Mechanism of sphingosine 1-phosphate clearance from blood

Abstract

The interplay of sphingosine 1-phosphate (S1P) synthetic and degradative enzymes as well as S1P exporters creates concentration gradients that are a fundamental to S1P biology. Extracellular S1P levels, such as in blood and lymph, are high relative to cellular S1P. The blood-tissue S1P gradient maintains endothelial integrity while local S1P gradients influence immune cell positioning. Indeed, the importance of S1P gradients was recognized initially when the mechanism of action of an S1P receptor agonist used as a medicine for multiple sclerosis was revealed to be inhibition of T-lymphocytes’ recognition of the high S1P in efferent lymph. Furthermore, the increase in erythrocyte S1P in response to hypoxia influences oxygen delivery during high altitude acclimatization. However, understanding of how S1P gradients are maintained is incomplete. For example, S1P is synthesized but is only slowly metabolized by blood yet circulating S1P turns over quickly by an unknown mechanism. Prompted by the counterintuitive observation that blood S1P increases markedly in response to inhibition S1P synthesis (by sphingosine kinase 2 (SphK2)), we studied mice wherein several tissues were made deficient in either SphK2 or S1P degrading enzymes. Our data reveal a mechanism whereby S1P is de-phosphorylated at the hepatocyte surface and the resulting sphingosine is sequestered by SphK phosphorylation and in turn degraded by intracellular S1P lyase. Thus, we identify the liver as the primary site of blood S1P clearance and provide an explanation for the role of SphK2 in this process. Our discovery suggests a general mechanism whereby S1P gradients are shaped.

Depletion of adipocyte sphingosine kinase 1 leads to cell hypertrophy, impaired lipolysis, and nonalcoholic fatty liver disease

“…S1E). While adipose tissue homogenates showed similar S1P levels in SK1 fatKO mice and WT mice, S1P is found in micromolar amounts in plasma and even higher amounts in whole blood from erythrocytes (19)(20)(21), and therefore it is likely that these high levels obscured the differences in tissue S1P that would be expected based on reduced mRNA in the HFD-fed SK1 fatKO mice. These data also suggest that SPHK1 in adipocytes does not contribute to circulating levels of S1P, but rather acts in a localized fashion within the tissue.…”

Role of Sphingosine Kinase in Type 2 Diabetes Mellitus

“…Circulating S1P is mainly sourced from the SphK1 in erythrocytes ( 48 ). However, a recent study has found that SphK2 also determines the circulating level of S1P in the liver, where it dictates S1P clearance via a route of dephosphorylation, re-phosphorylation and lysis ( 49 ). Circulating S1P is undoubtedly implicated in whole-body metabolic regulation, but its physiological effects remain elusive.…”

A reference map of sphingolipids in murine tissues

“…When detectable, the highest levels of S1P were found in the brain, while the lowest were measured in skin, BAT, and liver (Figure S3C). Recently, Kharel et al (2020) demonstrated in murine models that indeed the liver is the primary site for clearance of S1P from the blood. According to this model, blood S1P is converted, via a cell surface phosphatase, to sphingosine at the hepatocyte surface.…”