{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T06:11:15Z","timestamp":1775369475179,"version":"3.50.1"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":4261,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,1]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Previously, we identified needle-like and filamentous, putatively \u201canhydrous\u201d cholesterol crystallization <jats:italic toggle=\"yes\">in vitro<\/jats:italic> at very low phospholipid concentrations in model and native biles. Our aim now was to address whether spontaneous gallstone formation occurs in <jats:italic toggle=\"yes\">Mdr2<\/jats:italic> (<jats:italic toggle=\"yes\">Abcb4<\/jats:italic>) knockout mice that are characterized by phospholipid-deficient bile. Biliary phenotypes and cholesterol crystallization sequences in fresh gallbladder biles and non-fixed liver sections were determined by direct and polarizing light microscopy. The physical chemical nature and composition of crystals and stones were determined by sucrose density centrifugation and before mass and infrared spectroscopy. Gallbladder biles of <jats:italic toggle=\"yes\">Mdr2<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice precipitate needle-like cholesterol crystals at 12 weeks of age on chow. After 15 weeks, more than 50% of <jats:italic toggle=\"yes\">Mdr2<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice develop gallbladder stones, with female mice displaying a markedly higher gallstone-susceptibility. Although gallbladder biles of <jats:italic toggle=\"yes\">Mdr2<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice contain only traces (\u2264 1.1 mM) of phospholipid and cholesterol, they become supersaturated with cholesterol and plot in the left 2-phase zone of the ternary phase diagram, consistent with \u201canhydrous\u201d cholesterol crystallization. Furthermore, more than 40% of adult female <jats:italic toggle=\"yes\">Mdr2<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice show intra- and extrahepatic bile duct stones. In conclusion, spontaneous gallstone formation is a new consistent feature of the <jats:italic toggle=\"yes\">Mdr2<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> phenotype. The <jats:italic toggle=\"yes\">Mdr2<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mouse is therefore a model for low phospholipid-associated cholelithiasis recently described in humans with a dysfunctional mutation in the orthologous <jats:italic toggle=\"yes\">ABCB4<\/jats:italic> gene. The mouse model supports the concept that this gene is a monogenic risk factor for cholesterol gallstones and a target for novel therapeutic strategies. (Hepatology 2004;39:117-128.)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.20022","type":"journal-article","created":{"date-parts":[[2004,1,7]],"date-time":"2004-01-07T09:00:27Z","timestamp":1073466027000},"page":"117-128","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":137,"title":["Spontaneous cholecysto- and hepatolithiasis in Mdr2 \u2212\/\u2212 mice: A model for low phospholipid-associated cholelithiasis\u2020"],"prefix":"10.1097","volume":"39","author":[{"given":"Frank","family":"Lammert","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David Q.-H.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja","family":"Hillebrandt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Geier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Fickert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Trauner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siegfried","family":"Matern","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beverly","family":"Paigen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin C.","family":"Carey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-18-20241201","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/0092-8674(93)90380-9","article-title":"Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.","volume":"75","author":"Smit","year":"1993","journal-title":"Cell"},{"key":"R2-18-20241201","first-page":"1237","article-title":"Mice with homozygous disruption of the mdr2 P-glycoprotein gene. 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