| Coadministration of a liver X receptor agonist and a peroxisome proliferator activator receptor-alpha agonist in Mice: effects of nuclear receptor interplay on high-density lipoprotein and triglyceride metabolism in vivo. | |
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MedLine Citation:
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PMID: 14960661 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Liver X receptors (LXRs) are master transcription factors regulating cholesterol and fatty acid metabolism. Treatment of C57B6 mice with a specific synthetic LXR agonist, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide (T0901317), resulted in elevated high-density lipoprotein (HDL) cholesterol as well as plasma and liver triglycerides. Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists are known to induce peroxisomal fatty acid beta-oxidation and also mediate HDL cholesterol metabolism. We have explored the hypothesis that simultaneous activation of PPARalpha and LXR may lead to additive effects on HDL cholesterol elevation as well as attenuation of triglyceride accumulation. Coadministration of T0901317 and the specific PPARalpha agonist [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy14643)] in mice led to synergistic elevation of HDL cholesterol that was primarily associated with enlarged HDL particles enriched with apoE and apoAI. Liver phospholipid transfer protein (PLTP) mRNA and plasma PLTP activity were additively elevated, suggesting a role of PLTP in the observed HDL cholesterol elevation. Moderate increases in plasma triglyceride levels induced by LXR activation was reduced, whereas the accumulation of triglyceride in the liver was not altered upon coadministration of the PPARalpha agonist. Peroxisomal fatty acid beta-oxidation in the liver was dramatically elevated upon PPARalpha activation as expected. Interestingly, activation of LXRs via T0901317 also led to a significant increase in peroxisomal fatty acid beta-oxidation. Sterol regulatory element binding protein 1c expression was dramatically up-regulated by the LXR agonist but was not changed with PPARalpha agonist treatment. Liver lipoprotein lipase expression was additively increased upon LXR agonist and PPARalpha agonist coadministration. Our studies mark the first exploration of nuclear receptor interplay on lipid homeostasis in vivo. |
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Authors:
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Thomas P Beyer; Robert J Schmidt; Patricia Foxworthy; Youyan Zhang; Jiannong Dai; William R Bensch; Raymond F Kauffman; Hong Gao; Timothy P Ryan; Xian-Cheng Jiang; Sotirios K Karathanasis; Patrick I Eacho; Guoqing Cao |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2004-02-11 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 309 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2004 Jun |
Date Detail:
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Created Date: 2004-05-26 Completed Date: 2004-07-01 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 861-8 Citation Subset: IM |
Affiliation:
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Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anticholesteremic Agents / pharmacology* Carrier Proteins / metabolism DNA-Binding Proteins Hydrocarbons, Fluorinated Lipoproteins, HDL / metabolism* Liver / drug effects*, metabolism Membrane Proteins / metabolism Mice Mice, Inbred C57BL Orphan Nuclear Receptors Phospholipid Transfer Proteins* Pyrimidines / pharmacology Receptors, Cytoplasmic and Nuclear / agonists*, metabolism* Sulfonamides Transcription Factors / agonists* Triglycerides / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Anticholesteremic Agents; 0/Carrier Proteins; 0/DNA-Binding Proteins; 0/Hydrocarbons, Fluorinated; 0/Lipoproteins, HDL; 0/Membrane Proteins; 0/Orphan Nuclear Receptors; 0/Phospholipid Transfer Proteins; 0/Pyrimidines; 0/Receptors, Cytoplasmic and Nuclear; 0/Sulfonamides; 0/TO-901317; 0/Transcription Factors; 0/Triglycerides; 0/liver X receptor; 50892-23-4/pirinixic acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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