Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human

Abstract

The role of sphingosine 1-phosphate (S1P) in liver fibrosis or inflammation was not fully examined in human. Controversy exists which S1P receptors, S1P1 and S1P3 vs S1P2, would be importantly involved in its mechanism. To clarify these matters, 80 patients who received liver resection for hepatocellular carcinoma and 9 patients for metastatic liver tumor were enrolled. S1P metabolism was analyzed in background, non-tumorous liver tissue. mRNA levels of sphingosine kinase 1 (SK1) but not SK2 were increased in livers with fibrosis stages 3–4 compared to those with 0–2 and to normal liver. However, S1P was not increased in advanced fibrotic liver, where mRNA levels of S1P transporter spinster homolog 2 (SPNS2) but not S1P-degrading enzymes were enhanced. Furthermore, mRNA levels of S1P2 but not S1P1 or S1P3 were increased in advanced fibrotic liver. These increased mRNA levels of SK1, SPNS2 and S1P2 in fibrotic liver were correlated with α-smooth muscle actin mRNA levels in liver, and with serum ALT levels. In conclusion, S1P may be actively generated, transported to outside the cells, and bind to its specific receptor in human liver to play a role in fibrosis or inflammation. Altered S1P metabolism in fibrotic liver may be their therapeutic target.

Involvement of Sphingosine 1-Phosphate in Palmitate-Induced Non-Alcoholic Fatty Liver Disease

“…In contrast to ceramide formation, increased levels of S1P can not only be detected within the cells but also in the extracellular environment. This is in accordance with the fact that S1P can be actively transported by ABC transporters, namely ABCC1 and ABCG2 [24] or via the S1P transporter spinster homolog 2 [25]. Most recently it has been indicated that mRNA of this transporter is increased in human liver with advanced fibrosis [25].…”

“…This is in accordance with the fact that S1P can be actively transported by ABC transporters, namely ABCC1 and ABCG2 [24] or via the S1P transporter spinster homolog 2 [25]. Most recently it has been indicated that mRNA of this transporter is increased in human liver with advanced fibrosis [25]. This is in conclusion with a variety of studies demonstrating that hepatic S1P formation is significantly increased in human fibrotic liver and S1P exerts a powerful migratory effect on hepatic myofibroblasts and in the progression of fibrosis in animal models [4,26].…”

Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology

“…Fibrosis is induced when quiescent hepatic stellate cells are induced to transdifferentiate to myofibroblasts, the cells responsible for laying down the fibrotic extracellular matrix (Pellicoro et al 2014). It was suggested that the myofibroblasts, which express α-smooth muscle actin and secrete collagen I to form the fibrotic extracellular matrix, are dependent on the S1P axis (Sato et al 2016). However, liver samples taken during resection for hepatocellular carcinoma showed no detectable differences in S1P levels between normal and fibrotic liver (Sato et al 2016).…”

“…It was suggested that the myofibroblasts, which express α-smooth muscle actin and secrete collagen I to form the fibrotic extracellular matrix, are dependent on the S1P axis (Sato et al 2016). However, liver samples taken during resection for hepatocellular carcinoma showed no detectable differences in S1P levels between normal and fibrotic liver (Sato et al 2016). Because SPNS2, a transporter of S1P, seemed to be elevated, it was suggested that S1P is transported out of hepatocytes and signals through S1PR2 in an autocrine loop that promotes fibrosis (Sato et al 2016).…”

“…However, liver samples taken during resection for hepatocellular carcinoma showed no detectable differences in S1P levels between normal and fibrotic liver (Sato et al 2016). Because SPNS2, a transporter of S1P, seemed to be elevated, it was suggested that S1P is transported out of hepatocytes and signals through S1PR2 in an autocrine loop that promotes fibrosis (Sato et al 2016). …”