The PLD2 Product Cyclic Phosphatidic Acid Is a Novel Lipid Second Messenger that Inhibits the Nuclear Hormone Receptor PPARγ

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 largely unknown function. We provide evidence 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 PPARγ with nanomolar affinity and high specificity through stabilizing its interaction with the corepressor SMRT. CPA production inhibits the PPARγ 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 PPARγ inhibition. Stimulation of PLD2 with low concentrations of insulin protected the carotid artery from PPARγ‐mediated neointima formation in rats. Inhibition of PLD2 activity using a small molecule inhibitor FIPI reversed the protective effect of insulin. This is consistent with a mechanism that PLD2‐mediated generation of CPA inhibits PPARγ function. We conclude that CPA is a second messenger and a physiological inhibitor of PPARγ, revealing that PPARγ is regulated by endogenous agonists as well as by antagonists. Supported by CA92160 and the Gerwin Graduate Fellowship.