.C., Huang C., Camacho R. i wsp.: Immune enhancing effect of a growth hormone secretagogue. J. Immunol. 2001; 166: 4195-4201.
• 33. Diano S., Farr S.A., Benoit S.C. i wsp.: Ghrelin controls hippocampal spine synapse density and memory performance. Nat. Neurosci. 2006; 9: 381-388.
• 34. Gaytan F., Barreiro M.L., Chopin L.K i wsp.: Immunolocal-ization of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in the cyclic human ovary. J. Clin. Endocrinol. Metab. 2003; 88: 879-887.
• 35. Gaytan F, Barreiro M.L., Chopin L.K. i wsp.: Expression of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in normal human testis and testicular tumors. J. Clin. Endocrinol. Metab. 2004; 89: 400-409.
• 36. Mészárosová M., Sirotkin A.V, Grossmann R. i wsp.: The effect of obestatin on porcine ovarian granulosa cells. Anim. Reprod. Sci. 2008; 108: 196-207.
• 37. Baldanzi G., Filigheddu N., Cutrupi S. i wsp.: Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT J. Cell Biol. 2002; 159: 1029-1037.
• 38. Mazzocchi G., Neri G., Rucinski M. i wsp.: Ghrelin enhances the growth of cultured human adrenal zona glomerulosa cells by exerting MAPK-mediated proliferogenic and anti-apoptotic effects. Peptides 2004; 25: 1269-1277.
• 39. Murata M., Okimura Y., Iida K. i wsp.: Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. J. Biol. Chem. 2002; 277: 5667-5674.
• 40. Duxbury M.S., Waseem T, Ito H. i wsp.: Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness. Biochem. Biophys. Res. Commun. 2003; 309: 464-468.
• 41. Jeffery P.L., Herington A.C., Chopin L.K.: Expression and action of the growth hormone releasing peptide ghrelin and its receptor in prostate cancer cell lines. J. Endocrinol. 2002; 172: R7-R11.
• 42. Cassoni P., Allia E., Marrocco T. i wsp.: Ghrelin and cor-tistatin in lung cancer: expression of peptides and related receptors in human primary tumors and in vitro effect on the H345 small cell carcinoma cell line. J. Endocrinol. Invest. 2006; 29: 781-790.
• 43. Cassoni P., Papotti M., Ghè C. i wsp.: Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secret-agogues and analogs in human breast carcinomas and cell lines. J. Clin. Endocrinol. Metab. 2001; 86: 1738-1745.
• 44. Kim K., Arai K., Sanno N. i wsp.: Ghrelin and growth hormone (GH) secretagogue receptor (GHSR) mRNA expression in human pituitary adenomas. Clin. Endocrinol. (Oxf.) 2001; 54: 759-768.
• 45. Cappiello V, Ronchi C., Morpurgo P.S. i wsp.: Circulating ghrelin levels in basal conditions and during glucose tolerance test in acromegalic patients. Eur. J. Endocrinol. 2002; 147: 189-194.
• 46. Barlier A., Zamora A.J., Grino M. i wsp.: Expression of functional growth hormone secretagogue receptors in human pituitary adenomas: polymerase chain reaction, triple in-situ hybridization and cell culture studies. J. Neuroendocrinol. 1999; 11: 491-502.
• 47. Skinner M.M., Nass R., Lopes B. i wsp.: Growth hormone secretagogue receptor expression in human pituitary tumors. J. Clin. Endocrinol. Metab. 1998; 83: 4314-4320.
• 48. Taal B.G., Visser O.: Epidemiology of neuroendocrine tumors. Neuroendocrinology 2004; 80 (supl. 1): 3-7.
• 49. Markowska A., Ziółkowska A., Nowinka K., Malendowicz L.K.: Elevated blood active ghrelin and normal total ghrelin and obestatin concentrations in uterine leiomyoma. Eur. J. Gynaecol. Oncol. 2009; 30: 281-284.
• 50. Markowska A., Ziółkowska A., Jaszczyńska-Nowinka K i wsp.: Elevated blood plasma concentrations of active ghre-lin and obestatin in benign ovarian neoplasm and ovarian cancers. Eur. J. Gynaecol. Oncol. 2009; 30: 518-522.

• Document Type: article