title: Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid.
abstract: 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.
authors: Department of Physiology, University of Tennessee Health Science Center Memphis, Memphis, TN 38163, USA.
authors: Tamotsu
authors: T
authors: Tsukahara
authors: Ryoko
authors: R
authors: Tsukahara
authors: Yuko
authors: Y
authors: Fujiwara
authors: Junming
authors: J
authors: Yue
authors: Yunhui
authors: Y
authors: Cheng
authors: Huazhang
authors: H
authors: Guo
authors: Alyssa
authors: A
authors: Bolen
authors: Chunxiang
authors: C
authors: Zhang
authors: Louisa
authors: L
authors: Balazs
authors: Fabio
authors: F
authors: Re
authors: Guangwei
authors: G
authors: Du
authors: Michael A
authors: MA
authors: Frohman
authors: Daniel L
authors: DL
authors: Baker
authors: Abby L
authors: AL
authors: Parrill
authors: Ayako
authors: A
authors: Uchiyama
authors: Tetsuyuki
authors: T
authors: Kobayashi
authors: Kimiko
authors: K
authors: Murakami-Murofushi
authors: Gabor
authors: G
authors: Tigyi
mesh_terms: 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
chemical_list: C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D047495:PPAR gamma; D010712:Phosphatidic Acids; C105606:phospholipase D2; D010739:Phospholipase D