Introduction: Group X secretory phospholipase A 2 (GX sPLA 2 ) has been implicated in a number of important biological processes, some of which appear to be independent of its lipolytic activity. These effects of GX sPLA 2 may be in part due to its high affinity binding to the M-type sPLA 2 receptor. To elucidate the physiological functions of this enzyme in vivo , we recently developed C57BL/6 mice with targeted deletion of GX sPLA 2 (GX KO mice). Results : Unexpectedly, GX KO mice have ~50% higher plasma corticosterone level compared to wild-type (WT) mice. Real-time RT-PCR and immunoblot analyses showed that expression of Steroidogenic Acute Regulatory Protein (StAR), a rate limiting protein in steroid production, is 2–5-fold higher in adrenals of GX KO mice compared to WT mice. GX KO mice responded normally to dexamethasone, indicating no impairment of the hypothalamic-pituitary axis. To provide additional evidence for a direct effect of Group X sPLA 2 on adrenal corticosteroid production, we performed studies in mouse adrenocortical tumor (Y-1) cells, which endogenously express GX sPLA 2 and the M-type receptor. Over-expression of GX sPLA 2 , or incubations with GX sPLA 2 , resulted in a significant reduction in progesterone production and StAR expression in Y-1 cells. Indoxam, an inhibitor of GX sPLA 2 activity and potent blocker of sPLA 2 binding to the M-type receptor, resulted in a significant increase in progesterone production and StAR expression in both control and GX sPLA 2 -overexpressing cells. Because several studies have implicated the extracellular signal-regulated kinase (ERK) cascade in the regulation of steroidogenesis, we investigated whether GX sPLA 2 altered adrenal ERK1/2 activation. Over-expression of GX sPLA 2 in Y-1 cells resulted in significantly increased ERK1/2 phosphorylation, whereas deficiency of GX sPLA 2 was accompanied by a significant decrease in phosphorylated ERK1/2 in mouse adrenals. Conclusions: We provide the novel finding that GX sPLA 2 has a direct effect on adrenal cells to regulate glucocorticoid production. Our in vivo and in vitro data indicate that Group X sPLA 2 down-regulates the expression of StAR, possibly through M-type receptor-mediated activation of ERK1/2.
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