{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T23:27:39Z","timestamp":1788478059526,"version":"build-2803163510"},"reference-count":165,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,11,29]],"date-time":"2020-11-29T00:00:00Z","timestamp":1606608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK106249, DK114516, DK126369, and AA025737"],"award-info":[{"award-number":["DK106249, DK114516, DK126369, and AA025737"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The cholecystokinin A receptor (CCKAR) is expressed predominantly in the gallbladder and small intestine in the digestive system, where it is responsible for CCK\u2019s regulation of gallbladder and small intestinal motility. The effect of CCKAR on small intestinal transit is a physiological response for regulating intestinal cholesterol absorption. The CCKAR gene has been identified to be an important gallstone gene, Lith13, in inbred mice by a powerful quantitative trait locus analysis. Knockout of the CCKAR gene in mice enhances cholesterol cholelithogenesis by impairing gallbladder contraction and emptying, promoting cholesterol crystallization and crystal growth, and increasing intestinal cholesterol absorption. Clinical and epidemiological studies have demonstrated that several variants in the CCKAR gene are associated with increased prevalence of cholesterol cholelithiasis in humans. Dysfunctional gallbladder emptying in response to exogenously administered CCK-8 is often found in patients with cholesterol gallstones, and patients with pigment gallstones display an intermediate degree of gallbladder motility defect. Gallbladder hypomotility is also revealed in some subjects without gallstones under several conditions: pregnancy, total parenteral nutrition, celiac disease, oral contraceptives and conjugated estrogens, obesity, diabetes, the metabolic syndrome, and administration of CCKAR antagonists. The physical\u2013chemical, genetic, and molecular studies of Lith13 show that dysfunctional CCKAR enhances susceptibility to cholesterol gallstones through two primary mechanisms: impaired gallbladder emptying is a key risk factor for the development of gallbladder hypomotility, biliary sludge (the precursor of gallstones), and microlithiasis, as well as delayed small intestinal transit augments cholesterol absorption as a major source for the hepatic hypersecretion of biliary cholesterol and for the accumulation of excess cholesterol in the gallbladder wall that further worsens impaired gallbladder motor function. If these two defects in the gallbladder and small intestine could be prevented by the potent CCKAR agonists, the risk of developing cholesterol gallstones could be dramatically reduced.<\/jats:p>","DOI":"10.3390\/genes11121438","type":"journal-article","created":{"date-parts":[[2020,11,29]],"date-time":"2020-11-29T21:55:31Z","timestamp":1606686931000},"page":"1438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["An Update on the Lithogenic Mechanisms of Cholecystokinin a Receptor (CCKAR), an Important Gallstone Gene for Lith13"],"prefix":"10.3390","volume":"11","author":[{"given":"Helen H.","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5359-1471","authenticated-orcid":false,"given":"Piero","family":"Portincasa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, Clinica Medica \u201cA. Murri\u201d, University of Bari \u201cAldo Moro\u201d Medical School, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Tso","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5439-7651","authenticated-orcid":false,"given":"David Q.-H.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.gtc.2010.02.007","article-title":"Lith genes and genetic analysis of cholesterol gallstone formation","volume":"39","author":"Wang","year":"2010","journal-title":"Gastroenterol. 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