Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis
David Q.-H. Wang, … , Alan S. Kopin, Martin C. Carey
David Q.-H. Wang, … , Alan S. Kopin, Martin C. Carey
Published August 16, 2004
Citation Information: J Clin Invest. 2004;114(4):521-528. https://doi.org/10.1172/JCI16801.
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Article Hepatology

Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis

Abstract

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.

Authors

David Q.-H. Wang, Frank Schmitz, Alan S. Kopin, Martin C. Carey

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Small-intestinal transit rates in WT mice (top panels) and CCK-1R–/– mic...
Small-intestinal transit rates in WT mice (top panels) and CCK-1R–/– mice (bottom panels) ingesting chow (A) or the lithogenic diet (B) for 14 days. Data were determined by the distribution of radioactivity at 30 minutes along the entire length of the small intestine after intraduodenal instillation of [3H]sitostanol dissolved in medium-chain triglyceride (30). Each bar shows the mean percentage of radioactivity in each segment for n = 13 mice per group. Segments 1–20 represent evenly divided portions from the most proximal to the most distal parts of the small intestine placed on a 50-cm ruler (see Methods). (A) Arrows indicate the geometric center, which is significantly (P < 0.001) shorter in chow-fed CCK-1R–/– mice, indicating significantly slower small-intestinal transit times (geometric center = 7.8 ± 0.8) compared with the WT mice (geometric center = 10.8 ± 1.0). (B) Upon ingesting the lithogenic diet, CCK-1R–/– mice continue to display significantly slower small-intestinal transit times (geometric center = 9.1 ± 1.5) compared with the WT mice (geometric center = 13.3 ± 2.0).