Cyclic phosphatidic acid (cPA)

Lipidomics Gateway (26 August 2010) [doi:10.1038/lipidmaps.2010.27]

An analogue of lysophosphatidic acid, with diametric effects, cPA is an anti-metastatic signaling lipid that negatively regulates PPARγ.

Structure of 1-hexadecanoyl-sn-glycero-2,3-cyclic-phosphate. Visit 16:0 cyclic PA in the LIPID MAPS structure database for more molecular information.

cPA is related to LPA, and it can activate the LPA receptors. Nonetheless, many of its effects on cells are opposite to those of its non-cyclic cousin, including inhibition of cancer cell invasion and metastasis ¹ . The mechanisms of such actions are, however, incompletely understood.

Although cPA is a stable LPA analogue, opening of its ring could generate LPA, and metabolically stable carba analogues have been developed to avoid this. One such, thio-ccPA, markedly reduces the viability of melanoma cells ² .

It has been proposed that autotaxin, the enzyme that generates LPA from lysophosphatidylcholine (LPC), is mainly responsible for generating cPA in serum ³ . Autotaxin is subject to product inhibition, and the effects of cPA could thus be attributed to the dual effect of inhibition of LPA production, and antagonism of LPA signaling through the LPA receptors. Thio-ccPA is thought to inhibit ATX and the LPA3 receptor ² .

The possibility of other biosynthetic routes was never ruled out ¹ , and Gabor Tigyi and colleagues now show—in cell culture—that phospholipase D2 also produces cPA from LPC ⁴ . As we highlight this month in PPARγ regulators: Cyclic phosphatidic acid acts down, Tigyi and colleagues identify a new target of cPA: PPARγ. The finding of an endogenous negative regulator opens a new paradigm for PPARγ signaling, and might help in the development of drugs to treat type 2 diabetes.

Related articles:

Lysophosphatidic acid (LPA)
One of the most active of the bioactive phospholipids, LPA is soluble in both cell membranes and in aqueous fluid, and acts in many cell signaling pathways.

Emma Leah