Title:Update on the Molecular Mechanisms Underlying the Effect of Cholecystokinin and Cholecystokinin-1 Receptor on the Formation of Cholesterol Gallstones
Volume: 26
Issue: 19
Author(s): Helen H. Wang, Piero Portincasa and David Q.-H. Wang*
Affiliation:
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461,United States
Keywords:
Bile salt, biliary sludge, cholesterol crystallization, gallbladder motility, lithogenic bile, Cholecystokinin
(CCK).
Abstract: Cholecystokinin (CCK) is an important neuro-intestinal peptide hormone produced
by the enteroendocrine I-cells in the upper part of small intestine. Protein- and fat-enriched
food plays an important role in triggering CCK secretion from the intestine. Carbohydrates
stimulate only small amounts of CCK release. The CCK-1 receptor (CCK-1R) is largely localized
in the gallbladder, sphincter of Oddi, pancreas, small intestine, gastric mucosa, and
pyloric sphincter, where it is responsible for CCK to regulate multiple digestive processes including
gallbladder contraction, pancreatic secretion, small intestinal transit, and gastric emptying.
Accumulated evidence clearly demonstrates that CCK regulates gallbladder and small
intestinal motility through CCK-1R signaling cascade and the effect of CCK-1R on small intestinal
transit is a physiological response for regulating intestinal cholesterol absorption. Disruption
of the Cck or the Cck-1r gene in mice significantly increases the formation of cholesterol
gallstones by disrupting gallbladder emptying and biliary cholesterol metabolism, as
well as promoting intestinal absorption of cholesterol. Abnormalities in gallbladder motility
function in response to exogenously administered CCK are found primarily in patients with
cholesterol gallstones. Patients with pigment gallstones display an intermediate degree of
gallbladder motility defect without gallbladder inflammation and enlarged fasting gallbladder.
Dysfunctional gallbladder contractility has been found under several conditions such as pregnancy,
obesity, diabetes, celiac disease, and total parenteral nutrition although gallstones are
not observed. The gallbladder-specific CCK-1R-selective agonist may lead to an efficacious
novel way for preventing gallstone formation by promoting gallbladder emptying, particularly
for pregnant women and subjects with dysfunctional gallbladder motility function such as celiac
patients, as well as patients with total parenteral nutrition.
