Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|TI-induced AC tumors||KeyEvent|
|Homo sapiens||Homo sapiens||High||NCBI|
|Macaca fascicularis||Macaca fascicularis||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|All life stages||High|
Key Event Description
Pancreatic exocrine secretion is controlled by multiple mechanisms [Caron J et al, 2017; Wang BJ and Cui ZJ, 2007; Wang Y et al, 2011], many of which are mediated by CCK secreted by CCK-producing I cells lining the mucosa of the small intestine [Singer MV and Niebergall-Roth E, 2009; Rehfeld JF, 2017]. CCK is also synthesized in cerebral neurons and expressed in several endocrine and certain other cells, and they are involved in many functions other than pancreatic exocrine secretion, including gall bladder contraction, gut motility, and satiety [Rehfeld JF, 2017].
CCK is initially synthesized as a peptide prohormone comprising 150 amino acids, which is processed into active CCK by prohormone convertases specific to the cell type and species [Rehfeld JF et al, 2003; Wang BJ and Cui ZJ, 2007]. CCKs exist as several isoforms that differ due to post-translational modifications, although the C-terminal amino acid sequences are conserved among these isoforms [Rehfeld JF et al, 2001; Rehfeld JF, 2017].
CCK release is stimulated mainly by gastric contents containing fatty acids and amino acids transported into the small intestine. The factors in gastric chyme that stimulate CCK release differ among species, with fats, fatty acids, proteins, and amino acids being the key players in humans, fatty acids and amino acids in canines, and digested/undigested proteins in rats [Wang BJ and Cui ZJ, 2007; Caron J et al, 2017]. These factors stimulate intestinal mucosal I cells to release CCK into the blood either directly via specific receptors such as calcium-sensing receptors and the G protein-coupled receptor GPR93 or indirectly via luminal CCK-releasing factors (LCRFs) [Caron J et al, 2017]. LCRFs are released from intestinal mucosal cells in response to amino acids and fatty acids in humans [Liddle RA, 1997; Liddle RA, 2000] ; however, the peptides mediate negative feedback regulation of CCK release via CCK degradation by pancreatic proteases [Wang BJ and Cui ZJ, 2007].
In addition to the negative feedback regulation of CCK release in rodents, CCK release is stimulated by monitor peptide (MP), a pancreatic soluble trypsin inhibitor (PSTI) secreted into the upper intestine from pancreatic acinar cells [Wang BJ and Cui ZJ, 2007]. MP, which is trypsin-sensitive, stimulates intestinal I cells to release CCK via positive feedback regulation, in that the resulting increased CCK level stimulates the secretion of MP together with other pancreatic enzymes [Liddle RA, 1995; Wang BJ and Cui ZJ, 2007; Miyasaka K and Funakoshi A, 1998]
When trypsin is inhibited in rodents, trypsin-sensitive MP-induced CCK release is overstimulated due to positive feedback regulation of CCK release by trypsin.
How It Is Measured or Detected
Plasma was first extracted on octadecylsilyl silica columns, and the CCK concentration was measured in the resulting extracts, based on the ability of the extracts to stimulate amylase release from isolated rat pancreatic acini [Liddle RA et al, 1984].
The STC-1 cell line, which is derived from murine enteroendocrine tumor cells, secretes several enteroendocrine hormones including CCK, GLP-1, and GLP-2 in response to many different stimulants such as monosaccharides, aromatic amino acids, peptidomimetic compounds, and bitter tastants [Wang BJ and Cui ZJ, 2007].
CCK release from STC-1 cells or intestinal cell preparation were measured by sensitive and specific radioimmunoassay, which recognizes biologically active forms of CCK [Wang Y et al, 2002; Wang Y et al, 2011].
In order to assess the effects of protein hydrolysates on CCK release from enteroendocrine cells, each of protein hydrolysates and STC-1 cells were incubated and CCK release is measured by ELISA [Foltz M et al, 2008].
Domain of Applicability
There are species differences in the regulation of CCK release.
Fats, fatty acids, proteins, and amino acids stimulate CCK release in humans, and fatty acids and amino acids are the key factors regulating CCK release in dogs. These factors stimulate intestinal I cells to release CCK either directly via cell surface receptors such as Ca-sensing receptors and the G protein-coupled receptor GPR93 or indirectly via LCRFs [Caron J et al, 2017]. Amino acids directly stimulate LCRF release from small intestinal mucosal cells in humans [Wang BJ and Cui ZJ, 2007].
On the other hand, in rodents, trypsin-mediated negative and positive feedback regulation loops involved in CCK release have been identified; the former is mediated by LCRF secreted from intestinal mucosal cells and the latter via MP secreted from pancreatic acinar cells [Liddle RA, 1995; Wang BJ and Cui ZJ, 2007; Miyasaka K and Funakoshi A, 1998]. This mechanism of CCK release regulation is plausible in rodents, because of their diet of wild legumes and cereal grains, which contain trypsin inhibitors, and the short digestion time in the stomach.
Multiple isoforms of CCKs (e.g., CCK-83, -58, -39, -33, -22, -8, and others) have been identified, and their expression differs among species (humans express CCK-33, -22, and -58; dogs express CCK-58; cats express CCK-8, -33, and -58; pigs express CCK-22, -58, -3, and -8; rabbits express CCK-22 and -8; and rats express CCK-58). All CCK isoforms contain a highly conserved region of amino acids and serve as ligands for CCK1 receptors [Wang BJ and Cui ZJ, 2007; Rehfeld JF, 2017].
1. Caron J, Domenger D, Dhulster P, Ravallec R, Cudennec B: Protein digestion-derived peptides and the peripheral regulation of food intake. Front Endocrinol (Lausanne) 8:85,2017
2. Foltz M, Ansems P, Schwarz J, Tasker MC, Lourbakos A, Gerhardt CC: Protein hydrolysates induce CCK release from enteroendocrine cells and act as partial agonists of the CCK1 receptor. J Agric Food Chem 56:837-843,2008
3. Goke B, Printz H, Koop I, Rausch U, Richter G, Arnold R, Adler G: Endogenous CCK release and pancreatic growth in rats after feeding a proteinase inhibitor (camostate). Pancreas 1:509-515,1986
4. Liddle RA, Goldfine ID, Williams JA: Bioassay of plasma cholecystokinin in rats: effects of food, trypsin inhibitor, and alcohol. Gastroenterology 87:542-549,1984
5. Liddle RA: Regulation of cholecystokinin secretion by intraluminal releasing factors. Am J Physiol 269:G319-27,1995
6. Liddle RA: Cholecystokinin cells. Annu Rev Physiol 59:221-242,1997
7. Liddle RA: Regulation of cholecystokinin secretion in humans. J Gastroenterol 35:181-187,2000
8. Miyasaka K, Funakoshi A: Luminal feedback regulation, monitor peptide, CCK-releasing peptide, and CCK receptors. Pancreas 16:277-283,1998
9. Rehfeld JF, Sun G, Christensen T, Hillingso JG: The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33. J Clin Endocrinol Metab 86:251-258,2001
10. Rehfeld JF, Bungaard JR, Friis-Hansen L, Goetze JP: On the tissue-specific processing of procholecystokinin in the brain and gut--a short review. J Physiol Pharmacol 54 Suppl 4:73-79,2003
11. Rehfeld JF: Cholecystokinin-From Local Gut Hormone to Ubiquitous Messenger. Front Endocrinol (Lausanne) 8:47,2017
12. Singer MV, Niebergall-Roth E: Secretion from acinar cells of the exocrine pancreas: role of enteropancreatic reflexes and cholecystokinin. Cell Biol Int 33:1-9,2009
13. Wang BJ, Cui ZJ: How does cholecystokinin stimulate exocrine pancreatic secretion? From birds, rodents, to humans. Am J Physiol Regul Integr Comp Physiol 292:R666-78,2007
14. Wang Y, Prpic V, Green GM, Reeve JR Jr, Liddle RA: Luminal CCK-releasing factor stimulates CCK release from human intestinal endocrine and STC-1 cells. Am J Physiol Gastrointest Liver Physiol 282:G16-22,2002
15. Wang Y, Chandra R, Samsa LA, Gooch B, Fee BE, Cook JM, Vigna SR, Grant AO, Liddle RA: Amino acids stimulate cholecystokinin release through the Ca2+-sensing receptor. Am J Physiol Gastrointest Liver Physiol 300:G528-537,2011