The nuclear receptor PPARγ individually responds to serotonin- and fatty acid-metabolites.
The nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ), recognizes various synthetic and endogenous ligands by the ligand-binding domain. Fatty-acid metabolites reportedly activate PPARγ through conformational changes of the Ω loop. Here, we report that serotonin metabolites act as endogenous agonists for PPARγ to regulate macrophage function and adipogenesis by directly binding to helix H12. A cyclooxygenase inhibitor, indomethacin, is a mimetic agonist of these metabolites. Crystallographic analyses revealed that an indole acetate functions as a common moiety for the recognition by the sub-pocket near helix H12. Intriguingly, a serotonin metabolite and a fatty-acid metabolite each bind to distinct sub-pockets, and the PPARγ antagonist, T0070907, blocked the fatty-acid agonism, but not that of the serotonin metabolites. Mutational analyses on receptor-mediated transcription and coactivator binding revealed that each metabolite individually uses coregulator and/or heterodimer interfaces in a ligand-type-specific manner. Furthermore, the inhibition of the serotonin metabolism reduced the expression of the endogenous PPARγ-target gene. Collectively, these results suggest a novel agonism, in which PPARγ functions as a multiple sensor in response to distinct metabolites.
Waku
Tsuyoshi
T
The Takara Bio Endowed Division, Department of Biomolecular Recognition, Institute for Protein Research, Osaka University, Open Laboratories of Advanced Bioscience and Biotechnology, Furuedai, Suita, Osaka, Japan.
Shiraki
Takuma
T
Oyama
Takuji
T
Maebara
Kanako
K
Nakamori
Rinna
R
Morikawa
Kosuke
K
D050156:Adipogenesis / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D005227:Fatty Acids / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011725:Pyridines / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*
D001549:Benzamides; D005227:Fatty Acids; D008024:Ligands; D047495:PPAR gamma; D011725:Pyridines; C458508:T 0070907; D012701:Serotonin