| Malignant obstructive cholestasis is caused by cholangiocarcinoma overgrowth,bile duct obstruction and ablation of bile acid’s hepatoenteral circulation,it is often a surgical incidental symptom of malignant biliary obstruction like gallbladder carcinoma,intrahepatic cholangiocarcinoma and especially peri-hilar cholangiocarcinoma(PHCC).Patients with PHCC often need major hepatectomy to achieve radical resection,but whether obstructive cholestasis impairs liver regeneration after major hepatectomy is still controversial.And meanwhile,regards to the side effects of preoperative biliary drainage,new auxiliary methods should be raised to relieve obstructive cholestasis rapidly and effectively in patients with malignant obstructive cholestasis.Thus,this research was carried out to uncover these key issues based on experimental animals.In this current study,we firstly compared liver restoration capacity after hepatectomy in CTL and BDL groups in rats thourgh ligation of common bile duct and 50%hepatectomy.Results implied that rats in BDL group had impaired liver restoration capacity,which caused by the hepatocytes proliferation inhibition in early phase after hepatectomy.Inordinate hepatic triglyceride content and expressions of cytokines and growth factors were also found in BDL group.Further investigation showed that expressions of genes related to fatty acid synthesis and utilization(PPARa,CTP1,SREBP-lc and FASN)were reduced in BDL group rats,which revealed the interrupted fatty acid synthesis and utilization process,thus,obstructive cholestasis interfered expressions of hepatic cytokines and growth factors and impaired triglyceride accumulation,and finally inhibited liver regeneration after hepatectomy.And these results indicated that to avoid postoperative liver function failure,relief of obstructive cholestasis should be performed.Preoperative biliary drainage used in clinical practice can induce perioperative morbidity and even metastases,thus new methods should be raised.Hepatic hydrophobic bile acids accumulation leads to obstructive cholestatic liver injury.GGPPS is the key enzyme in modulating cholesterol synthesis,which is the substrate for bile acids synthesis.Thereafter,reduced hepatic GGPPS expression was found in both of PHCC patients and cholestatic mice,indicated that GGPPS may play a crucial role in modulating obstructive cholestatic liver injury.And thus,we generated liver-specific Ggpsl knockout mice through Cre-Loxp system.Compared with that in WT group mice,it was found that liver-specific Ggpsl deletion could largely reversed cholestatic liver injury.Overall survival and serum AST index were improved in KO mice after BDL,and more specifically,necrosis was disappeared in KO mice livers through morphological analysis after BDL.Meanwhile,Enhanced hepatocytes proliferation activities and reduced hepatocytes apoptosis behaviors were also observed in KO mice livers after BDL.Furthermore,LC-MS showed that hepatic hydrophobic bile acids were largely reduced,Expressions of hepatic bile acid transporters and pumps were stimulated in KO mice though Real time PCR,which indicated that hepatic hydrophobic bile acids were excreted in KO mice.MS also indicated that liver-specific Ggpsl knockout enhanced hepatic FOH and FPP content,which thereafter was proved to activate FXR luciferase activity in vitro.More importantly,FXR luciferase activity was also enhanced in primary hepatocytes in KO mice.We proved that specific targeting GGPPS improved obstructive cholestatic liver injury.Herein,we down-regulated GGPPS activity through administrating DGBP,a proved GGPPS inhibitor in vitro,which attenuated obstructive cholestatic liver injury.Taken together,our results indicated that liver-specific Ggpsl ablation-induced FOH and FPP elevations activated FXR signaling,which stimulated hepatic bile acid transporters and pumps,and protected liver from obstructive cholestasis injury.And thus,targeting GGPPS provides a novel management for patients with extrahepatic cholestasis. |
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