Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis.
Cholecystokinin (CCK) modulates contractility of the gallbladder, the sphincter of Oddi, and the stomach. These effects are mediated through activation of gastrointestinal smooth muscle as well as enteric neuron CCK-1 receptors (CCK-1Rs). To investigate the potential physiological and pathophysiological functions linked to CCK-1R-mediated signaling, we compared male WT and CCK-1R-deficient mice (129/SvEv). After 12 weeks on either a standard mouse chow or a lithogenic diet (containing 1% cholesterol, 0.5% cholic acid, and 15% dairy fat), small-intestinal transit time, intestinal cholesterol absorption, biliary cholesterol secretion, and cholesterol gallstone prevalence were compared in knockout versus WT animals. Analysis of mice on either the chow or the lithogenic diet revealed that CCK-1R(-/-) animals had larger gallbladder volumes (predisposing to bile stasis), significant retardation of small-intestinal transit times (resulting in increased cholesterol absorption), and increased biliary cholesterol secretion rates. The elevation in bile cholesterol, coupled with a tendency toward gallbladder stasis (due to the absence of CCK-induced contraction), facilitates nucleation, growth, and agglomeration of cholesterol monohydrate crystals; this sequence of events in turn results in a significantly higher prevalence of cholesterol gallstones in the CCK-1R-null mice.
Wang
David Q-H
DQ
Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Schmitz
Frank
F
Kopin
Alan S
AS
Carey
Martin C
MC
D000818:Animals; D001647:Bile Acids and Salts / Q000032:analysis / Q000378:metabolism; D002769:Cholelithiasis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000008:administration & dosage* / Q000494:pharmacology; D004198:Disease Susceptibility; D005704:Gallbladder / Q000503:physiopathology; D007408:Intestinal Absorption / Q000502:physiology*; D008055:Lipids / Q000032:analysis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D013997:Time Factors
D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D008055:Lipids; D011949:Receptors, Cholecystokinin; D002784:Cholesterol