{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T14:57:22Z","timestamp":1761663442282,"version":"3.41.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:p>The adenosine triphosphate\u2010binding cassette (ABC) sterol transporter,<jats:italic toggle=\"yes\">Abcg5\/g8<\/jats:italic>, is<jats:italic toggle=\"yes\">Lith9<\/jats:italic>in mice, and two gallstone\u2010associated variants in<jats:italic toggle=\"yes\">ABCG5\/G8<\/jats:italic>have been identified in humans. Although ABCG5\/G8 plays a critical role in determining hepatic sterol secretion, cholesterol is still secreted to bile in sitosterolemic patients with a defect in either<jats:italic toggle=\"yes\">ABCG5<\/jats:italic>or<jats:italic toggle=\"yes\">ABCG8<\/jats:italic>and in either<jats:italic toggle=\"yes\">Abcg5\/g8<\/jats:italic>double\u2010 or single\u2010knockout mice. We hypothesize that in the defect of ABCG5\/G8, an ABCG5\/G8\u2010independent pathway is essential for regulating hepatic secretion of biliary sterols, which is independent of the lithogenic mechanism of the ABCG5\/G8 pathway. To elucidate the effect of the ABCG5\/G8\u2010independent pathway on cholelithogenesis, we investigated the biliary and gallstone characteristics in male wild\u2010type (WT), ABCG5(\u2010\/\u2010)\/G8(\u2010\/\u2010), and ABCG8 (\u2010\/\u2010) mice fed a lithogenic diet or varying amounts of cholesterol, treated with a liver X receptor (LXR) agonist, or injected intravenously with [<jats:sup>3<\/jats:sup>H]sitostanol\u2010 and [<jats:sup>14<\/jats:sup>C]cholesterol\u2010labeled high\u2010density lipoprotein (HDL). We found that ABCG5(\u2010\/\u2010)\/G8(\u2010\/\u2010) and ABCG8 (\u2010\/\u2010) mice displayed the same biliary and gallstone phenotypes. Although both groups of knockout mice showed a significant reduction in hepatic cholesterol output compared to WT mice, they still formed gallstones. The LXR agonist significantly increased biliary cholesterol secretion and gallstones in WT, but not ABCG5(\u2010\/\u2010)\/G8(\u2010\/\u2010) or ABCG8 (\u2010\/\u2010), mice. The 6\u2010hour recovery of [<jats:sup>14<\/jats:sup>C]cholesterol in hepatic bile was significantly lower in both groups of knockout mice than in WT mice and [<jats:sup>3<\/jats:sup>H]sitostanol was detected in WT, but not ABCG5(\u2010\/\u2010)\/G8(\u2010\/\u2010) or ABCG8 (\u2010\/\u2010), mice.<jats:italic toggle=\"yes\">Conclusions:<\/jats:italic>The ABCG5\/G8\u2010independent pathway plays an important role in regulating biliary cholesterol secretion, the transport of HDL\u2010derived cholesterol from plasma to bile, and gallstone formation, which works independently of the ABCG5\/G8 pathway. Further studies are needed to observe whether this pathway is also operational in humans. (H<jats:sc>epatology<\/jats:sc>2016;64:853\u2010864)<\/jats:p>","DOI":"10.1002\/hep.28570","type":"journal-article","created":{"date-parts":[[2016,3,25]],"date-time":"2016-03-25T23:15:21Z","timestamp":1458947721000},"page":"853-864","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":24,"title":["Evidence that the adenosine triphosphate\u2010binding cassette G5\/G8\u2010independent pathway plays a determinant role in cholesterol gallstone formation in mice"],"prefix":"10.1097","volume":"64","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"},{"name":"Department of Internal Medicine, Division of Gastroenterology and Hepatology,Saint Louis University School of Medicine,St. Louis,MO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaodan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Gastroenterology and Hepatology,Saint Louis University School of Medicine,St. Louis,MO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shailendra B.","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism and Clinical Nutrition,Medical College of Wisconsin,Milwaukee,WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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"},{"name":"Department of Internal Medicine, Division of Gastroenterology and Hepatology,Saint Louis University School of Medicine,St. 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