Physiology of cholecystokinin

INTRODUCTION — Cholecystokinin (CCK) is the major hormone responsible for gallbladder contraction and pancreatic enzyme secretion. CCK, like other gastrointestinal hormones, is produced in discrete endocrine cells that line the mucosa of the small intestine [1]. It is also found in the central nervous system and peripheral nerves innervating the intestine. In these locations, CCK probably functions as a neurotransmitter.

The original discovery of CCK in 1928 was based upon the observation that a substance within intestinal extracts stimulated gallbladder contraction in dogs (hence the name cholecystokinin). In 1943, a similar extract (which has been called pancreozymin) was noted to stimulate pancreatic enzyme secretion. However, purification of the hormone and determination of its amino acid sequence showed that the actions on the gallbladder and pancreas were due to the same hormone [2].

Advances in protein biochemistry, molecular biology, and the development of specific CCK receptor antagonists have increased our understanding of the physiologic and potential pathophysiologic actions of CCK. In humans, physiologic properties of CCK include the ability to stimulate gallbladder contraction, increase pancreatic enzyme secretion, delay gastric emptying, potentiate insulin secretion, and regulate food intake (table 1). In addition, CCK stimulates bowel motility and has growth promoting effects on the pancreas in certain animals [3,4].

MOLECULAR FORMS — A number of molecular forms of cholecystokinin (CCK) have been identified in brain, intestine, and blood of experimental animals and humans. The original form of CCK purified was a tritriacontapeptide (CCK-33) [5]. CCK is produced from a single gene, and different molecular forms are the result of posttranslational processing. Molecular forms ranging in size from 4 to 83 amino acids have been identified in tissue and blood with the predominant molecular form being CCK-58, and less commonly CCK-8 and CCK-33. (See "Overview of gastrointestinal peptides in health and disease".)

CCK possesses a five amino acid sequence at the carboxyl terminus that is identical to that of gastrin (figure 1). The carboxyl terminus confers the biologic activity of CCK; as a result, gastrin has weak CCK-like activity and CCK has weak gastrin-like activity. The amino acid sequence similarity has also made assays for CCK difficult, since antibodies specific for the biologically active end of the molecule often crossreact with gastrin, which circulates in the blood at concentrations 10 to 100 times greater than that of CCK [6]. (See "Physiology of gastrin".)

DISTRIBUTION — Cholecystokinin (CCK)-containing cells (known as I cells) are concentrated in the proximal small intestine and decrease in number toward the distal jejunum and ileum. CCK cells originate from stem cells in the intestinal crypts and migrate up the villus, where the apical surface is exposed to intestinal contents. CCK cells possess basal processes known as neuropods that extend to other cells in the mucosa and submucosa [7]. It is possible that through this mechanism CCK cells communicate with neighboring cells to exert paracrine actions. It has been shown that gut endocrine cells, including CCK cells, connect to enteric nerves including the vagus nerve [8-10]. This newly described neural circuit offers a route for direct communication between the gut lumen and the nervous system.

It has long been thought that each enteroendocrine cell produced only a single hormone. However, with improved immunohistochemical methods and gene profiling, it is now known that CCK cells can produce other hormones such as PYY and serotonin [11]. CCK cells of the small intestine express the fatty-acid-sensing receptors Gpr120, Gpr40, and Gpr43, and the oleoylethanolamide receptor Gpr119, while CCK cells throughout the small intestine and colon express glucose and fructose transporters Sglt1, Glut2, and Glut 5, indicating differential sensing of nutrients by CCK cells throughout the intestine [12]. CCK is a member of the family of "brain-gut" peptides in which the same transmitter is found in the intestine and central nervous system. Although CCK is found in neurons throughout the brain, it is most highly concentrated in the cerebral cortex. CCK has been colocalized in neurons containing dopamine [13]. These neurons project to the limbic forebrain and ventromedial hypothalamus, which may be important for regulating food intake. It has been suggested that CCK has an important role in the regulation of satiety [14].

CCK is also abundant in peripheral nerves of the gastrointestinal tract, which innervate the colon, ileum, and myenteric and submucosal plexus, and in the celiac plexus and vagus nerve. Although the exact physiologic actions of CCK in the nervous system are unknown, it most likely functions as a neurotransmitter.

CCK RECEPTORS — Receptors for cholecystokinin (CCK) within the gastrointestinal tract have been identified in the pancreas, gallbladder, stomach, lower esophageal sphincter, ileum, and colon. CCK receptors are also abundant in brain and on some peripheral nerves.

Two types of CCK receptors have been identified based upon receptor binding characteristics: CCK1 receptors (formerly known as CCK-A receptors) and CCK2 receptors (formerly known as CCK-B receptors). These receptors arise from separate genes but are both G-protein coupled, seven membrane-spanning proteins [15,16] (see "Peptide hormone signal transduction and regulation"). The CCK2 receptor is identical to the gastrin receptor and is present in the stomach and brain. Thus, the receptor is often referred to as the CCK2/gastrin receptor [16].

The development of antagonists to the two CCK receptors has been useful for defining the biologic actions of CCK. Four types of CCK receptor antagonists have been used in pharmacologic and physiologic studies. These include cyclic nucleotide analogues (eg, dibutyryl cGMP), amino acid derivatives (eg, loxiglumide [CR-1409]), carboxyl terminal CCK analogues, and substituted benzodiazepines (eg, devazepide). CCK receptor antagonists inhibit CCK- and meal-stimulated gallbladder contraction and have effects on gastric emptying and satiety.

In addition to the study of receptor function using pharmacologic interventions, a number of animal models lacking CCK receptors have been studied. In a rat strain in which the CCK1 receptor is disrupted, animals develop hyperglycemia, hyperinsulinemia and obesity, suggesting that normal CCK action is important for these metabolic processes [17]. In other studies, cloning of the CCK1 and 2 receptors has made it possible to delete these genes in experimental animals. CCK1 receptor deficient mice appear to maintain normal body weight, although satiety responses to exogenous CCK are impaired [14]. Deletion of the CCK2 (gastrin) receptor in mice resulted in decreased gastric acid production, elevated plasma gastrin levels, and reduced numbers of parietal and ECL cells in the stomach, indicating the importance of the CCK2 receptor in maintaining gastric morphology and acid secretion [18].

REGULATION OF SECRETION — As with most gastrointestinal hormones, cholecystokinin (CCK) is secreted in response to ingestion of a meal, after which plasma concentrations increase approximately five- to ten-fold. Postprandial levels remain elevated for three to five hours while food empties from the stomach into the upper small intestine. The primary stimulants of CCK release are ingested fat and protein; carbohydrates have a less potent effect on secretion.

The release of CCK is controlled by negative feedback regulation. This concept arose from studies demonstrating that inactivation or removal of proteolytic activity from the small intestine of rodents resulted in increased pancreatic exocrine secretion [19]. Similar findings have been made in other species, including humans, whereby pancreatic secretion is controlled in part by the presence or absence of pancreatic enzymes (eg, trypsin) in the intestine (figure 2) [20].

This observation led to the discovery in animals of intestinal releasing factors that are secreted into the intestine and stimulate CCK secretion [21-23]. These releasing factors are inactivated by pancreatic enzymes in the intestine. However, they are able to stimulate CCK secretion when pancreatic secretion is reduced or with ingestion of a meal that temporarily binds trypsin and other digestive enzymes. Whether these releasing factors are present in humans remains unclear.

BIOLOGIC ACTIONS — Cholecystokinin (CCK) is the primary hormone responsible for gallbladder contraction. Coincident with stimulating gallbladder contraction, CCK also relaxes the sphincter of Oddi, which facilitates bile secretion into the intestine. Although CCK is a potent stimulant of pancreatic exocrine secretion in most species, the predominant CCK receptor type in the pancreas in humans is CCK2, which has a much higher affinity for gastrin than for CCK. As a result, CCK may have a limited role as a pancreatic secretagogue in humans. On the other hand, CCK receptors are present on the vagus nerve and appear to mediate the effects of CCK on pancreatic secretion by causing the release of acetylcholine locally in the pancreas [24]. CCK may have weak incretin action. Experimentally in humans, CCK was shown to potentiate amino acid-stimulated insulin secretion and in patients with type II diabetes, CCK infusion-enhanced insulin release, and reduced postprandial glucose levels [4,25].

Gastric emptying is delayed by CCK, which may be one mechanism by which CCK can reduce food intake and induce satiety [3]. The effects of CCK on the stomach appear to occur with physiologic postprandial blood levels of the hormone [26]. Since CCK levels increase after ingestion of a meal, its effects on gallbladder contraction, pancreatic secretion, and gastric emptying serve to coordinate many digestive processes. Thus, CCK is a key regulator of the ingestion and digestion of a meal.

CCK acts on vagal afferent nerve fibers and sends signals to the dorsal hindbrain to terminate meal size and increasing the intermeal interval [27]. Administration of CCK antagonists to animals and humans increases food intake by increasing meal size [28]. Continuous administration of CCK to animals reduces food intake but this effect is lost after 24 hours. However, a long-acting CCK analog resistant to enzyme degradation produced sustained food reduction in non-human primates [29].

A large clinical trial was conducted evaluating the ability of an orally active CCK analog, GI181771X, to induce weight loss over a 24-week period [30]. Drug- and placebo-treated subjects were restricted to hypocaloric diets. Both drug- and placebo-treated subjects lost weight, but a greater weight loss was not observed in drug-treated subjects. Although the authors concluded that CCK does not have a role in long-term energy balance, this trial did not test the appetite suppressing effects of the CCK analog [31]. Therefore, it remains to be determined if there is a therapeutic role for CCK agonists in the regulation of human food intake. CCK1 receptor signaling is reduced by excess membrane cholesterol, a condition that has been described in obesity and metabolic syndrome and may explain impaired CCK-induced satiety in affected individuals [32,33].

A systematic review examining the effects of CCK on satiety and body weight reported that active CCK or CCK analogues at both physiologic and pharmacologic doses increased satiation but did not reduce long-term body weight [34].

CCK also increases transient lower esophageal sphincter relaxations (tLESRs), an effect mediated through the CCK1 receptor [35]. It remains uncertain whether CCK-stimulated tLESRs is hormonal or occurs through CCK neurons.

Receptors for CCK have been identified on a number of tumors, including gastrointestinal, gallbladder, pancreas, and lung cancers [36-39]. Aberrant beta cell expression of CCK in obesity showed that islet CCK promotes oncogenic Kras-driven pancreatic ductal cancer growth [40]. It remains to be seen how CCK affects tumorigenesis in humans.

CCK enhances pain perception in models of inflammatory and neuropathic pain, although it is generally agreed that CCK does not cause pain under normal conditions. Through its ability to facilitate nociception CCK has "anti-opioid" properties. These effects occur through direct actions on specific peripheral neural pathways or neural centers such as the rostral ventromedial medulla [41].

CLINICAL USES — Cholecystokinin (CCK) has a number of roles in clinical medicine, most of which currently involve diagnostic testing. Examples include:

●Radiographic examinations of the gallbladder

●Measurement of pancreatic exocrine secretion

●Stimulation of bile and pancreatic juice for collection for cytology or other testing

●Sphincter of Oddi manometry .

For patients with suspected gallbladder disease, a cholecystokinin (CCK)-enhanced hepatobiliary iminodiacetic acid (HIDA) scan can be used to evaluate gallbladder ejection or pain reproduction with CCK administration [42].

Therapeutic uses of CCK are limited. In patients who are unable to eat (eg, parental alimentation), CCK injections can stimulate gallbladder contraction and reduce gallbladder sludge and gallstone formation [43,44]. Due to CCK's ability to reduce food intake and produce weight loss in animals, small molecule CCK agonists are currently being developed for treatment of obesity.

Peptide hormones are being developed as radiopharmaceuticals to treat certain tumors. Radiolabeled cholecystokinin/gastrin analogs are under investigation for treating small cell lung cancers, ovarian and colon cancers, and some gastroenteropancreatic cancers that express the CCK2 receptor [45].

A number of studies in humans suggest a potential role for CCK receptor antagonists. However no drug is currently approved for clinical use:

●Selective CCK1 receptor antagonists increase hunger in humans, indicating that endogenous CCK has a physiologic role in regulating appetite [46].

●In animal models, CCK1 receptor blockade improved survival and reduced the severity of pancreatitis [47]. However, because the human pancreas expresses lower levels of CCK1 receptor mRNA, it is less clear that CCK antagonists will be beneficial in human disease. Nevertheless, preliminary reports suggest that loxiglumide may be clinically useful in the treatment of acute pancreatitis [48].

●The ability of a CCK receptor antagonist to increase appetite lends itself to the treatment of anorexia nervosa or anorexia associated with cancer or other diseases [4].

●Antagonists selective for the CCK2 receptor (gastrin antagonists) appear to have potent anxiolytic activity and may be useful for treatment of anxiety or panic attacks [49].

●Gastrin antagonists have been shown to reduce acid secretion in humans and may be useful adjuncts to H2 blockers or H/K proton pump inhibitors [50]. Trophic effects (such as occur on ECL cells) of hypergastrinemia would not occur with gastrin receptor blockade.

CLINICAL ASSOCIATIONS — The discovery of elevated cholecystokinin (CCK) in a patient with diarrhea, severe weight loss, gallstones, and peptic ulcer disease [51] led to a search for ectopic expression of CCK in other neuroendocrine tumors (NETs) [52]. Although CCK may be identified by immunohistochemical staining in some NETs, clinical evidence of excessive CCK secretion is rare. A diagnosis of CCKoma is based on elevated circulating CCK levels in the absence of elevated gastrin. Abnormally low CCK levels have been reported in patients with bulimia nervosa (but not purging alone), celiac disease, and in conditions that delay gastric emptying [53-56]. The pathophysiologic role of CCK in these disorders is unknown.

Genetic polymorphisms or reduced expression of the CCK1 receptor in the gallbladder have been reported in gallstone disease [57,58]. Reduced expression of the CCK1 receptor would be expected to impair the ability of CCK to stimulate gallbladder contraction and lead to bile stasis, which is a known predisposing factor in gallstone formation. This mechanism is supported by the observation in mice with genetic deletion of the CCK1 receptor gene (Cckar), which exhibit enhanced cholesterol cholelithogenesis due to impaired gallbladder contraction and emptying, which promotes cholesterol crystallization and growth [59].

Genetic polymorphisms have been found in the promoter region of the CCK1 receptor in some obese individuals [60]. It has been proposed that these polymorphisms alter CCK-induced satiety signals, contributing to abnormal weight control; however, the molecular mechanisms of these polymorphisms remain to be elucidated.

Weight loss is associated with a reduction in circulating levels of CCK and other hormones involved in the homeostatic regulation of body weight [61]. It is possible that these low levels encourage weight regain following weight reduction. Significant changes in serum CCK levels are not found in obesity [62].

SUMMARY

●Cholecystokinin (CCK) is a key regulator of the ingestion and digestion of a meal. CCK stimulates gallbladder contraction and relaxes the sphincter of Oddi, thereby facilitating bile secretion into the intestine. By delaying gastric emptying, it can reduce food intake and induce satiety. CCK also acts on vagal afferent nerve fibers and sends signals to the dorsal hindbrain to terminate meal size. CCK may have a limited role as a pancreatic secretagogue. (See 'Biologic actions' above.)

●CCK is produced from a single gene but different molecular forms result from posttranslational processing. CCK possesses a five amino acid sequence at the carboxyl terminus that is identical to that of gastrin (figure 1). The carboxyl terminus confers the biologic activity of CCK; as a result, gastrin has weak CCK-like activity and CCK has weak gastrin-like activity. (See 'Molecular forms' above.)

●CCK-containing cells are concentrated in the proximal small intestine and decrease in number toward the distal jejunum and ileum. CCK is highly concentrated in the cerebral cortex and is also found in peripheral nerves of the gastrointestinal tract. (See 'Distribution' above.)

●The release of CCK is controlled by negative feedback regulation. The primary stimulants of CCK release are ingested fat and protein; carbohydrates have a less potent effect on secretion. (See 'Regulation of secretion' above.)

●Abnormally low CCK levels have been reported in patients with bulimia nervosa, celiac disease, and in conditions that delay gastric emptying. Reduced expression of the CCK1 receptor in the gallbladder has been reported in gallstone disease.

It has been hypothesized that genetic polymorphisms in the promoter region of the CCK1 receptor as noted in patients with obesity may alter CCK-induced satiety signals, and contribute to abnormal weight control. Weight loss is associated with a reduction in circulating levels of CCK and other hormones involved in the homeostatic regulation of body weight. It is possible that these low levels encourage weight regain following weight reduction. (See 'Clinical associations' above.)

●Diagnostic uses of CCK include radiographic examinations of the gallbladder, measurement of pancreatic exocrine secretion, stimulation of bile and pancreatic juice for collection for cytology or other testing, and sphincter of Oddi manometry. Therapeutic uses of CCK are in development. (See 'Clinical uses' above.)