Journal of Biological Chemistry
Volume 287, Issue 32, 3 August 2012, Pages 27244-27254
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Lipids
Palmitoleate Is a Mitogen, Formed upon Stimulation with Growth Factors, and Converted to Palmitoleoyl-phosphatidylinositol*

https://doi.org/10.1074/jbc.M111.274829Get rights and content
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Controversial correlations between biological activity and concentration of the novel lipokine palmitoleate (9Z-hexadecenoate, 16:1) might depend on the formation of an active 16:1 metabolite. For its identification, we analyzed the glycerophospholipid composition of mouse Swiss 3T3 fibroblasts in response to 16:1 using LC-MS/MS. 16:1 was either supplemented to the cell culture medium or endogenously formed when cells were stimulated with insulin or growth factors as suggested by the enhanced mRNA expression of 16:1-biosynthetic enzymes. The proportion of 1-acyl-2–16:1-sn-phosphatidylinositol (16:1-PI) was time-dependently and specifically increased relative to other glycerophospholipids under both conditions and correlated with the proliferation of fatty acid (16:1, palmitate, oleate, or arachidonate)-supplemented cells. Accordingly, cell proliferation was impaired by blocking 16:1 biosynthesis using the selective stearoyl-CoA desaturase-1 inhibitor CAY10566 and restored by supplementation of 16:1. The accumulation of 16:1-PI occurred throughout cellular compartments and within diverse mouse cell lines (Swiss 3T3, NIH-3T3, and 3T3-L1 cells). To elucidate further whether 16:1-PI is formed through the de novo or remodeling pathway of PI biosynthesis, phosphatidate levels and lyso-PI-acyltransferase activities were analyzed as respective markers. The proportion of 16:1-phosphatidate was significantly increased by insulin and growth factors, whereas lyso-PI-acyltransferases showed negligible activity for 16:1-coenzyme A. The relevance of the de novo pathway for 16:1-PI biosynthesis is supported further by the comparable incorporation rate of deuterium-labeled 16:1 and tritium-labeled inositol into PI for growth factor-stimulated cells. In conclusion, we identified 16:1 or 16:1-PI as mitogen whose biosynthesis is induced by growth factors.

Cell Growth
Fatty Acid
Mass Spectrometry
Membrane Biogenesis
Phospholipid
Acyltransferase
Cell Signaling
Metabolism

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*

This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (to T. S.) and a Global COE Program (The University of Tokyo) from the Japan Society for Promotion of Sciences (to T. S.).

This article contains supplemental Table S1 and supplemental Figs. S1 and S2.

1

Recipient of a research fellowship from the Takeda Science Foundation.

2

Supported by the Center for NanoBio Integration at The University of Tokyo.

3

Supported by Health and Labour Sciences Research grants (Research on Allergic Disease and Immunology) of the Ministry of Health, and Labour and grant-in-aid for Young Scientists (B) from the MEXT of Japan and The Uehara Memorial Foundation, The Cell Science Research Foundation, and Gushinkai Foundation.