The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination[S]

• Published in: Journal of lipid research 2015-04, Vol.56 (4), p.810-820
• Main Authors: Wang, Yuhuan, Liu, Xiaoxi, Pijut, Sonja S., Li, Jianing, Horn, Jamie, Bradford, Emily M., Leggas, Markos, Barrett, Terrence A., Graf, Gregory A.
• Format: Article
• Language: English
• Subjects: Animals; ATP binding cassette transporter G5; ATP binding cassette transporter G8; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - deficiency; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; bile; Bile Acids and Salts - biosynthesis; biliary cholesterol secretion; Biliary Tract - drug effects; Biliary Tract - metabolism; Biological Transport - drug effects; Cholesterol - metabolism; cholesterol 7-alpha hydroxylase; cholesterol/biosynthesis; Dose-Response Relationship, Drug; Drug Synergism; Ezetimibe - pharmacology; Feces - chemistry; Female; Gene Knockout Techniques; high density lipoprotein; Intestinal Mucosa - metabolism; Intestines - drug effects; Lipoproteins - chemistry; Lipoproteins - deficiency; Lipoproteins - genetics; Lipoproteins - metabolism; Male; Mice; nonalcoholic fatty liver disease; Protein Multimerization; Protein Structure, Quaternary; reverse cholesterol transport; ursodeoxycholic acid; Ursodeoxycholic Acid - pharmacology
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M053454

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.