Mechanism Of S1P Regulating Liver Regeneration By Enhancing Expression Of ANG1 In Hepatocytes

AimsLivers are different from other organs in our bodies.After partial liver resection,livers have great potential for regeneration.Hepatectomy is an effective method for the treatment of various benign and malignant liver diseases.Radical resection of liver remains the only curative method in liver cancer and the recovery of postoperative liver function is the key factor affecting the prognosis of liver cancer,considering liver failure is the most deadly complication of radical hepatectomy.Therefore,it is of great urgency and necessities to understand the early initiating factors of liver regeneration.At present,the molecular mechanism of liver regeneration after hepatectomy remains unclear,especially the initiating factors of early liver regeneration and its related molecular mechanisms,as well as the need for further improvement in serum markers.This study is designed to uncover novel early initiation factors and related molecular mechanisms of liver regeneration after hepatectomy.MethodsWe first performed metabolomics and protein chip tests on the serum of 5 patients before and after hepatectomy.Two high-throughput data results were combined with bioinformatics analysis to screen out the related molecules such as sphingosine 1-phosphate(S1P)and angiopoietin-1(ANG1),which were synthesized early in liver regeneration.Next,we collected 20 patients with hemihepatectomy and verified the preoperative and postoperative expression of S1 P and ANG1 by enzyme-linked immunosorbent assay(ELISA).The three-dimensional visualization technique was used to analyze the correlation between the liver hyperplasia volume and the changes of S1 P and ANG1 in 50 patients after hepatectomy,and the correlation analysis between S1 P and ANG1 was also carried out.At the same time,we also constructed mouse models of liver regeneration,and the expression of S1 P and ANG1 in the liver regeneration mice model was also detected by enzyme-linked immunosorbent assay(ELISA).Second,we used S1 P antagonists in the mouse models to detect the pre-and post-operative expression level of S1 P and ANG1 and treat normal liver cell lines with S1 P agonists,and then detect the expression of ANG in normal liver cells.Postoperative expression and validation.Finally,the molecular mechanisms involved in the early initiation of liver regeneration by S1 P and ANG1 were investigated by Western Blot,immunohistochemistry and CHIP.ResultsIn our study,we found that the expression of S1 P and ANG1 in the serum of patients after surgery was up-regulated,and the same result was confirmed in animal models.Based on our study on previously published papers,we identified SIP specific antagonist.Furthermore,the treatment of liver regeneration mouse models with S1 P inhibitors confirmed that S1 P promoted the expression of vascular ANG1 in livers.In the cellular functional experiments,we found that S1 P binds to ANG1 promoter region EGR1 through its receptor 2(S1PR2),and activates ANG1 transcriptional expression,thereby promoting the completion of early liver regeneration.ConclusionsThe results of the study indicate that up-regulation of S1 P in serum during early liver regeneration promotes an increase in serum ANG1 in livers.Our results suggest that S1 P and ANG1 may be the triggers for liver regeneration after hepatectomy,and may provide a predictor of liver function and proliferative liver volume after surgery.The corresponding activators of these molecules might have a role in promoting liver regeneration and preventing liver failure,which shows great clinical conversion potential.