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Published in: Obesity Surgery 11/2011

01-11-2011 | Clinical Research

Association of Obestatin, Ghrelin, and Inflammatory Cytokines in Obese Patients with Non-alcoholic Fatty Liver Disease

Authors: Michael Estep, Massih Abawi, Mohammed Jarrar, Lei Wang, Maria Stepanova, Hazem Elariny, Amir Moazez, Zachary Goodman, Vikas Chandhoke, Ancha Baranova, Zobair M. Younossi

Published in: Obesity Surgery | Issue 11/2011

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Abstract

Background

Three protein products of ghrelin gene (acylated ghrelin, des-acylated ghrelin, and obestatin) are involved in appetite stimulation and suppression. Additionally, there is some evidence suggesting their involvement in metabolic and inflammatory pathways which may be implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to examine the relationships of ghrelin gene products in patients with NAFLD.

Methods

We included 75 morbidly obese patients with biopsy-proven NAFLD (41 with histologic non-alcoholic steatohepatitis (NASH)) with clinical and laboratory data as well as frozen serum samples from the time of liver biopsy. Fasting serum was assayed for obestatin as well as acylated and des-acyl-ghrelin concentrations using ELISA. Bio-Plex inflammatory cytokine assays were used to profile expression of 17 inflammatory mediators, including IL-6, IL-7, IL-8, G-CSF, CCL2, and MIP-1β.

Results

Patients with NASH had twofold higher concentration of des-acyl-ghrelin than patients with non-NASH (2.58 vs. 1.24 pg/ml, P < 0.02). Ghrelin concentrations in NASH patients with fibrosis stage ≥2 were almost double the concentration of NASH patients with fibrosis stage <2 (8.73 vs. 4.22 pg/ml, P < 0.04). Obestatin levels also increased with the fibrosis stage (2.54 vs. 3.46 pg/ml, P < 0.03). NAFLD patients with higher fibrosis stage had lower IL-7 concentrations (16.89 vs. 10.68 pg/ml, P = 0.014). Obestatin levels at baseline significantly correlated with rate of weight loss after bariatric surgery at various time points.

Conclusions

This study suggests that products of the GHRL gene may be important for the pathogenesis of NASH and fibrosis. Additional confirmatory studies are needed.
Literature
1.
go back to reference Ariyasu H, Takaya K, Iwakura H, et al. Transgenic mice overexpressing des-acyl ghrelin show small phenotype. Endocrinology. 2005;146(1):355–64.PubMedCrossRef Ariyasu H, Takaya K, Iwakura H, et al. Transgenic mice overexpressing des-acyl ghrelin show small phenotype. Endocrinology. 2005;146(1):355–64.PubMedCrossRef
2.
go back to reference Asakawa A, Inui A, Fujimiya M, et al. Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut. 2005;54(1):18–24.PubMedCrossRef Asakawa A, Inui A, Fujimiya M, et al. Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut. 2005;54(1):18–24.PubMedCrossRef
3.
go back to reference Ashley DT, O’Sullivan EP, Davenport C, et al. Similar to adiponectin, serum levels of osteoprotegerin are associated with obesity in healthy subjects. Metabolism. 2011;60(7):994–1000.PubMedCrossRef Ashley DT, O’Sullivan EP, Davenport C, et al. Similar to adiponectin, serum levels of osteoprotegerin are associated with obesity in healthy subjects. Metabolism. 2011;60(7):994–1000.PubMedCrossRef
4.
go back to reference Barker KB, Palekar NA, Bowers SP, et al. Non-alcoholic steatohepatitis: effect of Roux-en-Y gastric bypass surgery. Am J Gastroenterol. 2006;101(2):368–73.PubMedCrossRef Barker KB, Palekar NA, Bowers SP, et al. Non-alcoholic steatohepatitis: effect of Roux-en-Y gastric bypass surgery. Am J Gastroenterol. 2006;101(2):368–73.PubMedCrossRef
5.
go back to reference Broglio F, Gottero C, Prodam F, et al. Nonacylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab. 2004;89:3062–5.PubMedCrossRef Broglio F, Gottero C, Prodam F, et al. Nonacylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab. 2004;89:3062–5.PubMedCrossRef
6.
go back to reference Chmielewska J, Szczepankiewicz D, Skrzypski M, et al. Ghrelin but not obestatin regulates insulin secretion from INS1 beta cell line via UCP2-dependent mechanism. J Biol Regul Homeost Agents. 2010;24(4):397–402.PubMed Chmielewska J, Szczepankiewicz D, Skrzypski M, et al. Ghrelin but not obestatin regulates insulin secretion from INS1 beta cell line via UCP2-dependent mechanism. J Biol Regul Homeost Agents. 2010;24(4):397–402.PubMed
7.
go back to reference Chung H, Kim E, Lee DH, et al. Ghrelin inhibits apoptosis in hypothalamic neuronal cells during oxygen-glucose deprivation. Endocrinology. 2007;148(1):148–59.PubMedCrossRef Chung H, Kim E, Lee DH, et al. Ghrelin inhibits apoptosis in hypothalamic neuronal cells during oxygen-glucose deprivation. Endocrinology. 2007;148(1):148–59.PubMedCrossRef
8.
go back to reference Delhanty PJ, Sun Y, Visser JA, et al. Unacylated ghrelin rapidly modulates lipogenic and insulin signaling pathway gene expression in metabolically active tissues of GHSR deleted mice. PLoS One. 2010;5(7):e11749.PubMedCrossRef Delhanty PJ, Sun Y, Visser JA, et al. Unacylated ghrelin rapidly modulates lipogenic and insulin signaling pathway gene expression in metabolically active tissues of GHSR deleted mice. PLoS One. 2010;5(7):e11749.PubMedCrossRef
9.
go back to reference Estep M, Armistead D, Hossain N, et al. Differential expression of miRNAs in the visceral adipose tissue of patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;32(3):487–97.PubMedCrossRef Estep M, Armistead D, Hossain N, et al. Differential expression of miRNAs in the visceral adipose tissue of patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;32(3):487–97.PubMedCrossRef
10.
go back to reference Friedman SL. Mechanisms of disease: mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol. 2004;1(2):98–105.PubMedCrossRef Friedman SL. Mechanisms of disease: mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol. 2004;1(2):98–105.PubMedCrossRef
11.
go back to reference Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010;316(2):129–39. Review.PubMedCrossRef Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010;316(2):129–39. Review.PubMedCrossRef
12.
go back to reference Gauna C, Kiewiet RM, Janssen JA, et al. Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions. Am J Physiol Endocrinol Metab. 2007;293:E697–704.PubMedCrossRef Gauna C, Kiewiet RM, Janssen JA, et al. Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions. Am J Physiol Endocrinol Metab. 2007;293:E697–704.PubMedCrossRef
13.
go back to reference Gauna C, Meyler FM, Janssen JA, et al. Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity. J Clin Endocrinol Metab. 2004;89:5035–42.PubMedCrossRef Gauna C, Meyler FM, Janssen JA, et al. Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity. J Clin Endocrinol Metab. 2004;89:5035–42.PubMedCrossRef
14.
go back to reference Hou Y, An J, Hu XR, et al. Ghrelin inhibits interleukin-8 production induced by hydrogen peroxide in A549 cells via NF-kappaB pathway. Int Immunopharmacol. 2009;9(1):120–6.PubMedCrossRef Hou Y, An J, Hu XR, et al. Ghrelin inhibits interleukin-8 production induced by hydrogen peroxide in A549 cells via NF-kappaB pathway. Int Immunopharmacol. 2009;9(1):120–6.PubMedCrossRef
15.
go back to reference Kiewiet RM, Hazell MJ, van Aken MO, et al. Acute effects of acylated and unacylated ghrelin on total and high molecular weight adiponectin in morbidly obese subjects. J Endocrinol Invest. 2010 Oct 15. [Epub ahead of print] PubMed PMID: 20959720. Kiewiet RM, Hazell MJ, van Aken MO, et al. Acute effects of acylated and unacylated ghrelin on total and high molecular weight adiponectin in morbidly obese subjects. J Endocrinol Invest. 2010 Oct 15. [Epub ahead of print] PubMed PMID: 20959720.
16.
go back to reference Kim S, Richards WO. Long-term follow-up of the metabolic profiles in obese patients with type 2 diabetes mellitus after Roux-en-Y gastric bypass. Ann Surg. 2010;251(6):1049–55.PubMedCrossRef Kim S, Richards WO. Long-term follow-up of the metabolic profiles in obese patients with type 2 diabetes mellitus after Roux-en-Y gastric bypass. Ann Surg. 2010;251(6):1049–55.PubMedCrossRef
17.
go back to reference Knerr I, Herzog D, Rauh M, et al. Leptin and ghrelin expression in adipose tissues and serum levels in gastric banding patients. Eur J Clin Invest. 2006;36(6):389–94.PubMedCrossRef Knerr I, Herzog D, Rauh M, et al. Leptin and ghrelin expression in adipose tissues and serum levels in gastric banding patients. Eur J Clin Invest. 2006;36(6):389–94.PubMedCrossRef
18.
go back to reference Koca SS, Ozgen M, Aydin S, et al. Ghrelin and obestatin levels in rheumatoid arthritis. Inflammation. 2008;31(5):329–35.PubMedCrossRef Koca SS, Ozgen M, Aydin S, et al. Ghrelin and obestatin levels in rheumatoid arthritis. Inflammation. 2008;31(5):329–35.PubMedCrossRef
19.
go back to reference Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–60.PubMedCrossRef Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–60.PubMedCrossRef
20.
go back to reference Lear PV, Iglesias MJ, Feijóo-Bandín S, et al. Des-acyl ghrelin has specific binding sites and different metabolic effects from ghrelin in cardiomyocytes. Endocrinology. 2010;151(7):3286–98.PubMedCrossRef Lear PV, Iglesias MJ, Feijóo-Bandín S, et al. Des-acyl ghrelin has specific binding sites and different metabolic effects from ghrelin in cardiomyocytes. Endocrinology. 2010;151(7):3286–98.PubMedCrossRef
21.
go back to reference Liu X, Lazenby AJ, Clements RH, et al. Resolution of nonalcoholic steatohepatits after gastric bypass surgery. Obes Surg. 2007;17(4):486–92.PubMedCrossRef Liu X, Lazenby AJ, Clements RH, et al. Resolution of nonalcoholic steatohepatits after gastric bypass surgery. Obes Surg. 2007;17(4):486–92.PubMedCrossRef
22.
go back to reference Mafra D, Farage NE, Lobo JC, et al. Relationship between total ghrelin and inflammation in hemodialysis patients. Peptides. 2011;32(2):358–61.PubMedCrossRef Mafra D, Farage NE, Lobo JC, et al. Relationship between total ghrelin and inflammation in hemodialysis patients. Peptides. 2011;32(2):358–61.PubMedCrossRef
23.
go back to reference Miegueu P, Pierre DS, Broglio F, et al. Effect of desacyl ghrelin, obestatin and related peptides on triglyceride storage, metabolism and GHSR signaling in 3 T3-L1 adipocytes. J Cell Biochem. 2011;112(2):704–14.PubMedCrossRef Miegueu P, Pierre DS, Broglio F, et al. Effect of desacyl ghrelin, obestatin and related peptides on triglyceride storage, metabolism and GHSR signaling in 3 T3-L1 adipocytes. J Cell Biochem. 2011;112(2):704–14.PubMedCrossRef
24.
go back to reference Patterson M, Murphy KG, le Roux CW, et al. Characterization of ghrelin-like immunoreactivity in human plasma. J Clin Endocrinol Metab. 2005;90(4):2205–11.PubMedCrossRef Patterson M, Murphy KG, le Roux CW, et al. Characterization of ghrelin-like immunoreactivity in human plasma. J Clin Endocrinol Metab. 2005;90(4):2205–11.PubMedCrossRef
25.
go back to reference Qader SS, Hakanson R, Rehfeld JF, et al. Proghrelin-derived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin: a study on isolated islets from mouse and rat pancreas. Regul Pept. 2008;146:230–7.PubMedCrossRef Qader SS, Hakanson R, Rehfeld JF, et al. Proghrelin-derived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin: a study on isolated islets from mouse and rat pancreas. Regul Pept. 2008;146:230–7.PubMedCrossRef
26.
go back to reference Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7(2):234–8.PubMedCrossRef Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7(2):234–8.PubMedCrossRef
27.
go back to reference Shimbara T, Mondal MS, Kawagoe T, et al. Central administration of ghrelin preferentially enhances fat ingestion. Neurosci Lett. 2004;369(1):75–9.PubMedCrossRef Shimbara T, Mondal MS, Kawagoe T, et al. Central administration of ghrelin preferentially enhances fat ingestion. Neurosci Lett. 2004;369(1):75–9.PubMedCrossRef
28.
go back to reference Stengel A, Goebel M, Wang L, et al. Lipopolysaccharide differentially decreases plasma acyl and desacyl ghrelin levels in rats: potential role of the circulating ghrelin-acylating enzyme GOAT. Peptides. 2010;31(9):1689–96.PubMedCrossRef Stengel A, Goebel M, Wang L, et al. Lipopolysaccharide differentially decreases plasma acyl and desacyl ghrelin levels in rats: potential role of the circulating ghrelin-acylating enzyme GOAT. Peptides. 2010;31(9):1689–96.PubMedCrossRef
29.
go back to reference Stepanova M, Aquino R, Alsheddi A, et al. Clinical predictors of fibrosis in patients with chronic liver disease. Aliment Pharmacol Ther. 2010;31(10):1085–94.PubMed Stepanova M, Aquino R, Alsheddi A, et al. Clinical predictors of fibrosis in patients with chronic liver disease. Aliment Pharmacol Ther. 2010;31(10):1085–94.PubMed
30.
go back to reference St-Pierre DH, Settanni F, Olivetti I, et al. Circulating obestatin levels in normal and type 2 diabetic subjects. J Endocrinol Invest. 2010;33(4):211–4.PubMed St-Pierre DH, Settanni F, Olivetti I, et al. Circulating obestatin levels in normal and type 2 diabetic subjects. J Endocrinol Invest. 2010;33(4):211–4.PubMed
31.
go back to reference Strohacker K, McFarlin BK. Influence of obesity, physical inactivity, and weight cycling on chronic inflammation. Front Biosci (Elite Ed). 2010;2:98–104. Review.CrossRef Strohacker K, McFarlin BK. Influence of obesity, physical inactivity, and weight cycling on chronic inflammation. Front Biosci (Elite Ed). 2010;2:98–104. Review.CrossRef
32.
go back to reference Sun J, Xu Y, Dai Z, et al. Intermittent high glucose stimulate MCP-l, IL-18, and PAI-1, but inhibit adiponectin expression and secretion in adipocytes dependent of ROS. Cell Biochem Biophys. 2009;55(3):173–80.PubMedCrossRef Sun J, Xu Y, Dai Z, et al. Intermittent high glucose stimulate MCP-l, IL-18, and PAI-1, but inhibit adiponectin expression and secretion in adipocytes dependent of ROS. Cell Biochem Biophys. 2009;55(3):173–80.PubMedCrossRef
33.
go back to reference Sung EZ, Da Silva NF, Goodyear SJ, et al. Ghrelin promotes nuclear factor kappa-B activation in a human B-lymphocyte cell line. Mol Biol Rep. 2010 Dec 5. [Epub ahead of print]. Sung EZ, Da Silva NF, Goodyear SJ, et al. Ghrelin promotes nuclear factor kappa-B activation in a human B-lymphocyte cell line. Mol Biol Rep. 2010 Dec 5. [Epub ahead of print].
34.
go back to reference Tateya S, Tamori Y, Kawaguchi T, et al. An increase in the circulating concentration of monocyte chemoattractant protein-1 elicits systemic insulin resistance irrespective of adipose tissue inflammation in mice. Endocrinology. 2010;151(3):971–9.PubMedCrossRef Tateya S, Tamori Y, Kawaguchi T, et al. An increase in the circulating concentration of monocyte chemoattractant protein-1 elicits systemic insulin resistance irrespective of adipose tissue inflammation in mice. Endocrinology. 2010;151(3):971–9.PubMedCrossRef
35.
go back to reference Thompson NM, Gill DA, Davies R, et al. 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(1):234–42.PubMedCrossRef Thompson NM, Gill DA, Davies R, et al. 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(1):234–42.PubMedCrossRef
36.
go back to reference Togliatto G, Trombetta A, Dentelli P, et al. Unacylated ghrelin rescues endothelial progenitor cell function in individuals with type 2 diabetes. Diabetes. 2010;59(4):1016–25.PubMedCrossRef Togliatto G, Trombetta A, Dentelli P, et al. Unacylated ghrelin rescues endothelial progenitor cell function in individuals with type 2 diabetes. Diabetes. 2010;59(4):1016–25.PubMedCrossRef
37.
go back to reference Toshinai K, Yamaguchi H, Sun Y, et al. Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology. 2006;147(5):2306–14.PubMedCrossRef Toshinai K, Yamaguchi H, Sun Y, et al. Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology. 2006;147(5):2306–14.PubMedCrossRef
38.
go back to reference Uribe M, Zamora-Valdés D, Moreno-Portillo M, et al. Hepatic expression of ghrelin and adiponectin and their receptors in patients with nonalcoholic fatty liver disease. Ann Hepatol. 2008;7(1):67–71.PubMed Uribe M, Zamora-Valdés D, Moreno-Portillo M, et al. Hepatic expression of ghrelin and adiponectin and their receptors in patients with nonalcoholic fatty liver disease. Ann Hepatol. 2008;7(1):67–71.PubMed
39.
go back to reference Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86(12):5992.PubMedCrossRef Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86(12):5992.PubMedCrossRef
40.
go back to reference Wu R, Dong W, Ji Y, et al. Orexigenic hormone ghrelin attenuates local and remote organ injury after intestinal ischemia–reperfusion. PLoS One. 2008;3(4):e2026.PubMedCrossRef Wu R, Dong W, Ji Y, et al. Orexigenic hormone ghrelin attenuates local and remote organ injury after intestinal ischemia–reperfusion. PLoS One. 2008;3(4):e2026.PubMedCrossRef
41.
go back to reference Yamada G, Ariyasu H, Iwakura H, et al. Generation of transgenic mice overexpressing a ghrelin analog. Endocrinology. 2010;151(12):5935–40. PMID: 20962048.PubMedCrossRef Yamada G, Ariyasu H, Iwakura H, et al. Generation of transgenic mice overexpressing a ghrelin analog. Endocrinology. 2010;151(12):5935–40. PMID: 20962048.PubMedCrossRef
42.
go back to reference Yamanaka O, Saika S, Ikeda K, et al. Interleukin-7 modulates extracellular matrix production and TGF-beta signaling in cultured human subconjunctival fibroblasts. Curr Eye Res. 2006;31(6):491–9.PubMedCrossRef Yamanaka O, Saika S, Ikeda K, et al. Interleukin-7 modulates extracellular matrix production and TGF-beta signaling in cultured human subconjunctival fibroblasts. Curr Eye Res. 2006;31(6):491–9.PubMedCrossRef
43.
go back to reference Zhang W, Chai B, Li JY, et al. Effect of des-acyl ghrelin on adiposity and glucose metabolism. Endocrinology. 2008;149(9):4710–6.PubMedCrossRef Zhang W, Chai B, Li JY, et al. Effect of des-acyl ghrelin on adiposity and glucose metabolism. Endocrinology. 2008;149(9):4710–6.PubMedCrossRef
44.
go back to reference Zhang Q, Huang WD, Lv XY, et al. Ghrelin protects H9c2 cells from hydrogen peroxide-induced apoptosis through NF-κB and mitochondria-mediated signaling. Eur J Pharmacol. 2011;654(2):142–9.PubMedCrossRef Zhang Q, Huang WD, Lv XY, et al. Ghrelin protects H9c2 cells from hydrogen peroxide-induced apoptosis through NF-κB and mitochondria-mediated signaling. Eur J Pharmacol. 2011;654(2):142–9.PubMedCrossRef
Metadata
Title
Association of Obestatin, Ghrelin, and Inflammatory Cytokines in Obese Patients with Non-alcoholic Fatty Liver Disease
Authors
Michael Estep
Massih Abawi
Mohammed Jarrar
Lei Wang
Maria Stepanova
Hazem Elariny
Amir Moazez
Zachary Goodman
Vikas Chandhoke
Ancha Baranova
Zobair M. Younossi
Publication date
01-11-2011
Publisher
Springer-Verlag
Published in
Obesity Surgery / Issue 11/2011
Print ISSN: 0960-8923
Electronic ISSN: 1708-0428
DOI
https://doi.org/10.1007/s11695-011-0475-1

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