| A novel potent synthetic steroidal liver X receptor agonist lowers plasma cholesterol and triglycerides and reduces atherosclerosis in LDLR(-/-) mice. | |
| | |
MedLine Citation:
|
PMID: 21232031 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Dacheng Peng; Richard A Hiipakka; Jing-Tian Xie; Qing Dai; John M Kokontis; Catherine A Reardon; Godfrey S Getz; Shutsung Liao |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: British journal of pharmacology Volume: 162 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2011 Apr |
Date Detail:
|
Created Date: 2011-03-23 Completed Date: 2011-07-18 Revised Date: 2012-04-02 |
Medline Journal Info:
|
Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
|
Languages: eng Pagination: 1792-804 Citation Subset: IM |
Copyright Information:
|
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Affiliation:
|
Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Atherosclerosis / drug therapy*, physiopathology Cholesterol / blood, metabolism Dose-Response Relationship, Drug Gene Expression Regulation / drug effects Hydroxysteroids / administration & dosage, adverse effects, pharmacology* Intestines / drug effects, metabolism Liver / drug effects, metabolism Macrophages / drug effects, metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Orphan Nuclear Receptors / agonists* Receptors, LDL / genetics* Triglycerides / blood, metabolism |
| Grant Support | |
ID/Acronym/Agency:
|
AT00850/AT/NCCAM NIH HHS; CA58073/CA/NCI NIH HHS; R01 CA058073-19/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/ATI-111 cpd; 0/Hydroxysteroids; 0/Orphan Nuclear Receptors; 0/Receptors, LDL; 0/Triglycerides; 0/liver X receptor; 57-88-5/Cholesterol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Vascular responses to 8-nitro-cyclic GMP in non-diabetic and diabetic mice.
Next Document: Endothelial dysfunction of rat coronary arteries after exposure to low concentrations of mercury is ...