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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Reardon, Catherine A. Getz, Godfrey S. Liao, Shutsung Xie, Jing-tian Dai, Qing Peng, Dacheng Hiipakka, Richard A. Kokontis, John M. |
| Description | Author Affiliation: Peng D ( Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.) |
| Abstract | BACKGROUND AND PURPOSE: Potent synthetic nonsteroidal liver X receptor (LXR) agonists like T0901317 induce triglyceridaemia and fatty liver, effects not observed with some natural and synthetic steroidal, relatively weak agonists of LXR. To determine if potency is responsible for the lack of side effects with some steroidal agonists, we investigated the in vivo effects of a novel steroidal LXR agonist, ATI-111, that is more potent than T0901317. EXPERIMENTAL APPROACH: Eight week old male LDLR(-/-) mice fed an atherogenic diet were orally treated with vehicle or ATI-111 at 3 and 5 mg·kg(-1) ·day(-1) for 8 weeks, and effects on plasma and liver lipid levels, expression of genes involved in lipid metabolism and on atherogenesis were analysed. KEY RESULTS: ATI-111 increased the expression of genes involved in lipid transport, such as ABCA1, ABCG1 and ABCG5/G8, in intestine and macrophages; decreased ABCG1, apoE; and slightly increased ABCA1 and ABCG5/G8 expression in liver. ATI-111 markedly increased sterol regulatory element-binding protein (SREBP)-1c mRNA in some tissues, whereas acetyl-coenzyme A carboxylase and fatty acid synthase expression was unaffected or only slightly increased in intestine and liver. ATI-111 inhibited the conversion of SREBP-1c precursor form to its active form. Compared with vehicle-treated mice, the levels of hepatic lipids and liver-secreted nascent lipoproteins were not altered, while a significant decrease in plasma cholesterol and triglyceride levels was observed in ATI-111-treated mice. ATI-111 significantly inhibited atherogenesis in three separate vascular sites. CONCLUSIONS AND IMPLICATIONS: ATI-111 is a promising candidate for further development as a treatment of certain vascular diseases as it lacks the significant side effects associated with nonsteroidal LXR agonists, the induction of fatty liver and hypertriglyceridaemia. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 8 |
| Volume Number | 162 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2011-04-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Atherosclerosis Drug Therapy Hydroxysteroids Pharmacology Orphan Nuclear Receptors Agonists Receptors, LDL Genetics Animals Physiopathology Cholesterol Blood Metabolism Dose-Response Relationship, Drug Gene Expression Regulation Drug Effects Administration & Dosage Adverse Effects Intestines Liver Macrophages Mice Mice, Inbred C57BL Mice, Knockout Triglycerides Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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