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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

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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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Figure 1

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Relative lipid compositions of bile specimens from CCK-1R–/– and WT mice...
Relative lipid compositions of bile specimens from CCK-1R–/– and WT mice. Relative lipid compositions (mol per 100 mol) are plotted on partial condensed phase diagrams according to the approximate total lipid concentrations of the bile samples (A, 10.0 g/dl for gallbladder bile; B, 2.0 g/dl for hepatic bile; see Table 1). The one-phase micellar zone (at bottom) is enclosed by a solid curved line, and two solid and two dashed lines divide the phase diagram into regions a–e with different crystallization sequences (see ref. 24). (A) Lipid compositions of pooled gallbladder bile specimens (n = 20 per group) from the CCK-1R–/– (circle) and WT mice (square) fed the lithogenic diet for 12 weeks are located in a central three-phase area where, at equilibrium, bile samples are composed of cholesterol-saturated mixed micelles, solid cholesterol crystals, and liquid crystals, as observed by microscopy. (B) Analogous regions of the condensed phase diagram exhibit the same physical states at equilibrium as those in the phase diagram shown in A; however, with decreases in total lipid concentration all crystallization pathways are shifted to the left and the micellar zone becomes smaller. These alterations generate a new condensed phase diagram with an enlarged region e. Lipid compositions of individual hepatic bile specimens (n = 6 per group) from both WT (squares) and CCK-1R–/– mice (circles) locate in region e, where, at equilibrium, the bile samples are composed of liquid crystals and saturated micelles, but no solid cholesterol monohydrate crystals are present.

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