Update on the Molecular Mechanisms Underlying the Effect of Cholecystokinin and Cholecystokinin-1 Receptor on the Formation of Cholesterol Gallstones

Helen H. Wang, Piero Portincasa, David Q.H. Wang

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3407-3423
Number of pages17
JournalCurrent medicinal chemistry
Volume26
Issue number19
DOIs
StatePublished - Jan 1 2019

Fingerprint

Cholecystokinin Receptors
Cholecystokinin
Gallstones
Gallbladder
Cholesterol
Gallbladder Emptying
Total Parenteral Nutrition
Intestinal Absorption
Nutrition
Small Intestine
Enteroendocrine Cells
Fortified Food
Sphincter of Oddi
Intestinal Secretions
Gastrointestinal Hormones
Cholecystitis
Gastrointestinal Motility
Peptide Hormones
Gastric Emptying
Pylorus

Keywords

  • Bile salt
  • biliary sludge
  • Cholecystokinin (CCK)
  • cholesterol crystallization
  • gallbladder motility
  • lithogenic bile.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Update on the Molecular Mechanisms Underlying the Effect of Cholecystokinin and Cholecystokinin-1 Receptor on the Formation of Cholesterol Gallstones. / Wang, Helen H.; Portincasa, Piero; Wang, David Q.H.

In: Current medicinal chemistry, Vol. 26, No. 19, 01.01.2019, p. 3407-3423.

Research output: Contribution to journalArticle

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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.",
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