FGF15 improves outcomes after brain dead donor liver transplantation with steatotic and non-steatotic grafts in rats

J Hepatol. 2020 Nov;73(5):1131-1143. doi: 10.1016/j.jhep.2020.05.007. Epub 2020 May 15.

Abstract

Background & aims: Donation after brain death (DBD) grafts are associated with reduced graft quality and function post liver transplantation (LT). We aimed to elucidate i) the impact of FGF15 levels on DBD grafts; ii) whether this impact resulted from altered intestinal FXR-FGF15; iii) whether administration of FGF15 to donors after brain death could confer a benefit on graft function post LT; and iv) whether FGF15 affects bile acid (BA) accumulation.

Methods: Steatotic and non-steatotic grafts from DBD donors and donors without brain death were transplanted in rats. FGF15 was administered alone or combined with either a BA (cholic acid) or a YAP inhibitor.

Results: Brain death induced intestinal damage and downregulation of FXR. The resulting reduced intestinal FGF15 was associated with low hepatic FGF15 levels, liver damage and regenerative failure. Hepatic FGFR4-Klb - the receptor for FGF15 - was downregulated whereas CYP7A1 was overexpressed, resulting in BA accumulation. FGF15 administration to DBD donors increased hepatic FGFR4-Klb, reduced CYP7A1 and normalized BA levels. The benefit of FGF15 on liver damage was reversed by cholic acid, whereas its positive effect on regeneration was maintained. YAP signaling in DBD donors was activated after FGF15 treatment. When a YAP inhibitor was administered, the benefits of FGF15 on regeneration were abolished, whereas its positive effect on hepatic damage remained. Neither the Hippo-YAP-BA nor the BA-IQGAP1-YAP axis was involved in the benefits of FGF15.

Conclusion: Alterations in the gut-liver axis contribute to the reduced quality of DBD grafts and the associated pathophysiology of LT. FGF15 pre-treatment in DBD donors protected against damage and promoted cell proliferation.

Lay summary: After brain death, potential liver donors have reduced intestinal FXR, which is associated with reduced intestinal, circulatory and hepatic levels of FGF15. A similar reduction in the cell-surface receptor complex Fgfr4/Klb is observed, whereas CYP7A1 is overexpressed; together, these molecular events result in the dangerous accumulation of bile acids, leading to damage and regenerative failure in brain dead donor grafts. Herein, we demonstrate that when such donors receive appropriate doses of FGF15, CYP7A1 levels and hepatic bile acid toxicity are reduced, and liver regeneration is promoted.

Keywords: Brain death; FGF15; Ischemia-reperfusion; Liver transplantation; Steatotic liver grafts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts* / blood
  • Bile Acids and Salts* / metabolism
  • Brain Death / metabolism*
  • Cholesterol 7-alpha-Hydroxylase / metabolism
  • Delayed Graft Function / metabolism
  • Delayed Graft Function / pathology
  • Delayed Graft Function / prevention & control
  • Down-Regulation
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fibroblast Growth Factors* / administration & dosage
  • Fibroblast Growth Factors* / metabolism
  • Fragile X Mental Retardation Protein / metabolism
  • Intestinal Mucosa / metabolism
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Liver / metabolism*
  • Liver Regeneration / drug effects
  • Liver Transplantation* / adverse effects
  • Liver Transplantation* / methods
  • Protective Agents / administration & dosage
  • Protective Agents / metabolism
  • Rats
  • Signal Transduction
  • YAP-Signaling Proteins

Substances

  • Bile Acids and Salts
  • FGF19 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Protective Agents
  • YAP-Signaling Proteins
  • Yap1 protein, rat
  • Fragile X Mental Retardation Protein
  • Fibroblast Growth Factors
  • CYP7A1 protein, rat
  • Cholesterol 7-alpha-Hydroxylase