| Fenofibrate reduces intestinal cholesterol absorption via PPARalpha-dependent modulation of NPC1L1 expression in mouse. | |
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MedLine Citation:
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PMID: 17726195 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Fibrates, including fenofibrate, exert their biological effects by binding peroxisome proliferator-activated receptor alpha (PPARalpha), a member of the nuclear receptor superfamily of ligand-activated transcription factors. Treatment with PPARalpha agonists enhances fatty acid oxidation, decreases plasma triglycerides, and may promote reverse cholesterol transport. In addition, fibrate administration can reduce intestinal cholesterol absorption in patients, although the molecular mechanism for this effect is unknown. Because Niemann-Pick C1-Like 1 (NPC1L1) is already known to be a critical protein for cholesterol absorption, we hypothesized that fenofibrate might modulate NPC1L1 expression to alter intestinal cholesterol transport. Here, we find that fenofibrate-treated wild-type mice have decreased fractional cholesterol absorption (35-47% decrease) and increased fecal neutral sterol excretion (51-83% increase), which correspond to decreased expression of NPC1L1 mRNA and protein (38-66% decrease) in the proximal small intestine. These effects of fenofibrate are dependent on PPARalpha, as Ppar alpha-knockout mice fail to respond like wild-type littermates. Fenofibrate affects the ezetimibe-sensitive pathway and retains the ability to decrease cholesterol absorption and NPC1L1 mRNA expression in chow-fed liver X receptor alpha/beta-double-knockout mice and high-cholesterol- or cholic acid-fed wild-type mice. These data demonstrate that fenofibrate specifically acts via PPARalpha to decrease cholesterol absorption at the level of intestinal NPC1L1 expression. |
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Authors:
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Mark A Valasek; Stephen L Clarke; Joyce J Repa |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2007-08-28 |
Journal Detail:
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Title: Journal of lipid research Volume: 48 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2007 Dec |
Date Detail:
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Created Date: 2007-11-20 Completed Date: 2008-04-07 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 2725-35 Citation Subset: IM |
Affiliation:
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Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antilipemic Agents / pharmacology* Cholesterol / administration & dosage, metabolism* Cholic Acid / administration & dosage DNA-Binding Proteins / metabolism Intestinal Absorption / drug effects*, physiology Intestine, Small / metabolism Membrane Transport Proteins / genetics*, metabolism Mice Mice, Inbred Strains Mice, Knockout Orphan Nuclear Receptors PPAR alpha / metabolism* Procetofen / pharmacology* RNA, Messenger / metabolism Receptors, Cytoplasmic and Nuclear / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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T32 DK-007665/DK/NIDDK NIH HHS; T32 GM-07062/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antilipemic Agents; 0/DNA-Binding Proteins; 0/Membrane Transport Proteins; 0/Npc1l1 protein, mouse; 0/Orphan Nuclear Receptors; 0/PPAR alpha; 0/RNA, Messenger; 0/Receptors, Cytoplasmic and Nuclear; 0/liver X receptor; 49562-28-9/Procetofen; 57-88-5/Cholesterol; 81-25-4/Cholic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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