title: The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination.
abstract: Previous studies suggest an interdependent relationship between liver and intestine for cholesterol elimination from the body. We hypothesized that a combination of ursodiol (Urso) and ezetimibe (EZ) could increase biliary secretion and reduce cholesterol reabsorption, respectively, to promote cholesterol excretion. Treatment with Urso increased hepatic ABCG5 ABCG8 (G5G8) protein and both biliary and fecal sterols in a dose-dependent manner. To determine whether the drug combination (Urso-EZ) further increased cholesterol excretion, mice were treated with Urso alone or in combination with two doses of EZ. EZ produced an additive and dose-dependent increase in fecal neutral sterol (FNS) elimination in the presence of Urso. Finally, we sequentially treated wide-type and G5G8-deficient mice with Urso and Urso-EZ to determine the extent to which these effects were G5G8 dependent. Although biliary and FNS were invariably lower in G5G8 KO mice, the relative increase in FNS following treatment with Urso alone or the Urso-EZ combination was not affected by genotype. In conclusion, Urso increases G5G8, biliary cholesterol secretion, and FNS and acts additively with EZ to promote fecal sterol excretion. However, the stimulatory effect of these agents was not G5G8 dependent.
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY.
authors: Yuhuan
authors: Y
authors: Wang
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY.
authors: Xiaoxi
authors: X
authors: Liu
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY.
authors: Sonja S
authors: SS
authors: Pijut
authors: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY.
authors: Jianing
authors: J
authors: Li
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY.
authors: Jamie
authors: J
authors: Horn
authors: Division of Gastroenterology, University of Kentucky, Lexington, KY.
authors: Emily M
authors: EM
authors: Bradford
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY.
authors: Markos
authors: M
authors: Leggas
authors: Division of Gastroenterology, University of Kentucky, Lexington, KY.
authors: Terrence A
authors: TA
authors: Barrett
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY.
authors: Gregory A
authors: GA
authors: Graf
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000069438:Ezetimibe / Q000494:pharmacology*; D005243:Feces / Q000737:chemistry*; D005260:Female; D055786:Gene Knockout Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008074:Lipoproteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D008074:Lipoproteins; D014580:Ursodeoxycholic Acid; D002784:Cholesterol; D000069438:Ezetimibe
keywords: ATP binding cassette transporter G5; ATP binding cassette transporter G8; bile; bile acids and salts/biosynthesis; biliary cholesterol secretion; cholesterol 7-alpha hydroxylase; cholesterol/biosynthesis; high density lipoprotein; nonalcoholic fatty liver disease; reverse cholesterol transport; ursodeoxycholic acid
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