| Backgroud and Objective:Partial liver resection is often the only curative option for various liver diseases, but many patients are evaluated as unable to tolerate the procedure due to an insufficient future remnant liver (FRL). To acquire resectability, portal vein ligation (PVL) has been established as a routine procedure. After PVL, atrophy/hypertrophy complex (AHC) were induced. However, PVL is associated with a prolonged waiting and frequent poor responses clinically. Improved methods are needed. Bile acids has been tested as being able to enhance and/or initiate hepatocyte proliferation via FXR-dependent signaling pathway, and can impose an apoptotic effect in case of prolonged retention. At the same time, bile acid has been recently found to promote hepatocyte polarization and accelerate the establishment of canalicular network in vitro. We hypothesized that combining bile duct ligation with PVL will enhance the bile acid retention, thereby increasing the efficiency with which the atrophy/hypertrophy complex is induced, and increasing the speed of canalicular network reconstruction, and thus improve the tolerance of extended hepatectomy.Methods:We established a rat model of 90% bile duct and portal vein double ligation (BPL) and 90% PVL, sham operation were used as control. Liver weight, serum markers, western blot, PCR, H&E staining, immubostaining, etc. were used. We chose 3days and 5days after Sham/BPL/PVL as the time points for early/late stage hepatectomy. After BPL/PVL, second stage hepatectomy were performed as hepatectomy preserving the posterior caudate lobe, and 90%and 95%hepatectomy after sham were used as controls. We monitored the survival rate and assess the regenerative response after second stage hepactectomy. To further investigated the mechanism underline the effects, we decreased the bile acid pools in the rats that underwent BPL by switching to diets containing 2% cholestyramine, and increased the bile acid pools of rats that underwent PVL by switching to diets containing 0.2% taurocholate.Results:We found that BPL was well-tolerated and significantly accelerated the AHC. The enhanced bile acid retention in the intact liver promoted hepatocyte proliferation by promoting the activation of FXR signalling, while that in the ligated liver intensified apoptosis. Decreasing the BA pools in the rats that underwent BPL could compromise these effects, whereas increasing the bile acid pools of rats that underwent PVL could induce similar effects. The survival after late second-stage resection of was93.3% after BPL-5d-Hx,0% after Sham-5d-95%Hx,26.7%, after Sham-5d-90%Hx, and 56.7% after PVL-5d-Hx. After BPL-5d-Hx, the remanint liver were the largest among the groups and showed the most sustained regeneration. We also found that compare to PVL, BPL promoted the activation of the MEK-AMPK-LKB1 signaling pathway of polarization, and accelerated the reconstruction of canalicular network by at least 24 hours. Decreasing the B A pools in the rats that underwent BPL could compromise these effects, whereas increasing the bile acid pools of rats that underwent PVL could induce similar effects. The survival rates after early stage hepatectomy were 86.7% after BPL-3d-Hx, 23.3%, after Sham-3d-90%Hx, and 47.0% after PVL-3d-Hx and were found to be revelant with hepatocyte polarization and canalicular integrity. Decreasing the BA pools in the rats that underwent BPL could resulted in lower survival, and increasing the bile acid pools of rats that underwent PVL significantly improved prognosis after staged hepatectomy.Conclusions:BPL promoted AHC and accelerated hepatocyte polarization and canalicular network reconstruction. Following BPL, the hypertrophied liver manifested significantly improved tolerance to second-stage resection. We conclude that BPL is a safe and effective method, and that the acceleration of atrophy/hypertrophy complex and hepatocyte polarization and canalicular network reconstruction were bile acid-dependent. |
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