| Identification and mechanism of a ten carbon fatty acid as a modulating ligand of peroxisome proliferator activated receptors. | |
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MedLine Citation:
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PMID: 22039047 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Peroxisome proliferator activated receptors- (PPARα, β/δ, and γ) are a subfamily of nuclear receptors that play key roles in glucose and lipid metabolism. PPARγ is the molecular target of the thiazolidinedione (TZDs) class of antidiabetic drugs that have many side effects. PPARγ is also activated by long chain unsaturated or oxidized/nitrated fatty acids, but its relationship with the medium chain fatty acids remains unclear despite that the medium chain triglyceride oils (MCT oils) have been used to control weight gain and glycemic index. Here we show that decanoic acid (DA), a ten-carbon fatty acid and a major component MCT oils, is a direct ligand of PPARγ. DA binds and partially activates PPARγ without leading to adipogenesis. Crystal structure reveals that DA occupies a novel binding site and only partially stabilizes the AF-2 helix. DA also binds weakly to PPARα and PPARβ/δ. Treatments with DA and its triglyceride form improve glucose sensitivity and lipid profiles without weight gain in diabetic mice. Together, these results suggest that DA is a natural modulating ligand for PPARs and the structure can aid in designing better and safer PPARγ-based drugs. |
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Authors:
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Raghu R V Malapaka; Sok Kean Khoo; Jifeng Zhang; Jang Hyun Choi; X Edward Zhou; Yong Xu; Yinhan Gong; Jun Li; Eu-Leong Eu Yong; Michael J Chalmers; Lin Chang; James H Resau; Patrick R Griffin; Y Eugene Chen; H Eric Xu |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-28 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: - ISSN: 1083-351X ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-31 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Brigham and Women's Hospital, United States; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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