Ghrelin gene‐related peptides: Multifunctional endocrine / autocrine modulators in health and disease

Abstract

1. Ghrelin is a multifunctional peptide hormone that affects various processes, including growth hormone and insulin release, appetite regulation, gut motility, metabolism and cancer cell proliferation. Ghrelin is produced in the stomach and in other normal and pathological cell types. It may act as an endocrine or autocrine/paracrine factor. 2. The present article reviews recent findings in the study of ghrelin and its receptor that suggest that the ghrelin gene locus may give rise to a number of functional molecules (peptides and RNA transcripts) in addition to ghrelin. 3. The ghrelin gene encodes a precursor protein, preproghrelin, from which ghrelin and other potentially active peptides are derived by alternative mRNA splicing and/or proteolytic processing. The metabolic role of the peptide obestatin, derived from the preproghrelin C-terminal region, is contentious. However, obestatin has direct effects on cell proliferation. 4. The regulation of ghrelin expression and the mechanisms through which the peptide products arise are unclear. We have recently re-examined the organization of the ghrelin gene and identified several novel exons and transcripts. One transcript, which lacks the ghrelin-coding region of preproghrelin, contains the coding sequence of obestatin. 5. Furthermore, we have identified an overlapping gene on the antisense strand of ghrelin, namely GHRLOS, which generates transcripts that may function as non-coding regulatory RNAs or code for novel, short bioactive peptides. 6. The identification of these novel ghrelin-gene related transcripts and peptides raises critical questions regarding their physiological function and their potential role in obesity, diabetes and cancer.

Ghrelin and obestatin in thyroid gland — immunohistochemical expression in nodular goiter, papillary and medullary cancer

“…The differences between ghrelin and obestatin immunoreactivity in benign and malignant thyroid tumors could support the theory of alternative transcription of pre-proghrelin gene and thus of independent production of ghrelin and obestatin [38]. In this study there was no correlation between ghrelin and obestatin immunoreactivity in any of the analyzed groups.…”

A role of ghrelin in cancerogenesis

“…Then, the proghrelin undergoes proteolytic process which results in the mature ghrelin (28 AA) and the C-terminal propeptide C-ghrelin (66 remaining AA) production. C-ghrelin may be further cleaved to discharge obestatin (23AA) and/or other peptides (Pemberton et al 2008, Seim et al 2010.…”

Diabetes, Ghrelin And Related Peptides: From Pathophysiology To Vasculopathy

“…From the same gene of ghrelin, through a posttranslational or an alternative splicing process, a peptide named obestatin is obtained [3,9]. This is a 23 amino acid amidated peptide identical to residues 76-98 of the C-terminal peptide of preproghrelin, also isolated in the rat stomach [9].…”

“…Another reason for the metabolic discrepancies can be related to the peculiar U-shape of the dose response curve [57]. The opposing effects of obestatin and ghrelin are controversial and some authors suggest that obestatin could act as a paracrine/autocrine factor, being degradated rapidly in the serum [62].Some studies have demonstrated that obestatin stimulates cell proliferation in prostate cancer cells, ovarian cancer cells [3], gastric cancer cells [63] and ovarian granulosa cells [64]. Obestatin has also been reported to regulate sleep [65], to affect memory and anxiety [66], and to inhibit thirst [67].…”

“…It is the natural ligand of the GHSR-1a receptor [1]. For it to act on the GHSR-1a ghrelin has an n-octanoic acid modification on serine 3 residue [2].The ghrelin gene is located in chromosome 3 (3p25-26) [1], contains four preproghrelin-coding exons, and encodes a precursor of 117aa (preproghrelin) with 82% of homology between species [3]. As a result of alternative splicing of this gene, a 27 aa acylated peptide was identified with the same activity potency as ghrelin (des-Gln14-ghrelin) [4].…”