Elucidation of the mechanism of the inhibitory effect of sphingosine 1-phosphate on hepatocyte proliferation and the significance in liver regeneration

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Background & Aims: Sphingosine 1-phosphate (S1P), a ligand for G protein-coupled endothelial differentiation gene-I1(Edg-1), Edg-3, Edg-S, Edg-6 and Edg-8, elicits a variety of responses by cells: prominent among these is cell proliferation. S1P is abundantly stored in platelets and released upon their activation, suggesting that S1P plays a pathophysiological role in vivo. Because the major part of injected S1P was distributed into the liver in mice, we wondered whether the liver would be one of its targets. The effects of S1P on hepatocytes, the major constituent cells in the liver, were examined. Methods & Results: Northern blot analysis revealed the expression of Edg-1 and Edg-5 mRNAs in cultured rat hepatocytes, where S1P decreased DNA synthesis induced by HGF or EGF without affecting total protein synthesis. This inhibitory effect was attenuated by inactivation of small GTPase Rho with 03 exotoxin, but not by inactivation of G1 with pertussis toxin. Moreover, in the presence of JTE-013, a newly developed and specific binding antagonist for Edg-5, the inhibitory effect was also cancelled. Finally, the administration of S1P after 70% partial hepatectomy in rats reduced the peak of DNA synthesis in hepatocytes with increased Rho activity Furthermore, Edg-5 but not Edg-i mRNA expression was enhanced in hepatocytes 24-72 hours after partial hepatectomy, which coincides with decreasing hepatocyte. proliferation. Conclusions: S1P has an antiproliferative property in rat hepatocytes by activating Rho via Edg-5. Our results raise the possibility that S1P is a negative regulator in liver regeneration.