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J. Biol. Chem., Vol. 281, Issue 1, 187-198, January 6, 2006

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Effects of Stable Suppression of Group VIA Phospholipase A₂ Expression on Phospholipid Content and Composition, Insulin Secretion, and Proliferation of INS-1 Insulinoma Cells^*

From the Medicine Department Mass Spectrometry Facility and Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110

Studies involving pharmacologic inhibition or transient reduction of Group VIA phospholipase A₂ (iPLA₂) expression have suggested that it is a housekeeping enzyme that regulates cell 2-lysophosphatidylcholine (LPC) levels, rates of arachidonate incorporation into phospholipids, and degradation of excess phosphatidylcholine (PC). In insulin-secreting islet -cells and some other cells, in contrast, iPLA₂ signaling functions have been proposed. Using retroviral vectors, we prepared clonal INS-1 -cell lines in which iPLA₂ expression is stably suppressed by small interfering RNA. Two such iPLA₂ knockdown (iPLA₂-KD) cell lines express less than 20% of the iPLA₂ of control INS-1 cell lines. The iPLA₂-KD INS-1 cells exhibit impaired insulin secretory responses and reduced proliferation rates. Electrospray ionization mass spectrometric analyses of PC and LPC species that accumulate in INS-1 cells cultured with arachidonic acid suggest that 18:0/20:4-glycerophosphocholine (GPC) synthesis involves sn-2 remodeling to yield 16:0/20:4-GPC and then sn-1 remodeling via a 1-lyso/20:4-GPC intermediate. Electrospray ionization mass spectrometric analyses also indicate that the PC and LPC content and composition of iPLA₂-KD and control INS-1 cells are nearly identical, as are the rates of arachidonate incorporation into PC and the composition and remodeling of other phospholipid classes. These findings indicate that iPLA₂ plays signaling or effector roles in -cell secretion and proliferation but that stable suppression of its expression does not affect -cell GPC lipid content or composition even under conditions in which LPC is being actively consumed by conversion to PC. This calls into question the generality of proposed housekeeping functions for iPLA₂ in PC homeostasis and remodeling.

Received for publication, August 17, 2005 , and in revised form, October 12, 2005.

^* This work was supported by United States Public Health Service Grants R37-DK34388, P01-HL57278, P41-RR00954, P60-DK20579, RO1-69455, and P30-DK56341. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Washington University School of Medicine, Campus Box 8127, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-8190; Fax: 314-362-8188; E-mail: jturk{at}wustl.edu.

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