Document Detail


Identification and mechanism of 10-carbon fatty acid as modulating ligand of peroxisome proliferator-activated receptors.
MedLine Citation:
PMID:  22039047     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Peroxisome proliferator-activated receptors (PPARα, -β/δ, and -γ) are a subfamily of nuclear receptors that plays key roles in glucose and lipid metabolism. PPARγ is the molecular target of the thiazolidinedione class of antidiabetic drugs that has 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 even though the medium chain triglyceride oils have been used to control weight gain and glycemic index. Here, we show that decanoic acid (DA), a 10-carbon fatty acid and a major component of medium chain triglyceride 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 modulating ligand for PPARs, and the structure can aid in designing better and safer PPARγ-based drugs.
Authors:
Raghu R V Malapaka; Sokkean Khoo; Jifeng Zhang; Jang H Choi; X Edward Zhou; Yong Xu; Yinhan Gong; Jun Li; Eu-Leong Yong; Michael J Chalmers; Lin Chang; James H Resau; Patrick R Griffin; Y Eugene Chen; H Eric Xu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-10-28
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-02     Completed Date:  2012-05-08     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  183-95     Citation Subset:  IM    
Affiliation:
Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA. vmalapaka@rics.bwh.harvard.edu
Data Bank Information
Bank Name/Acc. No.:
PDB/3U9Q
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Blood Glucose / metabolism
COS Cells
Cercopithecus aethiops
Decanoic Acids / metabolism*,  pharmacology,  therapeutic use
Diabetes Mellitus / drug therapy,  metabolism
Drug Design
Ligands
Male
Mice
Models, Molecular
Molecular Sequence Data
Peroxisome Proliferator-Activated Receptors / chemistry,  metabolism*
Protein Structure, Tertiary
Substrate Specificity
Grant Support
ID/Acronym/Agency:
DK066202/DK/NIDDK NIH HHS; DK071662/DK/NIDDK NIH HHS; HL089301/HL/NHLBI NIH HHS; HL089544/HL/NHLBI NIH HHS; HL68878/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Blood Glucose; 0/Decanoic Acids; 0/Ligands; 0/Peroxisome Proliferator-Activated Receptors; 4G9EDB6V73/decanoic acid
Comments/Corrections

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