Increased blood CCK level leads to Increased acinar cell exocrine secretion

Pancreatic exocrine secretion is regulated mainly by cholecystokinin (CCK) released by CCK-producing I cells located in the mucosa of the upper small intestine. CCK stimulates exocrine secretion directly via CCK receptors expressed on acinar cell surfaces or indirectly via vagal afferent nerves expressing CCK receptors.

There are two types of CCK receptors: CCK1 (CCK-A) and CCK2 (CCK-B or gastrin) receptors. The former shows high affinity to CCK and the latter to both CCK and gastrin [Wang BJ and Cui ZJ, 2007; Dufresne M et al, 2006].

There are species differences in CCK-mediated pancreatic exocrine secretion. In rats, exocrine secretion from pancreatic acinar cells is regulated directly by CCK1 receptors expressed on the surface of acinar cells and indirectly by vagal afferent nerves expressing CCK1 receptors. Meanwhile, in humans, pancreatic exocrine secretion is regulated mainly by vagal afferent nerves expressing CCK1 receptors [Wang BJ and Cui ZJ, 2007].

The major function of pancreatic exocrine secretion is the production and secretion of digestive enzymes. Zymogen granules located at the apical site of pancreatic acinar cells contain the precursors of multiple digestive enzymes such as trypsinogen, chymotrypsinogen, proesterases, procarboxypeptidase A and B, as well as pancreatic lipase and amylase α. These precursors are secreted by acinar cells into the small intestine, where they are activated by pepsins and peptidases [Berg JM et al, 2002].

Disruption of the CCK1 receptor in rats also affects pancreatic exocrine secretion [Miyasaka K et al, 1998].

Capsaicin and atropine inhibit cholinergic vagus nerve reflexes to reduce CCK-mediated pancreatic enzyme secretion [Li Y et al, 1997; Yamamoto M et al, 2003; Li Y and Owyang C, 1994; Soudah HC et al, 1992; Owyang C et al, 1986].

TBD

Species differences in the mechanism of CCK release

Pancreatic exocrine secretion is controlled mainly by CCK released into the blood steam from intestinal mucosal I cells of the small intestine in response to the gastric contents transported to the intestine [Singer MV and Niebergall-Roth E, 2009; Rehfeld JF, 2017]. Peptides released from gastrointestinal digestion, along with fatty acids, are the main stimuli of CCK release involving several direct and indirect pathways [Caron J et al, 2017].

In humans and canines, amino acids and fatty acids in the gastric contents transported to the small intestine play a major role in stimulating CCK release, which regulates pancreatic exocrine secretion, but MP is not involved in exocrine regulation [Wang BJ and Cui ZJ, 2007]. CCK-stimulated pancreatic exocrine secretion seems to be regulated with negative feedback manner via LCRF.

In rats, however, different from other mammalian species, nutrient protein and protein hydrolysate stimulate CCK release and MP secreted by pancreatic acinar cells plays an active role in protein/protein hydrolysate-stimulated CCK release [Iwai K et al, 1988; Fushiki T et al, 1989]. Ingestion of trypsin inhibitors increases the intestinal level of MP, especially after all nutrient protein is digested in the intestines, causing a subsequent increase in the blood level of CCK. The increased CCK level stimulates pancreatic exocrine secretion of proteins including MP, which in turn further increases the release of CCK. This positive feedback response associated with MP secretion might lead to continuously elevated plasma levels of CCK [Liddle RA, 1995].

Species differences in CCKs

Several isoforms of CCK, including CCK-83, -58, -39, -33, -22, and -8, have been identified, and there are species differences in CCK isoforms (e.g., CCK-33, -22 and -58 are expressed in humans, CCK-58 in dogs, CCK-8, -33 and -58 in cats, CCK-22, -58, -3 and -8 in pigs, CCK-22 and -8 in rabbits, and CCK-58 in rats). All of these CCK isoforms have a highly conserved region of amino acids, and all are ligands of CCK1 receptors [Wang BJ and Cui ZJ, 2007].

Species differences in pancreatic exocrine secretion

In rats, CCK stimulates pancreatic exocrine secretion and acinar cell growth directly via CCK1 receptors expressed on the cell surface, and exocrine secretion is also innervated by vagal afferent nerves expressing CCK1 receptors [Singer MV and Niebergall-Roth E, 2009; Pandiri AR, 2014; Yamamoto M et al, 2003].

On the other hand, human pancreatic acinar cells do not express CCK1 receptors, and CCK-mediated exocrine secretion is regulated exclusively by innervation of vagal nerves expressing CCK1 receptors [Soudah HC et al, 1992; Beglinger C et al, 1992; Singer MV and Niebergall-Roth E, 2009], although there is some evidence of direct stimulation of exocrine secretion of human pancreatic acinar cells [Murphy JA et al, 2008].

Species differences in CCK receptors

CCK1 and CCK2 receptors are expressed in various organs and tissues including digestive and nervous systems, and there are species differences in distribution and expression levels of the receptors.

In rats, pancreatic acinar cells express mainly CCK1 receptors and no CCK2 receptors [Bourassa J et al, 1999]. CCK1 receptors are also expressed in vagal afferent nerve fibers of the gastroduodenal tract. Stimulation of the vagal nerve via CCK1 receptors as well as via physical stimulation by stomach wall distention from ingested food also promotes pancreatic exocrine secretion [Dufresne M et al, 2006].

In humans, on the other hand, CCK2 receptors are dominantly expressed in pancreatic acinar cells, with low expression of CCK1 receptors [Nishimori I et al, 1999]. Ji reported the following: 1) the mRNA level of the CCK2 receptor is higher than that of the CCK1 receptor in the human pancreas; 2) an in situ hybridization experiment showed no expression of either receptor type in the human pancreas, and 3) human pancreatic cells did not show any response to the CCK1 receptor agonist CCK8 or the CCK2 receptor agonist gastrin in vitro [Ji B et al, 2001]. Therefore, human pancreatic acinar cells respond to CCK more weakly compared with the response in rodents.

Although the distribution of CCK receptors is different between humans and rodents, the structures of CCK1 receptors are highly conserved among mammalian species, with 98% homology between rats and mice, 90% between rats and humans, 98% between cynomolgus monkeys and humans, and 89% between dogs and humans [Wang BJ and Cui ZJ, 2007].