Identification and mechanism of 10-carbon fatty acid as modulating ligand of peroxisome proliferator-activated receptors.
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.
Laboratories of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan, 49503. Electronic address: vmalapaka@rics.bwh.harvard.edu.
Raghu R V
RRV
Malapaka
Laboratory of Microarray Technology, Van Andel Research Institute, Grand Rapids, Michigan, 49503; Laboratory of Analytical, Cellular, and Molecular Microscopy, Van Andel Research Institute, Grand Rapids, Michigan 49503.
SokKean
S
Khoo
Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
Jifeng
J
Zhang
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
Jang H
JH
Choi
Laboratories of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan, 49503.
X Edward
XE
Zhou
Laboratories of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan, 49503.
Yong
Y
Xu
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore 119228.
Yinhan
Y
Gong
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore 119228.
Jun
J
Li
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore 119228.
Eu-Leong
EL
Yong
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458.
Michael J
MJ
Chalmers
Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
Lin
L
Chang
Laboratory of Analytical, Cellular, and Molecular Microscopy, Van Andel Research Institute, Grand Rapids, Michigan 49503.
James H
JH
Resau
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458.
Patrick R
PR
Griffin
Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109. Electronic address: echenum@med.umich.edu.
Y Eugene
YE
Chen
Laboratories of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan, 49503; VARI-SIMM Center for Drug Discovery, Center for Structures and Function of Drug Targets, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: eric.xu@vai.org.
H Eric
HE
Xu
D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D003652:Decanoic Acids / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D047492:Peroxisome Proliferator-Activated Receptors / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
D001786:Blood Glucose; D003652:Decanoic Acids; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; C031071:decanoic acid