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

Authors

Tamotsu Tsukahara, University of Tennessee Health Science Center
Ryoko Tsukahara, University of Tennessee Health Science Center
Yuko Fujiwara, University of Tennessee Health Science CenterFollow
Junming Yue, University of Tennessee Health Science CenterFollow
Yunhui Cheng, University of Tennessee Health Science Center
Huazhang Guo, University of Tennessee Health Science Center
Alyssa Bolen, University of Tennessee Health Science CenterFollow
Chunxiang Zhang, University of Tennessee Health Science CenterFollow

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 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. 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. © 2010 Elsevier Inc.

Publication Title

Molecular Cell

Recommended Citation

Tsukahara, T., Tsukahara, R., Fujiwara, Y., Yue, J., Cheng, Y., Guo, H., Bolen, A., & Zhang, C. (2010). Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARγ by cyclic phosphatidic acid. Molecular Cell, 39 (3), 421-432. https://doi.org/10.1016/j.molcel.2010.07.022