Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice
Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice
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DOI：
10.1136/gutjnl-2012-302945
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发表时间：
2013-06-01
期刊：
影响因子：
24.5
通讯作者：
Avila, Matias A.
中科院分区：
文献类型：
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作者：
Uriarte, Iker;Fernandez-Barrena, Maite G.;Avila, Matias A.
目的胆汁淤积与肝部分切除术（PH）后肝损伤和发病率增加有关，而胆汁酸（BA）是肝再生的重要介质。成纤维细胞生长因子15（Fgf 15，人FGF 19）是BA诱导的回肠衍生的肠因子，其控制BA代谢。我们评估了Fgf 15在PH后BA稳态的保持中的相关性及其在再生过程中的潜在作用。设计在Fgf 15（-/-）和Fgf 15（+/+）小鼠中研究PH后的肝再生。在该模型中检查BA螯合剂考来烯胺和腺病毒递送的Fgf 15的作用。在Fgf 15-/-小鼠中测试了Fgf 15在BA诱导的肝脏生长中的作用，以胆酸（CA）喂养。结果Fgf 15（-/-）小鼠PH后肝细胞损伤明显，死亡率明显升高，肝内BA水平持续升高。考来烯胺喂养和腺病毒递送的Fgf 15降低了BA水平并显著防止了这种致命结果。Fgf 15还降低了Fgf 15（+/+）动物广泛肝切除术后的死亡率。在Fgf 15（-/-）小鼠中，CA喂养引起的肝脏生长显著减少。在CA喂养的Fgf 15（-/-）小鼠中，肝细胞和胆管细胞的增殖也显著降低。结论Fgf 15在肝再生过程中对维持BA稳态和防止肝损伤是必需的。此外，Fgf 15是BA促进肝脏生长作用的重要介质。肝切除术前给予这种肠因子可能有助于减少损伤和促进再生。
Objective Cholestasis is associated with increased liver injury and morbidity after partial hepatectomy (PH), yet bile acids (BAs) are emerging as important mediators of liver regeneration. Fibroblast growth factor 15 (Fgf15, human FGF19) is a BA-induced ileum-derived enterokine that governs BA metabolism. We evaluated the relevance of Fgf15 in the preservation of BA homeostasis after PH and its potential role in the regenerative process.Design Liver regeneration after PH was studied in Fgf15(-/-) and Fgf15(+/+) mice. The effects of the BA sequestrant cholestyramine and adenovirally delivered Fgf15 were examined in this model. The role of Fgf15 in BA-induced liver growth was tested in Fgf15-/- mice upon cholic acid (CA) feeding. The direct mitogenic effect of Fgf15 was evaluated in cultured mouse hepatocytes and cholangiocytes.Results Fgf15(-/-) mice showed marked liver injury and mortality after PH accompanied by persistently elevated intrahepatic BA levels. Cholestyramine feeding and adenovirally delivered Fgf15 reduced BA levels and significantly prevented this lethal outcome. Fgf15 also reduced mortality after extensive hepatectomy in Fgf15(+/+) animals. Liver growth elicited by CA feeding was significantly diminished in Fgf15(-/-) mice. Proliferation of hepatocytes and cholangiocytes was also noticeably reduced in CA-fed Fgf15(-/-) mice. Fgf15 induced intracellular signalling and proliferation of cultured hepatocytes and cholangiocytes.Conclusions Fgf15 is necessary to maintain BA homeostasis and prevent liver injury during liver regeneration. Moreover, Fgf15 is an essential mediator of the liver growth-promoting effects of BA. Preoperative administration of this enterokine to patients undergoing liver resection might be useful to reduce damage and foster regeneration.