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Event: 1722

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increased blood CCK level

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Increased blood CCK level
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Biological Context

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Level of Biological Organization

Organ term

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Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
TI-induced AC tumors KeyEvent Shigeru Hisada (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Macaca fascicularis Macaca fascicularis High NCBI
Rattus norvegicus Rattus norvegicus High NCBI
Mus musculus Mus musculus High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages High

Sex Applicability

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Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

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].


List of the literature that was cited for this KE description. More help

 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