Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8
The ATP binding cassette transporters ABCG5 (G5) and ABCG8 (G8) limit the accumulation of neutral sterols by restricting sterol uptake from the intestine and promoting sterol excretion into bile. Humans and mice lacking G5 and G8 (G5G8−/−) accumulate plant sterols in the blood and tissues. However,...
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| Format: | Article |
| Language: | English |
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Elsevier
2005-08-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520329734 |
| _version_ | 1818715707016216576 |
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| author | Liqing Yu Klaus von Bergmann Dieter Lütjohann Helen H. Hobbs Jonathan C. Cohen |
| author_facet | Liqing Yu Klaus von Bergmann Dieter Lütjohann Helen H. Hobbs Jonathan C. Cohen |
| author_sort | Liqing Yu |
| collection | DOAJ |
| description | The ATP binding cassette transporters ABCG5 (G5) and ABCG8 (G8) limit the accumulation of neutral sterols by restricting sterol uptake from the intestine and promoting sterol excretion into bile. Humans and mice lacking G5 and G8 (G5G8−/−) accumulate plant sterols in the blood and tissues. However, despite impaired biliary cholesterol secretion, plasma and liver cholesterol levels are lower in G5G8−/− mice than in wild-type littermates. To determine whether the observed changes in hepatic sterol metabolism were a direct result of decreased biliary sterol secretion or a metabolic consequence of the accumulation of dietary noncholesterol sterols, we treated G5G8−/− mice with ezetimibe, a drug that reduces the absorption of both plant- and animal-derived sterols. Ezetimibe feeding for 1 month sharply decreased sterol absorption and plasma levels of sitosterol and campesterol but increased cholesterol in both the plasma (from 60.4 to 75.2 mg/dl) and the liver (from 1.1 to 1.87 mg/g) of the ezetimibe-treated G5G8−/− mice. Paradoxically, the increase in hepatic cholesterol was associated with an increase in mRNA levels of HMG-CoA reductase and synthase.Together, these results indicate that pharmacological blockade of sterol absorption can ameliorate the deleterious metabolic effects of plant sterols even in the absence of G5 and G8. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T19:07:38Z |
| publishDate | 2005-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-a7e04addc0ac449dafc38f0357da97312022-12-21T21:35:57ZengElsevierJournal of Lipid Research0022-22752005-08-0146817391744Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8Liqing Yu0Klaus von Bergmann1Dieter Lütjohann2Helen H. Hobbs3Jonathan C. Cohen4Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390Department of Clinical Pharmacology, University of Bonn, D-53105 Bonn, GermanyDepartment of Clinical Pharmacology, University of Bonn, D-53105 Bonn, GermanyDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390To whom correspondence should be addressed.; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390; Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390The ATP binding cassette transporters ABCG5 (G5) and ABCG8 (G8) limit the accumulation of neutral sterols by restricting sterol uptake from the intestine and promoting sterol excretion into bile. Humans and mice lacking G5 and G8 (G5G8−/−) accumulate plant sterols in the blood and tissues. However, despite impaired biliary cholesterol secretion, plasma and liver cholesterol levels are lower in G5G8−/− mice than in wild-type littermates. To determine whether the observed changes in hepatic sterol metabolism were a direct result of decreased biliary sterol secretion or a metabolic consequence of the accumulation of dietary noncholesterol sterols, we treated G5G8−/− mice with ezetimibe, a drug that reduces the absorption of both plant- and animal-derived sterols. Ezetimibe feeding for 1 month sharply decreased sterol absorption and plasma levels of sitosterol and campesterol but increased cholesterol in both the plasma (from 60.4 to 75.2 mg/dl) and the liver (from 1.1 to 1.87 mg/g) of the ezetimibe-treated G5G8−/− mice. Paradoxically, the increase in hepatic cholesterol was associated with an increase in mRNA levels of HMG-CoA reductase and synthase.Together, these results indicate that pharmacological blockade of sterol absorption can ameliorate the deleterious metabolic effects of plant sterols even in the absence of G5 and G8.http://www.sciencedirect.com/science/article/pii/S0022227520329734ATP binding cassette transporter G5ATP binding cassette transporter G8sitosterolemiacholesterolbile |
| spellingShingle | Liqing Yu Klaus von Bergmann Dieter Lütjohann Helen H. Hobbs Jonathan C. Cohen Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8 Journal of Lipid Research ATP binding cassette transporter G5 ATP binding cassette transporter G8 sitosterolemia cholesterol bile |
| title | Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8 |
| title_full | Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8 |
| title_fullStr | Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8 |
| title_full_unstemmed | Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8 |
| title_short | Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8 |
| title_sort | ezetimibe normalizes metabolic defects in mice lacking abcg5 and abcg8 |
| topic | ATP binding cassette transporter G5 ATP binding cassette transporter G8 sitosterolemia cholesterol bile |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520329734 |
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