Changes in Subcellular Distribution of n-Octanoyl or n-Decanoyl Ghrelin in Ghrelin-Producing Cells

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Abstract

Background: The enzyme ghrelin O-acyltransferase (GOAT) catalyzes the acylation of ghrelin. The molecular form of GOAT, together with its reaction in vitro, has been reported previously. However, the subcellular processes governing the acylation of ghrelin remain to be elucidated.

Methods: Double immunoelectron microscopy was used to examine changes in the relative proportions of secretory granules containing n-octanoyl ghrelin (C8-ghrelin) or n-decanoyl ghrelin (C10-ghrelin) in ghrelin-producing cells of mouse stomachs. The dynamics of C8-type (possessing C8-ghrelin exclusively), C10-type (possessing C10-ghrelin only), and mixed-type secretory granules (possessing both C8- and C10-ghrelin) were investigated after fasting for 48 h or after 2 weeks feeding with chow containing glyceryl-tri-octanoate (C8-MCT) or glyceryl-tri-decanoate (C10-MCT). The dynamics of C8- or C10-ghrelin-immunoreactivity (ir-C8- or ir-C10-ghrelin) within the mixed-type granules were also investigated.

Results: Immunoelectron microscopic analysis revealed the co-existence of C8- and C10-ghrelin within the same secretory granules (mixed-type) in ghrelin-producing cells. Compared to control mice fed standard chow, the ratio of C10-type secretory granules increased significantly after ingestion of C10-MCT, whereas that of C8-type granules declined significantly under the same treatment. After ingestion of C8-MCT, the proportion of C8-type secretory granules increased significantly. Within the mixed-type granules the ratio of ir-C10-ghrelin increased significantly and that of ir-C8-ghrelin decreased significantly upon fasting.

Conclusion: These findings confirmed that C10-ghrelin, another acyl-form of active ghrelin, is stored within the same secretory granules as C8-ghrelin, and suggested that the types of medium-chain acyl-molecules surrounding and available to the ghrelin-GOAT system may affect the physiological processes of ghrelin acylation.

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Ghrelin octanoylation mediated by an orphan lipid transferase.

Jesus A Gutierrez, Patricia J Solenberg, Douglas R Perkins … (2008)

The peptide hormone ghrelin is the only known protein modified with an O-linked octanoyl side group, which occurs on its third serine residue. This modification is crucial for ghrelin's physiological effects including regulation of feeding, adiposity, and insulin secretion. Despite the crucial role for octanoylation in the physiology of ghrelin, the lipid transferase that mediates this novel modification has remained unknown. Here we report the identification and characterization of human GOAT, the ghrelin O-acyl transferase. GOAT is a conserved orphan membrane-bound O-acyl transferase (MBOAT) that specifically octanoylates serine-3 of the ghrelin peptide. Transcripts for both GOAT and ghrelin occur predominantly in stomach and pancreas. GOAT is conserved across vertebrates, and genetic disruption of the GOAT gene in mice leads to complete absence of acylated ghrelin in circulation. The occurrence of ghrelin and GOAT in stomach and pancreas tissues demonstrates the relevance of GOAT in the acylation of ghrelin and further implicates acylated ghrelin in pancreatic function.

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Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue.

H Hosoda, M. Kojima, H Matsuo … (2000)

Ghrelin, a novel peptide purified from stomach, is the endogenous ligand for the growth hormone secretagogue receptor and has potent growth hormone-releasing activity. The Ser3 residue of ghrelin is modified by n-octanoic acid, a modification necessary for hormonal activity. We established two ghrelin-specific radioimmunoassays; one recognizes the octanoyl-modified portion and another the C-terminal portion of ghrelin. Using these radioimmunoassay systems, we found that two major molecular forms exist-ghrelin and des-n-octanoyl ghrelin. While ghrelin activates growth-hormone secretagogue (GHS) receptor-expressing cells, the nonmodified des-n-octanyl form of ghrelin, designated as des-acyl ghrelin, does not. In addition to these findings, our radioimmunoassay systems also revealed high concentrations of ghrelin in the stomach and small intestine.

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Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration.

M. M. A. Mondal, N Murakami, K. Kangawa … (2001)

Ghrelin is a novel gut-brain peptide that binds to the growth hormone secretagogue receptor (GHS-R), thereby functioning in the regulation of growth hormone (GH) release and food intake. Ghrelin-producing cells are most abundant in the oxyntic glands of the stomach. The regulatory mechanism that governs the biosynthesis and secretion of ghrelin has not been clarified. We report that ghrelin mRNA expression in the gastric fundus was increased, but that ghrelin peptide content decreased after a 48-h fast. Both values returned to control levels after refeeding. The ghrelin plasma concentration in the gastric vein and systemic venous blood increased after 24- and 48-h fasts. Furthermore, des-octanoylated ghrelin and n-octanoylated ghrelin were found in rat stomach, with the ratio of des-octanoylated ghrelin to n-octanoylated ghrelin markedly increased after fasting. The ghrelin mRNA level in the stomach also increased after administration of insulin and leptin. Conversely, db/db mice, which are deficient in the leptin receptor, had lower ghrelin mRNA levels than control mice. These findings suggest that this novel gastrointestinal hormone plays a role in the regulation of energy balance. Copyright 2001 Academic Press.

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Author and article information

Journal

Journal ID (nlm-ta): Front Endocrinol (Lausanne)

Journal ID (iso-abbrev): Front Endocrinol (Lausanne)

Journal ID (publisher-id): Front. Endocrinol.

Title: Frontiers in Endocrinology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-2392

Publication date (Electronic): 09 July 2013

Publication date Collection: 2013

Volume: 4

Electronic Location Identifier: 84

Affiliations

[1] ¹Department of Physiology, School of Medicine, Kurume University , Kurume, Japan

[2] ²Institute of Animal Experimentation, School of Medicine, Kurume University , Kurume, Fukuoka, Japan

[3] ³Laboratory of Veterinary Clinical Pathology, Joint Faculty of Veterinary Medicine, Kagoshima University , Kagoshima, Japan

[4] ⁴Division of Endocrinology and Metabolism, School of Medicine, Kurume University , Kurume, Fukuoka, Japan

[5] ⁵Department of Pediatrics and Child Health, School of Medicine, Kurume University , Kurume, Fukuoka, Japan

[6] ⁶Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute , Osaka, Japan

[7] ⁷Molecular Genetics, Institute of Life Science, Kurume University , Kurume, Fukuoka, Japan

Author notes

Edited by: Hiroyuki Kaiya, National Cerebral and Cardiovascular Center Research Institute, Japan

Reviewed by: Isabel Navarro, University of Barcelona, Spain; Suraj Unniappan, York University, Canada

*Correspondence: Yoshihiro Nishi, Department of Physiology, School of Medicine, Kurume University, 67 Asahi-machi, Kurume 830-0011, Japan e-mail: nishiy@ 123456med.kurume-u.ac.jp ; Hiroharu Mifune, Institute of Animal Experimentation, Asahi-machi, Kurume University, 67 Asahi-machi, Kurume 830-0011, Japan e-mail: mifune@ 123456med.kurume-u.ac.jp

This article was submitted to Frontiers in Experimental Endocrinology, a specialty of Frontiers in Endocrinology.

Article

DOI: 10.3389/fendo.2013.00084

PMC ID: 3705199

PubMed ID: 23847595

SO-VID: 3de03457-b958-4032-ae19-cae85d8847a6

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

History

Date received : 29 March 2013

Date accepted : 26 June 2013

Page count

Figures: 3, Tables: 4, Equations: 0, References: 32, Pages: 8, Words: 6360

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Changes in Subcellular Distribution of n-Octanoyl or n-Decanoyl Ghrelin in Ghrelin-Producing Cells

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 28

Ghrelin octanoylation mediated by an orphan lipid transferase.

Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue.

Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration.

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