{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:14:17Z","timestamp":1789470857665,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2016,1,12]],"date-time":"2016-01-12T00:00:00Z","timestamp":1452556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK73917"],"award-info":[{"award-number":["DK73917"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK101793"],"award-info":[{"award-number":["DK101793"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK106249"],"award-info":[{"award-number":["DK106249"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>A defect in gallbladder contraction function plays a key role in the pathogenesis of gallstones. The cholecystokinin\u20101 receptor (<jats:styled-content style=\"fixed-case\">CCK<\/jats:styled-content>\u20101R) antagonists have been extensively investigated for their therapeutic effects on gastrointestinal and metabolic diseases in animal studies and clinical trials. However, it is still unknown whether they have a potential effect on gallstone formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>To study whether the <jats:styled-content style=\"fixed-case\">CCK<\/jats:styled-content>\u20101R antagonists enhance cholelithogenesis, we investigated cholesterol crystallization, gallstone formation, hepatic lipid secretion, gallbladder emptying function and intestinal cholesterol absorption in male C57<jats:styled-content style=\"fixed-case\">BL<\/jats:styled-content>\/6J mice treated by gavage with devazepide (4 mg\/day\/kg) or vehicle (as controls) twice per day and fed the lithogenic diet for 21 days.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>During 21 days of feeding, oral administration of devazepide significantly accelerated cholesterol crystallization and crystal growth to microlithiasis, with 40% of mice forming gallstones, whereas only agglomerated cholesterol monohydrate crystals were found in mice receiving vehicle. Compared to the vehicle group, fasting and postprandial residual gallbladder volumes in response to the high\u2010fat meal were significantly larger in the devazepide group during cholelithogenesis, showing reduced gallbladder emptying and bile stasis. Moreover, devazepide significantly increased hepatic secretion of biliary cholesterol, but not phospholipids or bile salts. The percentage of intestinal cholesterol absorption was higher in devazepide\u2010treated mice, increasing the bioavailability of chylomicron\u2010derived cholesterol in the liver for biliary hypersecretion into bile. These abnormalities induced supersaturated bile and rapid cholesterol crystallization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The potent <jats:styled-content style=\"fixed-case\">CCK<\/jats:styled-content>\u20101R antagonist devazepide increases susceptibility to gallstone formation by impairing gallbladder emptying function, disrupting biliary cholesterol metabolism and enhancing intestinal cholesterol absorption in mice.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.12580","type":"journal-article","created":{"date-parts":[[2015,12,19]],"date-time":"2015-12-19T01:42:05Z","timestamp":1450489325000},"page":"158-169","source":"Crossref","is-referenced-by-count":14,"title":["The cholecystokinin\u20101 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice"],"prefix":"10.1111","volume":"46","author":[{"given":"Helen H.","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medicine Liver Center and Gastroenterology Division Beth Israel Deaconess Medical Center Harvard Medical School and Harvard Digestive Diseases Center Boston MA USA"},{"name":"Department of Internal Medicine Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Portincasa","sequence":"additional","affiliation":[{"name":"Clinica Medica \u201cA. Murri\u201d Department of Biomedical Sciences and Human Oncology University of Bari Medical School Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Q.\u2010H.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine Liver Center and Gastroenterology Division Beth Israel Deaconess Medical Center Harvard Medical School and Harvard Digestive Diseases Center Boston MA USA"},{"name":"Department of Internal Medicine Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St. Louis MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,1,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802607780960483"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI16801"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.07.005"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111809"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110433"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(85)90638-1"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-003-1336-5"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.13.4923"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(90)91232-6"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802607780960537"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0031-9384(90)90239-Z"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/55.1.291s"},{"key":"e_1_2_8_14_1","first-page":"291","article-title":"Effect of CCK and its antagonists on gastric emptying","volume":"87","author":"Scarpignato C","year":"1993","journal-title":"J Physiol"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/dev.20148"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2007.04.017"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802607780960519"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22204"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-130-4-199902160-00016"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2009.10.003"},{"key":"e_1_2_8_21_1","first-page":"25","article-title":"Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans","volume":"170","author":"Sitzmann JV","year":"1990","journal-title":"Surg Gynecol Obstet"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1E153"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1016\/S0022-2275(20)37422-8","article-title":"Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical\u2010chemistry of gallbladder bile","volume":"38","author":"Wang DQ","year":"1997","journal-title":"J Lipid Res"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)37603-3"},{"key":"e_1_2_8_25_1","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1016\/S0022-2275(20)32430-5","article-title":"Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: pathophysiology of biliary lipid secretion","volume":"40","author":"Wang DQ","year":"1999","journal-title":"J Lipid Res"},{"key":"e_1_2_8_26_1","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/S0022-2275(20)40709-6","article-title":"Re\u2010evaluation of the 3 alpha\u2010hydroxysteroid dehydrogenase assay for total bile acids in bile","volume":"19","author":"Turley SD","year":"1978","journal-title":"J Lipid Res"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)38684-3"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)38331-0"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)70226-3"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)39833-3"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)40677-7"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.D200041-JLR200"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M059121"},{"key":"e_1_2_8_34_1","first-page":"165","article-title":"Cholesterol gallstone formation. 2. Pathobiology and pathomechanics","volume":"10","author":"Lamont JT","year":"1992","journal-title":"Prog Liver Dis"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110209"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(84)90700-5"},{"key":"e_1_2_8_37_1","first-page":"1100","volume-title":"Sleisenger and Fordtran's Gastrointestinal and Liver Disease","author":"Wang DQ","year":"2014"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.2000.00639.x"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.regpep.2007.09.024"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2007.09.011"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.10042"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.9.1.129"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2004.12.005"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.69.031905.160725"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.03.011"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/eci.12058"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2001.21190"},{"key":"e_1_2_8_48_1","first-page":"G1401","article-title":"CCK receptor dysfunction in muscle membranes from human gallbladders with cholesterol stones","volume":"276","author":"Xiao ZL","year":"1999","journal-title":"Am J Physiol"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.2000.278.2.G251"},{"key":"e_1_2_8_50_1","first-page":"G659","article-title":"Direct G protein activation reverses impaired CCK signaling in human gallbladders with cholesterol stones","volume":"269","author":"Yu P","year":"1995","journal-title":"Am J Physiol"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.07.020"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijo.0800634"},{"key":"e_1_2_8_53_1","first-page":"1000","article-title":"Gallstone formation after rapid weight loss: a prospective study in patients undergoing gastric bypass surgery for treatment of morbid obesity","volume":"86","author":"Shiffman ML","year":"1991","journal-title":"Am J Gastroenterol"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.soard.2014.10.015"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2013.11.031"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1111\/eci.12400"},{"key":"e_1_2_8_57_1","first-page":"273","article-title":"Crystal\u2010induced inflammation: studies of the mechanism of crystal\u2010membrane interactions","volume":"5","author":"Burt HM","year":"1991","journal-title":"Scanning Microsc"}],"container-title":["European Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Feci.12580","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.12580","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T14:46:24Z","timestamp":1695480384000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/eci.12580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,12]]},"references-count":56,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2016,2]]}},"alternative-id":["10.1111\/eci.12580"],"URL":"https:\/\/doi.org\/10.1111\/eci.12580","archive":["Portico"],"relation":{},"ISSN":["0014-2972","1365-2362"],"issn-type":[{"value":"0014-2972","type":"print"},{"value":"1365-2362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,12]]}}}