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P99 FXR stimulation with INT-747 in a rat biliary drainage model protects from hepatocellular injury after loss of enterohepatic circulation
  1. R G J Visschers1,2,
  2. K V K Koelfat1,2,
  3. C M Hodin1,2,
  4. R Shiri-Sverdlov2,3,
  5. W A Buurman1,2,
  6. R Mookerjee4,
  7. K Lenaerts1,2,
  8. S W M O Damink1,2,5
  1. 1Department of Surgery, Maastricht University Medical Centre+, Maastricht University, Maastricht, the Netherlands
  2. 2Nutrition and Toxicology Research Institute Maastricht, Maastricht University, the Netherlands
  3. 3Department of Molecular Genetics, Maastricht University Medical Centre+, the Netherlands
  4. 4UCL Hepatology, Royal Free Hospital, University College London, London, UK
  5. 5Department of HPB Surgery and Liver Transplantation, Royal Free Hospital, University College London, London, UK

Abstract

Introduction Enterocutaneous fistula are often associated with development of intestinal failure associated liver disease (IFALD), ultimately leading to liver damage. We hypothesise that this is caused by reduced farnosoid X receptor (FXR) stimulation, due to interruption of the enterohepatic circulation and consequent impact on bile acid synthesis.

Aim We aimed at investigating the effect of specific stimulation of the farnosoid X receptor (FXR) with INT-747, a synthetic agonist, in a rat biliary diversion model.

Methods Four groups of rats (n=6–8) were studied; two groups underwent bile duct cannulation and externalisation to achieve continuous biliary drainage, daily receiving either vehicle or INT-747 (Intercept Pharm LtD); two groups underwent laparotomy without cannulation also receiving either vehicle or INT-747. Loss of bile was recorded daily. After 7 days, plasma, serum and liver and intestinal tissue were collected. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), γ glutamyl transpeptidase (GGT) and total bilirubin were assessed, together with histological scoring of necrosis, inflammation, bile duct proliferation, fibrosis and steatosis. Expression of genes involved in the FXR pathway, and lipid and cholesterol metabolism were quantified by qPCR.

Results Loss of bile was significantly reduced in the INT-747 group compared to the vehicle group. Serum levels of ASAT, ALAT, AP, GGT, bilirubin (total and direct) were all significantly increased in the bile drainage group when compared to controls (p<0.05), suggesting hepatocellular damage. Interestingly, all parameters were significantly decreased in the bile drainage group receiving INT-747 (p<0.05). Histological analyses showed normal liver histology in both sham groups. In contrast, large necrotic areas were observed in the biliary diversion group receiving vehicle with a high number of infiltrating inflammatory cells, which decreased significantly in the biliary diversion group receiving INT-747 (p<0.05). Biliary diversion induced hepatic fibrosis and bile duct proliferation, which were both attenuated by INT-747 supplementation (p<0.05). Although genes involved in the FXR pathway (FXR, SHP, CYP7A1 and CYP8B1) were influenced by bile drainage, no significant change was observed when rats received INT-747.

Conclusion The present data demonstrate that stimulation of FXR with INT-747 can attenuate hepatocellular damage in an experimental model of IFALD. The results suggest a role of FXR in the development of hepatocellular damage, hepatic fibrosis and necrosis during biliary diversion. FXR stimulation has the potential to be a novel therapy for patients with IFALD.

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