Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid.
Cyclic phosphatidic acid (1-acyl-2,3-cyclic-glycerophosphate, CPA), one of nature's simplest phospholipids, is found in cells from slime mold to humans and has a largely unknown function. We find here that CPA is generated in mammalian cells in a stimulus-coupled manner by phospholipase D2 (PLD2) and binds to and inhibits the nuclear hormone receptor PPARgamma with nanomolar affinity and high specificity through stabilizing its interaction with the corepressor SMRT. CPA production inhibits the PPARgamma target-gene transcription that normally drives adipocytic differentiation of 3T3-L1 cells, lipid accumulation in RAW264.7 cells and primary mouse macrophages, and arterial wall remodeling in a rat model in vivo. Inhibition of PLD2 by shRNA, a dominant-negative mutant, or a small molecule inhibitor blocks CPA production and relieves PPARgamma inhibition. We conclude that CPA is a second messenger and a physiological inhibitor of PPARgamma, revealing that PPARgamma is regulated by endogenous agonists as well as by antagonists.
Tsukahara
Tamotsu
T
Department of Physiology, University of Tennessee Health Science Center Memphis, Memphis, TN 38163, USA.
Tsukahara
Ryoko
R
Fujiwara
Yuko
Y
Yue
Junming
J
Cheng
Yunhui
Y
Guo
Huazhang
H
Bolen
Alyssa
A
Zhang
Chunxiang
C
Balazs
Louisa
L
Re
Fabio
F
Du
Guangwei
G
Frohman
Michael A
MA
Baker
Daniel L
DL
Parrill
Abby L
AL
Uchiyama
Ayako
A
Kobayashi
Tetsuyuki
T
Murakami-Murofushi
Kimiko
K
Tigyi
Gabor
G
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010712:Phosphatidic Acids / Q000235:genetics / Q000378:metabolism*; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic / Q000502:physiology
C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D047495:PPAR gamma; D010712:Phosphatidic Acids; C105606:phospholipase D2; D010739:Phospholipase D