Sphingosine-1-Phosphate: Boon and Bane for the Brain

Abstract

Sphingosine-1-phosphate (S1P), an evolutionary conserved bioactive lipid, is essential for brain development, but might also exert detrimental effects in terminally differentiated post-mitotic neurons. Its concentration in the brain is tightly regulated by specific kinases and phosphatases, and mainly by the S1P degrading enzyme, S1P-lyase (S1PL). The role of S1P in neurons was initially studied in primary cultures by using structural analogues. During the last 3 years generation of a S1PL deficient mouse model substantially promoted our knowledge on the functional role of S1P metabolism in the brain, and its potential relation to neurodegenerative diseases. However, our understanding of the molecular mechanisms that underlie the physiological and pathophysiological actions of S1P in neurons remains rather scarce.

The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice

“…It is possible that alongside leptin and insulin pathways, S1P and ceramide may have an important role in signalling the energy status of the animal in the brain through specific kinases and phosphatases (van Echten‐Deckert et al ., 2014). Previous work suggested that in the hypothalamus, S1P regulates energy homeostasis in rats.…”

“…The physical changes we see with CR, along with the increase in S1P, may be downstream of other CR related responses such as lowered leptin levels. The observed increase in S1P may be liver‐specific and acting to promote cell survival, immune cell trafficking, cell motility and histone modification (van Echten‐Deckert et al ., 2014; Gomez‐Muñoz et al ., 2015). The increase in S1P we see with CR may also be acting as a switch to reduce ceramide, which can promote inflammation through NF‐ƙB (nuclear factor kappa‐light‐chain enhancer of activated B cells) in liver mitochondria, and conversion into S1P may act to attenuate this response (Gomez‐Muñoz et al ., 2015).…”

GluN2B-containing NMDA receptors are upregulated in plasma membranes by the sphingosine-1-phosphate analog FTY720P

“…In various cell types, sphingosine is produced through ceramide metabolism, a process catalyzed by enzymes such as ceramidases (Bartke and Hannun, 2009;Laurier-Laurin et al, 2014;Soliven et al, 2011;van Echten-Deckert et al, 2014).…”

Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy

“…22,23 Phosphoethanolamine can be used for phospholipid synthesis. Alternatively, S1P may re-enter the sphingolipid metabolism by dephosphorylation to sphingosine and subsequent conversion to ceramide and complex sphingolipids.…”

“…S1P itself is a potent signaling molecule involved in cell migration, proliferation, and apoptosis. 22 Thus, SPL acts at the crossroad of sphingolipid and phospholipid metabolism, and plays a pivotal role in fine-tuning the concentrations of its bioactive substrate. In patient plasma, S1P levels were significantly increased compared to parents or unrelated controls.…”