P105 Biliary drainage in a rat: a long-term continuous drainage model resulting in liver damage and an altered FXR pathway, lipid and cholesterol metabolism
Authors: K. V. K. Koelfat, R. G. J. Visschers, C. M. Hodin, R. Shiri-Sverdlov, W. A. Buurman, K. Lenaerts, S. W. M. O. Damink
Journal: Gut (2011)

<h3>Introduction</h3> We hypothesised that the development of intestinal failure associated liver disease (IFALD) caused by an enterocutaneous fistula in which the enterohepatic circulation is interrupted without obstructive cholestasis leads to reduced farnosoid X receptor (FXR) signalling, ultimately leading to liver damage. Previous studies have primarily been performed in models of bile duct obstruction. <h3>Aim</h3> Therefore we aimed to develop a biliary diversion model in the rat with long-term continuous biliary drainage and determined its effect on hepatic function and lipid metabolism. <h3>Methods</h3> In rats (n=7–9), the bile duct was cannulated and externalised to accomplish biliary drainage. Sham controls underwent laparotomy without cannulation. Rats were sacrificed after 3 and 7 days, and liver samples were collected for histological assessment (necrosis, inflammation, bile duct proliferation). Sirius red staining and Oil Red O staining were used for analysis of fibrosis and steatosis, respectively. Quantitative PCR was performed for genes involved in the FXR pathway (FXR, SHP, BSEP, CYP7A1 and CYP8B1), lipid and cholesterol metabolism (FAS, SREBF, ACACA, PPARg, SCD1, LDLr and HMG-CoA reductase). AST, ALT, AP, GGT and bilirubin (total and direct) were assessed. <h3>Results</h3> Continuous biliary diversion resulted in increased hepatic inflammation and necrosis at day 3 and day 7 (p&lt;0.05) and was accompanied by bile duct proliferation (absent in controls). Fibrosis was only seen at day 7 (p&lt;0.05). A trend towards decreased lipid droplets was apparent in the experimental group. Hepatic expression of FXR was markedly decreased in the experimental group at day 3 (1.11±0.19; p&lt;0.05) compared to sham (1.76±0.18) and at day 7 (0.58±0.16 vs 1±0.09; p&lt;0.05). As expected, SHP expression was downregulated at day 7 (0.29±0.15; p&lt;0.05) compared to sham (1.38±0.53). CYP7A1 was upregulated in the drainage group at day 3 (1.59±0.45 vs 0.32±0.11; p&lt;0.05) which suggests stimulation of bile acid biosynthesis. CYP8B1 also showed increased expression, although not significant. BSEP expression was decreased at day 3 (0.84±0.09 vs 1.34±0.24; p&lt;0.05) and at day 7 (0.58±0.16 vs 1±0.09;p&lt;0.05), suggesting impaired canulicular bile acid transport. Genes involved in the fatty acid metabolism were downregulated in biliary diverted rats. Fatty acid synthase (0.65±0.24) and acetyl-CoA carboxlyase (0.82±0.21) were decreased at day 7 (p&lt;0.05). HMG-CoA reductase expression was upregulated at day 3 (0.69±0.12;p&lt;0.05) compared to sham (0.35±0.06), suggesting stimulated cholesterol synthesis. AST, ALT, AP, GGT and bilirubin (total and direct) were significantly increased at day 7 (p&lt;0.05). <h3>Conclusion</h3> Biliary diversion in rats induced hepatic inflammation, necrosis, fibrosis and bile duct proliferation. Biliary diversion had evident hepatic effects with respect to FXR signalling and lipid metabolism. This model is suitable to assess long-term effects of continuous bile drainage to test therapeutic interventions aimed to reduce IFALD.