Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang 314001, China.
Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Biomolecules. 2021 Feb 10;11(2):260. doi: 10.3390/biom11020260.
In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.
在之前的一项研究中，奥贝胆酸（OCA）通过胆汁酸受体法尼醇 X 受体（FXR）在大鼠部分肝切除（PHx）前增加肝脏生长。在该模型中，OCA 在阻塞性胆汁淤积期间给药。然而，患者通常在胆道引流后几天进行 PHx。因此，研究了 OCA 对胆淤积后 Wistar 大鼠肝脏再生的影响。大鼠接受假手术或可逆胆管结扎（rBDL），7 天后解除结扎。在恢复胆汁流后一天进行 PHx。从恢复胆汁流开始，大鼠每天接受 10 mg/kg OCA 或接受载体治疗，直到 PHx 后 5 天处死。在接受 PHx 的大鼠中，胆淤积和非胆淤积肝脏的肝脏再生情况相当，这与人类验证队列的肝脏再生情况一致。OCA 治疗诱导回肠 mRNA 表达，但通过 FXR/SHP 信号通路并未增强 PHx 后肝细胞增殖。OCA 治疗既没有增加有丝分裂率，也没有恢复 PHx 后的肝重，但加速了未接受 rBDL 的大鼠的肝再生。OCA 没有增加胆管损伤。总之，OCA 不会在胆淤积后大鼠中诱导肝脏再生，也不会加重由胆淤积引起的胆管损伤。这项研究对之前报道的 OCA 在胆淤积大鼠肝脏再生中的有益作用提出了挑战。
