title: Augmented cholesterol absorption and sarcolemmal sterol enrichment slow small intestinal transit in mice, contributing to cholesterol cholelithogenesis.
abstract: Cholesterol gallstones are associated with slow intestinal transit in humans as well as in animal models, but the molecular mechanism is unknown. We investigated in C57L/J mice whether the components of a lithogenic diet (LD; 1.0% cholesterol, 0.5% cholic acid and 17% triglycerides), as well as distal intestinal infection with Helicobacter hepaticus, influence small intestinal transit time. By quantifying the distribution of 3H-sitostanol along the length of the small intestine following intraduodenal instillation,we observed that, in both sexes, the geometric centre (dimensionless) was retarded significantly (P <0.05) by LD but not slowed further by helicobacter infection (males, 9.4±0.5 (uninfected), 9.6±0.5 (infected) on LD compared with 12.5±0.4 and 11.4±0.5 on chow). The effect of the LD was reproduced only by the binary combination of cholesterol and cholic acid. We inferred that the LD-induced cholesterol enrichment of the sarcolemmae of intestinal smooth muscle cells produced hypomotility from signal-transduction decoupling of cholecystokinin (CCK), a physiological agonist for small intestinal propulsion in mice. Treatment with ezetimibe in an amount sufficient to block intestinal cholesterol absorption caused small intestinal transit time to return to normal. In most cholesterol gallstone-prone humans, lithogenic bile carries large quantities of hepatic cholesterol into the upper small intestine continuously, thereby reproducing this dietary effect in mice. Intestinal hypomotility promotes cholelithogenesis by augmenting formation of deoxycholate, a pro-lithogenic secondary bile salt, and increasing the fraction of intestinal cholesterol absorbed.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Meimin
authors.initials: M
authors.lastname: Xie
authors.forename: Vijay R
authors.initials: VR
authors.lastname: Kotecha
authors.forename: Jon David P
authors.initials: JD
authors.lastname: Andrade
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Martin C
authors.initials: MC
authors.lastname: Carey
mesh_terms: D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002766:Cholecystokinin / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D019826:Cholic Acid / Q000378:metabolism; D059305:Diet, High-Fat / Q000379:methods; D000069438:Ezetimibe; D005260:Female; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D042882:Gallstones / Q000378:metabolism; D005772:Gastrointestinal Transit / Q000187:drug effects / Q000502:physiology*; D016481:Helicobacter Infections / Q000378:metabolism; D044923:Helicobacter hepaticus / Q000302:isolation & purification; D007408:Intestinal Absorption / Q000187:drug effects; D007421:Intestine, Small / Q000378:metabolism* / Q000382:microbiology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism
chemical_list: D001384:Azetidines; D001647:Bile Acids and Salts; D013261:Sterols; D002766:Cholecystokinin; D002784:Cholesterol; D000069438:Ezetimibe; D019826:Cholic Acid