To Be or Not to Be: The Divergent Action and Metabolism of Sphingosine-1 Phosphate in Pancreatic Beta-Cells in Response to Cytokines and Fatty Acids

Abstract

Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid with multiple functions conveyed by the activation of cell surface receptors and/or intracellular mediators. A growing body of evidence indicates its important role in pancreatic insulin-secreting beta-cells that are necessary for maintenance of glucose homeostasis. The dysfunction and/or death of beta-cells lead to diabetes development. Diabetes is a serious public health burden with incidence growing rapidly in recent decades. The two major types of diabetes are the autoimmune-mediated type 1 diabetes (T1DM) and the metabolic stress-related type 2 diabetes (T2DM). Despite many differences in the development, both types of diabetes are characterized by chronic hyperglycemia and inflammation. The inflammatory component of diabetes remains under-characterized. Recent years have brought new insights into the possible mechanism involved in the increased inflammatory response, suggesting that environmental factors such as a westernized diet may participate in this process. Dietary lipids, particularly palmitate, are substrates for the biosynthesis of bioactive sphingolipids. Disturbed serum sphingolipid profiles were observed in both T1DM and T2DM patients. Many polymorphisms were identified in genes encoding enzymes of the sphingolipid pathway, including sphingosine kinase 2 (SK2), the S1P generating enzyme which is highly expressed in beta-cells. Proinflammatory cytokines and free fatty acids have been shown to modulate the expression and activity of S1P-generating and S1P-catabolizing enzymes. In this review, the similarities and differences in the action of extracellular and intracellular S1P in beta-cells exposed to cytokines or free fatty acids will be identified and the outlook for future research will be discussed.

Sphingosine 1‐phosphate lyase facilitates cancer progression through converting sphingolipids to glycerophospholipids

“…SPL is responsible for irreversible degradation of S1P, as described in the Introduction section, therefore, SPL may regulate not only the intracellular levels of S1P, but also the amount of S1P available for extracellular export, by influencing autocrine or paracrine signaling through extracellular S1P receptors, especially in colon cancer, in which the S1P release system is up‐regulated 21 . Moreover, the importance of the sphingolipids in chronic inflammation of the digestive system has accumulated attentions and these recent advances could promote the therapeutic applications, targeting SKs, S1P and S1PRs 82–84 . Therefore, both the SPL‐mediated pathway and S1P‐S1P receptors might be useful therapeutic targets for the treatment cancer and the importance of these targets might depend on the cancer species.…”

“…21 Moreover, the importance of the sphingolipids in chronic inflammation of the digestive system has accumulated attentions and these recent advances could promote the therapeutic applications, targeting SKs, S1P and S1PRs. [82][83][84] Therefore, both the SPL-mediated pathway and S1P-S1P receptors might be useful therapeutic targets for the treatment cancer and the importance of these targets might depend on the cancer species. Further studies are necessary to address these points.…”

The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target

“…Also, S1P attenuates the transcriptional regulator c-fos. Therefore, S1P can be considered one of epigenetic regulation machinery [ 53 , 67 , 68 ].…”

Lipid metabolism in type 1 diabetes mellitus: Pathogenetic and therapeutic implications

“…In Lewis rats pancreatic β cells, elevated extracellular S1P concentrations were found to antagonize insulin-mediated β cell growth and survival via S1PR2 and then to inhibit AKT signaling. Besides, the reduction of intracellular S1P concentration by an overexpression of S1P lyase in insulin-secreting INS1E cells is able to inhibit the cytokine-induced reduction in cell proliferation and activation of caspase-3 ( 29 ), which suggests that the effects of exogenously added and intracellularly produced S1P on β cells depend mainly on the local concentration of S1P and the duration of exposure to diabetogenic conditions ( 81 ). To determine whether S1P is able to protect β cells in T1DM conditions and protect pancreatic β cells, further validation is needed in animal models of autoimmune diabetes as well as in the human population.…”