Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid

Mol Cell. 2010 Aug 13;39(3):421-32. doi: 10.1016/j.molcel.2010.07.022.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / metabolism*
  • Animals
  • Cell Differentiation / physiology
  • Macrophages / metabolism*
  • Mice
  • Nuclear Receptor Co-Repressor 2 / genetics
  • Nuclear Receptor Co-Repressor 2 / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Phosphatidic Acids / genetics
  • Phosphatidic Acids / metabolism*
  • Phospholipase D / genetics
  • Phospholipase D / metabolism*
  • Rats
  • Transcription, Genetic / physiology


  • Ncor2 protein, mouse
  • Nuclear Receptor Co-Repressor 2
  • PPAR gamma
  • Phosphatidic Acids
  • phospholipase D2
  • Phospholipase D