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. 2021 Sep 22;62:100121. doi: 10.1016/j.jlr.2021.100121

Fig. 7.

Fig. 7

Scheme of the crosstalk of sphingolipid and eicosanoid metabolic pathways. The sphingolipid pathway is known to involve the SPT complex, which is negatively regulated by ORMDL family proteins. This pathway leads to the production of sphingosines and ceramides. The eicosanoid pathway involves PLA2 and 5-LO. When activated, PLA2 releases arachidonic acid (AA) from ER membranes, which is utilized by 5-LO and cyclooxygenases (COX) as a substrate for the production of precursors of leukotrienes and prostaglandins, respectively. The connection between eicosanoid and sphingolipid pathways is linked to the activity of their mediators. It has been shown that the nonvesicular C1P transfer regulates PLA2-dependent release of arachidonic acid (54) and that second messenger S1P induces expression of cyclooxygenase 2 (COX2) (55). Data in this study indicate that ORMDL3 interacts with 5-LO and that 5-LO interacts with SPT complex subunits, SPTLC1 and SPTLC2. The functional consequences of the leukotriene and sphingolipid pathway crosstalk are shown (in orange) and involve 1) inhibitory role of ORMDL3 on the activity of 5-LO and eicosanoid production; 2) activatory role of SPTLC1 on 5-LO activity; 3) inhibitory effect of 5-LO on ceramide levels. Moreover, reduced SPTLC1 levels are followed by decreased expression of SPTLC2 and ORMDL3 (dashed lines). Sphingolipid synthesis inhibitors, myriocin and fumonisin B1, which block the activity of SPT complex and ceramide synthase, respectively, affect the release of AA from membranes and subsequently the formation of LTB4 or PGD2. These data are in line with the regulatory roles of ceramides on the PLA2 activity (3954). Thus, the crosstalk between eicosanoid and sphingolipid pathways seems to be mediated via metabolic mediators (ceramides, S1P, and C1P) and physical interaction of ORMDL-SPT complex and 5-LO.