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Augmented cholesterol absorption and sarcolemmal sterol enrichment slow small intestinal transit in mice, contributing to cholesterol cholelithogenesis
Author(s) -
Xie Meimin,
Kotecha Vijay R.,
Andrade Jon David P.,
Fox James G.,
Carey Martin C.
Publication year - 2012
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2011.224717
Subject(s) - cholic acid , cholesterol , medicine , endocrinology , small intestine , sterol , bile acid , chenodeoxycholic acid , ileum , biology , enterohepatic circulation , cholecystokinin , gallbladder , chemistry , receptor
Key points • Peristaltic function of the small intestine is compromised in cholelithogenic humans and in animal models of cholesterol gallstones. • In a mouse gallstone model fed a cholesterol‐ and cholic acid‐enriched diet, we show that slowing of small intestinal transit is due to absorption of excess cholesterol molecules from the upper small intestine followed by their incorporation into sarcolemmal membranes of smooth muscle cells. • Blocking cholesterol absorption with ezetimibe (Zetia), an inhibitor of intestinal sterol transport, prevents cholesterol enrichment of sarcolemmal membranes and normalizes the motility disorder. • Although the primary source of intestinal cholesterol in mice is the lithogenic diet, in most cholesterol gallstone‐prone humans, the small intestine is flooded continuously with an abundance of liver‐secreted cholesterol molecules via bile. • Our findings imply that small intestinal hypomotility will amplify the cholelithogenic state because of hyperabsorption of cholesterol and ‘secondary’ bile salt synthesis by the gut's anaerobic microbiota.