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

Tsukahara, T. and Tsukahara, R. and Fujiwara, Y. and Yue, J. and Cheng, Y. and Tigyi, Gábor (2010) Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid. MOLECULAR CELL, 39 (3). pp. 421-432. ISSN 1097-2765

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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.

Item Type: Article
Uncontrolled Keywords: Transcription, Genetic/physiology; RATS; Phospholipase D/genetics/*metabolism; Phosphatidic Acids/genetics/*metabolism; PPAR gamma/genetics/*metabolism; Nuclear Receptor Co-Repressor 2/genetics/metabolism; MICE; Macrophages/*metabolism; Cell Differentiation/physiology; Animals; Adipocytes/*metabolism; 3T3-L1 Cells
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH426 Genetics / genetika, örökléstan
R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában
Depositing User: MTMT SWORD
Date Deposited: 05 Oct 2017 12:55
Last Modified: 05 Oct 2017 12:55

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