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||Low||NCBI|
|Macaca fascicularis||Macaca fascicularis||Low||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|All life stages||High|
Key Event Description
Trypsin-mediated feedback regulation of pancreatic exocrine secretion is commonly found among vertebrate species.
In rats, trypsin-sensitive monitor peptide (MP), a pancreatic soluble trypsin inhibitor (TI) found in pancreatic juice that protects against trypsin-induced auto-injury [Iwai K et al, 1987; Iwai K et al, 1988; Tsuzuki S et al, 1991; Tsuzuki S et al, 1992], plays a major role in stimulating pancreatic exocrine secretion via cholecystokinin (CCK) release [Miyasaka K et al, 1989; Fushiki T et al, 1989; Miyasaka K and Funakoshi A, 1998].
MP is a peptide consisting of 61 amino acids with a molecular weight of approximately 6000 and is secreted from pancreatic acinar cells along with other pancreatic enzymes [Iwai K et al, 1987].MP is reported to have trypsin inhibitory activity [Lin YZ et al, 1990], and it forms complexes with trypsin in the empty intestine, similar to other pancreatic soluble TIs [Voet D and Voet JG, 1995], which keeps the intestinal level of free MP low. However, once the gastric contents are transported to the small intestine, secretion of the pancreatic proteases with MP are induced, where trypsin is used for protein hydrolysis, and the level of free MP is subsequently increased [Iwai K et al, 1988; Graf R, 2006]. The increased MP level stimulates CCK release from I cells lining the small intestinal mucosa via MP receptors [Liddle RA et al, 1992; Yamanishi R et al, 1993; Yamanishi R et al, 1993; Liddle RA et al, 1992], and the resulting increase in CCK stimulates exocrine secretion from the pancreas. MP secretion is simultaneously increased to stimulate CCK release further. Therefore, MP-mediated regulation of trypsin and related proteases appears to act via a positive feedback loop as long as duodenal contents remain to consume trypsin for proteolysis.
In accordance with the increased secretion of pancreatic enzymes, proteolysis of the intestinal contents lowers protein levels in the intestinal lumen, which once again lowers the intestinal level of free MP due to the excess of trypsin. CCK release is decreased in accordance with the decreased intestinal MP level, followed by a decrease in pancreatic exocrine secretion [Liddle RA, 1995; Miyasaka K and Funakoshi A, 1998].
After ingestion of raw soya flour, which contains trypsin inhibitory activity, or TIs such as camostat, TI–trypsin complexes are formed, and the intestinal level of free MP is increased to stimulate CCK release [Yamanishi R et al, 1993], increasing the blood CCK level. Increased CCK further stimulates MP as well as other pancreatic enzymes via positive feedback regulation [Liddle RA, 1995].
How It Is Measured or Detected
No literatures that describe the methods of measuring intestinal concentration of MP are found although some authors reported the isolation and measurement of MP from synthesis reaction solution, pancreas or pancreatic juice.
Synthesized crude peptides were eluted through gel filtration chromatography. PSTI-I-specific peak was confirmed by mas spectrometric measurement and analytical HPLC was performed [Graf R et al, 2003].
In rats fed control and high protein diets, zymogen granules were isolated and concentrations of MP and PSTI-II in zymogen granules can be determined by HPLC [Tsuzuki S et al, 1991].
Rat anionic trypsinogen and a pancreatic secretory trypsin inhibitor were purified from the pure pancreatic juice of rats by reverse-phase HPLC [Iwai K et al, 1987].
Domain of Applicability
Feedback regulation of pancreatic enzyme secretion mediated by trypsin-sensitive intestinal peptides other than MP has been reported in mammals. Such peptides include luminal CCK-releasing factors (LCRFs) secreted by duodenal mucosal cells in response to intestinal diet in some mammalian species including rats, pigs (diazepam-binding inhibitor) and humans [Miyasaka K and Funakoshi A, 1998; Wang Y, 2002; Wang BJ and Cui ZJ, 2007]. In humans, different from rodents, LCRF is not secreted spontaneously in the intestine, however luminal amino acids and fatty acids were reported to induce CCK release [Liddle RA, 1997].
MP is one of pancreatic soluble TIs (PSTIs), which are found in the pancreatic juice of many mammalian species including pigs, dogs, and humans [Greene LJ et al, 1968; Pubols MH et al, 1974; Eddeland A and Ohlsson K, 1976; Kikuchi N et al, 1985]. Secreted PSTIs bind tightly to trypsin to protect against trypsin-induced auto-injury in the pancreas and intestinal tracts [Voet D and Voet JG, 1995].
In rats, two types of PSTIs have been isolated: MP (or PSTI-I) and PSTI-II [Tsuzuki S et al, 1991; Tsuzuki S et al, 1992]. Both are similar in amino acid sequence; however, the former directly stimulates CCK release from intestinal CCK I cells via their surface MP receptors [Yamanishi R et al, 1993], whereas the latter does not [Guan D et al, 1990].
Human PSTIs do not directly stimulate CCK release from intestinal mucosal cells [Miyasaka K et al, 1989], and no PSTI except MP has been reported to stimulate CCK release.
1. Eddeland A, Ohlsson K: Purification of canine pancreatic secretory trypsin inhibitor and interaction in vitro with complexes of trypsin-alpha-macroglobulin.. Scand J Clin Lab Invest 36:815-820,1976
2. Fushiki T, Kajiura H, Fukuoka S, Kido K, Semba T, Iwai K: Evidence for an intraluminal mediator in rat pancreatic enzyme secretion: reconstitution of the pancreatic response with dietary protein, trypsin and the monitor peptide.. J Nutr 119:622-627,1989
3. Graf R, Klauser S, Fukuoka SI, Schiesser M, Bimmler D: The bifunctional rat pancreatic secretory trypsin inhibitor/monitor peptide provides protection against premature activation of pancreatic juice. Pancreatology 3:195-206,2003
4. Graf R, Bimmler D: Biochemistry and biology of SPINK-PSTI and monitor peptide.. Endocrinol Metab Clin North Am 35:333-43, ix,2006
5. Greene LJ, DiCarlo JJ, Sussman AJ, Bartelt DC: Two trypsin inhibitors from porcine pancreatic juice. J Biol Chem 243:1804-1815,1968
6. Guan D, Ohta H, Tawil T, Liddle RA, Green GM: CCK-releasing activity of rat intestinal secretion: effect of atropine and comparison with monitor peptide. Pancreas 5:677-684,1990
7. Iwai K, Fukuoka S, Fushiki T, Tsujikawa M, Hirose M, Tsunasawa S, Sakiyama F: Purification and sequencing of a trypsin-sensitive cholecystokinin-releasing peptide from rat pancreatic juice. Its homology with pancreatic secretory trypsin inhibitor.. J Biol Chem 262:8956-8959,1987
8. Iwai K, Fushiki T, Fukuoka S: Pancreatic enzyme secretion mediated by novel peptide: monitor peptide hypothesis. Pancreas 3:720-728,1988
9. Kikuchi N, Nagata K, Yoshida N, Ogawa M: The multiplicity of human pancreatic secretory trypsin inhibitor. J Biochem 98:687-694,1985
10. Liddle RA, Misukonis MA, Pacy L, Balber AE: Cholecystokinin cells purified by fluorescence-activated cell sorting respond to monitor peptide with an increase in intracellular calcium. Proc Natl Acad Sci U S A 89:5147-5151,1992
11. Liddle RA: Regulation of cholecystokinin secretion by intraluminal releasing factors. Am J Physiol 269:G319-27,1995
12. Liddle RA: Cholecystokinin cells. Annu Rev Physiol 59:221-242,1997
13. Lin YZ, Isaac DD, Tam JP: Synthesis and properties of cholecystokinin-releasing peptide (monitor peptide), a 61-residue trypsin inhibitor. Int J Pept Protein Res 36:433-439,1990
14. Miyasaka K, Nakamura R, Funakoshi A, Kitani K: Stimulatory effect of monitor peptide and human pancreatic secretory trypsin inhibitor on pancreatic secretion and cholecystokinin release in conscious rats. Pancreas 4:139-144,1989
15. Miyasaka K, Funakoshi A: Luminal feedback regulation, monitor peptide, CCK-releasing peptide, and CCK receptors. Pancreas 16:277-283,1998
16. Pubols MH, Bartelt DC, Greene LJ: Trypsin inhibitor from human pancreas and pancreatic juice. J Biol Chem 249:2235-2242,1974
17. Tsuzuki S, Fushiki T, Kondo A, Murayama H, Sugimoto E: Effect of a high-protein diet on the gene expression of a trypsin-sensitive, cholecystokinin-releasing peptide (monitor peptide) in the pancreas. Eur J Biochem 199:245-252,1991
18. Tsuzuki S, Miura Y, Fushiki T, Oomori T, Satoh T, Natori Y, Sugimoto E: Molecular cloning and characterization of genes encoding rat pancreatic cholecystokinin (CCK)-releasing peptide (monitor peptide) and pancreatic secretory trypsin inhibitor (PSTI). Biochim Biophys Acta 1132:199-202,1992
19. Voet D, Voet JG: Biochemistry (2nd ed.). John Wiley & Sons (pp) 396-400,1995
20. 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
21. 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
22. Yamanishi R, Kotera J, Fushiki T, Soneda T, Iwanaga T, Sugimoto E: Characteristic and localization of the monitor peptide receptor. Biosci Biotechnol Biochem 57:1153-1156,1993
23. Yamanishi R, Kotera J, Fushiki T, Soneda T, Saitoh T, Oomori T, Satoh T, Sugimoto E: A specific binding of the cholecystokinin-releasing peptide (monitor peptide) to isolated rat small-intestinal cells. Biochem J 291 ( Pt 1):57-63,1993