The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination
| Autor: | Terrence A. Barrett, Jamie Horn, Yuhuan Wang, Xiaoxi Liu, Jianing Li, Emily M. Bradford, Sonja S. Pijut, Markos Leggas, Gregory A. Graf |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Lipoproteins bile bile acids and salts/biosynthesis QD415-436 Biology Cholesterol 7 alpha-hydroxylase Biochemistry Excretion biliary cholesterol secretion Bile Acids and Salts chemistry.chemical_compound Feces Gene Knockout Techniques Mice Endocrinology High-density lipoprotein Ezetimibe Internal medicine medicine Animals ATP Binding Cassette Transporter Subfamily G Member 5 Intestinal Mucosa Biliary Tract Protein Structure Quaternary Research Articles Dose-Response Relationship Drug Cholesterol Reverse cholesterol transport ATP Binding Cassette Transporter Subfamily G Member 8 Ursodeoxycholic Acid Biological Transport Drug Synergism Cell Biology cholesterol 7-alpha hydroxylase cholesterol/biosynthesis Ursodeoxycholic acid Sterol Intestines chemistry high density lipoprotein ATP-Binding Cassette Transporters Female Protein Multimerization medicine.drug |
| Zdroj: | Journal of Lipid Research, Vol 56, Iss 4, Pp 810-820 (2015) |
| ISSN: | 1539-7262 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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