| The present project will delineate the effect of intestinal function in a murine model of cholestasis and in children with ESLD. Insight into the pathophysiology of CIFTT is expected to be of value in the treatment of children suffering from CIFTT and ESLD. CIFTT is one of the parameters in the Pediatric End-stage Liver Disease-score, which estimates the risk of mortality in children with end-stage liver disease (ESLD). We speculate that elevated serum bile acid concentration during cholestasis impairs epithelial differentiation, resulting in a diminished capacity to absorb nutrients. We hypothesize that PL-EFA improve intestinal function through a direct effect of LCPUFA on the peroxisome proliferator activated receptor family of transcription factors (PPARs), leading to restoration of epithelial differentiation. In the present project, we will test the hypothesis that CIFTT can be treated via improvement of intestinal function. The following strategy is chosen to test this hypothesis: 1. CIFTT and intestinal function will be studied in a murine and a rat model of extrahepatic cholestasis (bile duct ligation). 2. The role of metabolites of LCPUFA on PPAR function (via ligand binding) and on inhibition of intracellular (MAPK) signaling with respect to intestinal differentiation and proliferation will be delineated in intestinal cell lines. 3. The impact of PL-EFA in comparison with TG-EFA in the treatment of children with ESLD will be determined in a randomized clinical study. |
