Cholecystokinin- and secretin-releasing peptides in the intestine—a new regulatory interendocrine mechanism in the gastrointestinal tract

Regulatory Peptides 73 (1998) 89–94

Cholecystokinin- and secretin-releasing peptides in the intestine—a new regulatory interendocrine mechanism in the gastrointestinal tract Karl-Heinz Herzig* ¨ , Schittenhelmstraße 12, 24105 Kiel, Germany Department of Internal Medicine, Christian-Albrechts-Universitat Received 14 March 1997; received in revised form 20 October 1997; accepted 20 October 1997

Abstract Maintenance of homeostasis in the upper small bowel is a vital process for the body and therefore highly controlled. The enteric nervous system and the endocrine system are the regulators in this process influencing each other. The endocrine system in the gut consists of the classical hormones [cholecystokinin (CCK, secretin] to evoke motility or secretion. They are under control of releasing factors which are probably influenced by the enteric nervous system. Diazepam binding inhibitor and luminal CCK-releasing factor are likely candidates for CCK-releasing peptides in the negative feedback process in the absence of pancreatic juice. Experimental evidence suggests a secretin-releasing peptide. Further studies will be needed to determine the physiological role of each of these peptides. Monitor peptide in the pancreatic juice seems to function as a specific positive enhancement for CCK release. All these peptides are inactivated by the proteolytic enzymes during the interdigestive period. The discovery of additional releasing peptides and factors is very likely.  1998 Elsevier Science B.V. Keywords: CCK; Secretin; Intestine; Feedback regulation; Releasing peptides

1. Introduction Feedback control systems are involved in maintaining homeostasis during the constant change of the environment and to adapt to physiological stimuli. The nervous and endocrine systems are the basic regulators to maintain homeostasis. In the feedback process, the product affects the release or action of the factors that cause secretion of the product. The product can either stimulate the release of the factors leading to secretion of more product (positive feedback) or inhibit the release of the factors leading to secretion of less product (negative feedback). In the gastrointestinal tract, certain proteases such as trypsin in the duodenum exert a negative feedback control for pancreatic secretion. Feeding raw soy flour containing a potent trypsin inhibitor to rats significantly stimulates exocrine pancreatic secretion [1]. Diversion of bile–pan*Corresponding author. Tel.: 1 49 431 5971393; fax: 1 49 431 5971302; email: [email protected] 0167-0115 / 98 / $19.00  1998 Elsevier Science B.V. All rights reserved. PII S0167-0115( 97 )01062-8

creatic juice also stimulates pancreatic enzyme secretion [2]. In man, a similar observation was made by Ihse et al. in a patient with complete obstruction of the papilla Vateri by a tumor [3]. Resection of the duodenum in rats prevents the feedback mechanism suggesting that the regulatory components are located in the upper small bowel [4]. The perfusion of isolated rat pancreas with plasma from a soy bean-fed animal significantly increases amylase secretion of the isolated organ [5] showing clearly that a peptide hormone from the upper bowel must be the mediator of this observed feedback mechanism. Following the development of specific cholecystokinin (CCK) assay systems, CCK was identified as the mediator of the protease-regulated feedback control of pancreatic enzyme secretion in rats [6,7]. In addition to the rise in CCK plasma levels during the diversion of pancreatic juice, Sun et al. reported a significant increase in plasma secretin levels indicating also the involvement of secretin in this regulatory mechanism [8]. However, the manner by which trypsin regulates CCK or

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secretin release is unknown. Trypsin does not directly affect the CCK-secreting cells simply by its enzymatic activity [9]. Rapid perfusion of the duodenum of a rat with phosphate-buffered saline completely inhibits diversionstimulated pancreatic enzyme secretion and CCK plasma levels [10,11]. The administration of the concentrated perfusate collected from a donor rat into the duodenum of a recipient rat with diversion of bile–pancreatic juice results in a stimulation of pancreatic enzyme output and CCK plasma levels [10,11]. Treatment of the perfusate with trypsin—but not with amylase, lipase, or by boiling— abolishes the stimulating effect of the perfusate. These experiments indicate that trypsin-sensitive CCK-releasing peptide(s) is(are) secreted into the duodenal lumen stimulating CCK release. The luminal secretion of these releasing peptides appears to be controlled by cholinergic and hormonal mechanisms [11,12]. A similar mechanism has been postulated for secretin release [13]. The control of intestinal endocrine secretion by releasing peptides provides an additional regulatory mechanism for the adequate fine tuned response to a luminal signal. This control mechanism has been well elucidated in the relationship between the hypothalamus pituitary endocrine axis. In the gastrointestinal tract, there is a constant change in the luminal environment by solid food and fluids. The control of homeostasis in the duodenum is unclear. Luminal peptides secreted from the intestinal mucosa may play a substantial role in the regulation of homeostasis. The newly discovered releasing peptides in the duodenal lumen [13–16] will be discussed in this article. A luminal pathway for peptide secretion has been described previously (for review, see Refs. [17,18]). Luminal peptides, for example transforming growth factor a, have been shown to maintain gastrointestinal mucosal integrity [18]. In addition, CCK, gastrin, secretin, somatostatin, vasoactive intestinal polypeptide, neurotensin, and substance P have been detected in the antral lumen and duodenal perfusates [17,19]. Luminal CCK and secretin release has been observed after an intraduodenal infusion with sodium oleate in anaesthetized dogs with diversion of

bile–pancreatic juice [19]. Luminal secretion of gastrin is stimulated by electrical vagal stimulation [20], bombesin and sulphonuric drugs and intraluminal stimulants [21]. Somatostatin is released by food into the circulation [22] but is also detected in the pancreatic juice and the gastric and duodenal lumen [23,24]. Sarfati and Morisset reported cholinergic stimulation of somatostatin release into the rat duodenal lumen [25]. The intraduodenal infusion of somatostatin significantly inhibits feedback-stimulated pancreatic exocrine secretion while intraileal infusion fails to inhibit pancreatic secretion suggesting that somatostatin may act in a paracrine fashion suppressing endogenous release of CCK / secretin. Intravenous administration of antisomatostatin-14 antibodies has no effect on the inhibition of pancreatic secretion by intraduodenal somatostatin indicating an intraduodenal site of action. Recently, somatostatin was shown to reduce CCK release by inhibiting the secretion and the action of the CCK-releasing peptide obtained from duodenal washings from a donor rat [12].

2. Rediscovery of diazepam binding inhibitor (DBI) In search for a CCK-releasing factor, we have recently isolated and sequenced DBI from porcine intestinal mucosa consisting of 86 amino acids and a molecular mass of 9810 daltons (Da) (Table 1) [15]. DBI was first isolated from rat brain in 1983 and named according to its ability to displace diazepam from the g-aminobutyric acid-A receptor [26]. A tryptic fragment of DBI called octadecaneuropeptide (ODN) consisting of the amino acids 33–50 is still biologically active [27]. ODN could be detected in the rat and human brain preparations [28,29]. In addition, two other fragments, DBI 17 – 50 or triakontatetraneuropeptide and DBI 39 – 75 have been purified from rat brain [30,31]. Subsequently, DBI has been detected in a number of organs outside the central nervous system with the highest concentration in the liver, duodenum, testis, kidney, and adrenals [32]. In the porcine duodenum, DBI 1 – 86 and DBI 32 – 86 have been found [33,34]. The

Table 1 Amino acid sequence of porcine diazepam binding inhibitor (DBI), rat luminal CCK-releasing factor (LCRF) and rat monitor peptide Pig DBI

Rat LCRF

Rat monitor peptide

Ac-Ser-Gln-Ala-Glu-Phe-Glu-Lys-Ala-Ala-Glu-Glu-Val-Lys-Asn-Leu-Lys-ThrLys-Pro-Ala-Asp-Asp-Glu-Met-Leu-Phe-Ile-Tyr-Ser-His-Tyr-Lys-Gln-Ala ThrVal-Gly-Asp-Ile-Asn-Thr-Glu-Arg-Pro-Gly-Ile-Leu-Asp-Leu-Lys-Gly-Lys-AlaLys-Trp-Asp-Als-Trp-Asn-Gly-Leu-Lys-Gly-Thr-Ser-Lys-Glu-Asp-Ala-Met-LysAla-Tyr-Ile-Asn-Lys-Val-Glu-Glu-Leu-Lys-Lys-Lys-Tyr-Gly-Ile Ser-Thr-Phe-Trp-Ala-Tyr-Gln-Pro-Asp-Gly-Asp-Asn-Asp-Pro-Thr-Asp-Tyr-GlnLys-Tyr-Glu-His-Thr-Ser-Ser-Pro-Ser-Gln-Leu-Leu-Ala-Pro-Gly-Asp-Tyr-ProCys-Val-Ile-Glu-Val partial sequence of 70–75 amino acid residues according to amino acid composition Gly-Asn-Pro-Pro-Ala-Glu-Val-Asn-Gly-Lys-Thr-Pro-Asn-Cys-Pro-Lys-Gln-IleMet-Gly-Cys-Pro-Arg-Ile-Tyr-Asp-Pro-Val-Cys-Gly-Thr-Asn-Gly-Ile-Thr-TyrPro-Ser-Glu-Cys-Ser-Leu-Cys-Phe-Glu-Asn-Arg-Lys-Phe-Gly-Thr-Ser-Ile-HisIle-Gln-Arg-Arg-Gly-Thr-Cys

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primary structure of this protein is highly conserved [33]. According to its wide distribution, multiple biological functions have been described [32]. DBI has been reported to function as a high affinity acetyl coenzyme A-binding protein in the liver [35], to stimulate steroidogenesis in adrenal cells [36], to act as an autocrine / paracrine regulator of Leydig cell function [37], and to inhibit glucosestimulated insulin release [33]. DBI 32 – 86 has been shown to have antibacterial properties [34]. DBI immunoreactivity is detected in the endocrine pancreas [38] and in the secretory epithelial cells of the gut [39]. We found that intraduodenal infusion of synthetic porcine DBI in rats significantly stimulates pancreatic amylase output and CCK release. Infusion of the CCK antagonist MK326 completely blocks DBI-stimulated amylase output. A tryptic cleavage product, the peptide fragment DBI 33 – 52 , also stimulates CCK release but is 100fold less potent than the whole peptide. Using a commercially available antibody against the DBI fragment, we also demonstrated DBI-like immunoreactivity of 7.5 3 10 211 M in the intestinal lumen of rats. We therefore postulate that intraduodenally secreted DBI releases CCK and may be the missing link in the regulation of exocrine pancreatic secretion. Using an in vitro system of isolated intestinal mucosal cells, we investigated whether inhibitory hormones or substances affect the action of DBI on the CCK-secreting cells [40]. Somatostatin, peptide YY (PYY) and the bile acid traurocholate have been shown to inhibit feedbackstimulated CCK release [12,41,42]. Somatostatin dosedependently inhibits DBI-stimulated CCK release at the same concentrations used by Sarfati and Morisset [25]. This inhibition could be reversed by pertussis toxin indicating that somatostatin acts via its receptor on I-cells coupled to an inhibitory guanine nucleotide-binding protein of adenylate cyclase [43]. In contrast to somatostatin, both PYY and traurocholate do not affect DBI-stimulated CCK release suggesting that these peptides act through other mechanisms to inhibit feedback-stimulated exocrine pancreatic secretion. The regulation of DBI’s action on CCK release by somatostatin adds another criterion for the involvement of DBI as a CCK-releasing peptide in the regulation of feedback-stimulated CCK release.

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Table 2 Comparison of the amino acid compositions of porcine diazepam binding inhibitor (DBI) and rat luminal CCK-releasing factor (LCRF) Amino acid

DBI

LCRF

Asx Thr Ser Glx Pro Gly Ala Val Met Ile Leu Tyr Phe Lys His Arg Cys

10 4 6 13 2 9 9 3 0 5 6 3 2 13 2 2 0

9.4 7.2 6.6 10.9 6.9 6.2 4 2.6 0.5 1.7 4.7 2.1 1.7 1.6 0.9 1.1 Not detected

degradable by tryptic cleavage. Microsequence analysis revealed a partial sequence of 41 residues, the rest of the sequence structure of LCRF is not known (Table 1). Intraduodenal infusion of this peptide dose-dependently stimulates pancreatic fluid and protein secretion concomitantly with increased CCK plasma levels. LCRF-like immunoreactivity is observed in the myenteric and submucosal plexus of the duodenum, the extraintestinal nerve bundles, and in nerve fibers throughout the pancreas [44]. Both peptides originate from the intestinal mucosa, but the technique used to accomplish their isolation was different. LCRF was isolated from jejunal secretions collected from conscious rats [16], while DBI was isolated from porcine intestinal mucosal tissue [15]. The perfusion rate for the collections of LCRF was 2 ml / h excluding distention effects. Since DBI was isolated from the duodenal mucosa from pigs, regulated release of the peptide into the lumen has to be demonstrated in additional studies. Using a DBI-antibody against a tryptic cleavage fragment of DBI, DBI-like immunoreactivity has been shown in the small bowel lumen [15].

4. Monitor peptide 3. Discovery of luminal CCK-releasing factor (LCRF) Recently, another CCK-releasing peptide named LCRF has been isolated from jejunal perfusate of conscious rats [16]. The peptide has a mass of 8136 Da and is composed of 70–75 amino acids. LCRF exhibits a completely different amino acid composition and no sequence homology with DBI (Table 2). In contrast to DBI, which contains 13 lysine and two arginine residues representing possible cleavage sites for trypsin, LCRF has only one lysine and one arginine residue, therefore making it less

Diversion of pancreatic juice or intraduodenal instillation of protease inhibitors resulting in a reduced tryptic activity in the duodenum, enhances CCK-stimulated pancreatic enzyme secretion while it is inhibited by trypsin infusion showing a negative feedback relationship. In addition to this negative feedback mechanism in the absence of pancreatic secretion, a ‘‘positive feedback’’ mechanism in the regulation of pancreatic exocrine secretion has also been found, in which a secreted product in the pancreatic juice itself stimulates further secretion by CCK release. Iwai et al. isolated this peptide from pancreatic

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juice [14]. The peptide was designated as ‘‘monitor peptide’’ for its proposed function of monitoring the intraduodenal environment [45,46]. Purification and sequencing of monitor peptide revealed 61 amino acids exhibiting substantial homology to the family of pancreatic secretory trypsin inhibitors (Table 1) [14]. Despite being a member of the family of protease inhibitors, this monitor peptide directly stimulates CCK release during vascular perfusion of the intestine devoid of intraluminal proteases [47]. CCK release from isolated perfused intestinal mucosal cells is also observed [48]. Liddle et al. showed that monitor peptide directly increases intracellular calcium concentrations in an enriched population of CCK cells [49]. In addition, Yamanishi et al. demonstrated a reversible, temperature- and pH-dependent binding to dispersed intestinal mucosal cells [50]. Using 125 I-labeled monitor peptide, this group could crosslink a potential receptor of 53 kDa. Feeding a high-protein diet [51] or exogenous CCK [52] increases monitor peptide expression at the RNA level. Consequently, monitor peptide seems to function as a specific positive intraluminal feedback stimulus. A proposed model for the role of DBI, LCRF and

monitor peptide in the regulation of CCK secretion is shown in Fig. 1.

5. Secretin-releasing peptide In addition to CCK, diversion of pancreatic juice from the duodenum raised plasma secretin levels suggesting also a role of secretin in the duodenal feedback mechanisms [8]. To investigate the mechanism of secretin release, rats were intraduodenally infused with 0.01% hydrochloric acid [13]. After adjustment of the perfused solution to pH 6.0 and a threefold concentration, the perfusate was reinfused into a recipient rat where it significantly stimulated volume flow, bicarbonate output and raised plasma secretin levels. These effects were completely blocked by intravenous infusion of rabbit antisecretin serum 15 min prior to the intraduodenal perfusion of the concentrated perfusate from the donor rats [13]. Treatment of the perfusate with trypsin also abolished the effect suggesting that acid-stimulated secretin release is mediated by a secretin-releasing peptide in the upper small bowel. The release and the action of this peptide have been shown to be neuromodulated [53]. Further structural characterization of this peptide is necessary.

Acknowledgements This work was supported by the Deutsche Forschungsgemeinschaft He 1965 / 1-1; 1-2; 1-3.

References

Fig. 1. Proposed model for the role of DBI, LCRF, and monitor peptide in the regulation of CCK secretion. DBI located in the secretory epithelial cells of the proximal small intestine is secreted to the luminal side in a paracrine fashion. LCRF may be released in a similar way. DBI and LCRF raise CCK release from the CCK cells into the bloodstream stimulating pancreatic enzyme secretion. Trypsin inactivates DBI and LCRF by proteolytic cleavage. Postprandially, the proteolytic activity in the duodenum will be reduced by acid and food entering the duodenum preventing DBI and LCRF from inactivation by cleavage. In the interdigestive state trypsin will again inactivate the peptides. Release of CCK by DBI is negatively regulated by somatostatin, while PYY or traurocholate have no effect. Monitor peptide is secreted with the pancreatic juice into the duodenum stimulating CCK release.

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