Alteration of Canalicular Transporters in a Mouse Model of Total Parenteral Nutrition

Objectives: Parenteral nutrition–associated liver disease (PNALD) is a major problem with prolonged total parenteral nutrition (TPN) administration. Our laboratory previously demonstrated significant changes in the expression of multidrug resistance genes (MDRs) 1 and 2, hepatocyte transporters, in a TPN mouse model. The present study hypothesized that these changes would lead to functional changes in the liver, and would contribute to the development of liver dysfunction. Materials and Methods: Mice received either intravenous saline and standard chow or TPN with or without intravenous lipids. Functional assays were performed after 7 days of infusion. Results: TPN with lipids led to a significant increase in serum bile acid levels, consistent with an early state of PNALD. Use of TPN without lipids prevented an elevation in bile acid levels. In both TPN groups, MDR2 expression was significantly (68%) lower than controls and bile phosphatidylcholine content, a functional measure of MDR2, was 40% less than controls. MDR1 expression in the TPN with lipid group was 31% higher than controls, whereas in the TPN without lipids mice there was no significant change. Hepatocyte extrusion of rhodamine dye, a measure of MDR1 function, declined only in the TPN with lipid group. Peroxisome proliferator–activated receptor‐α expression decreased in both TPN groups. Fenofibrate given with TPN resulted in an increased expression of MDR1 and MDR2, and functionally increased hepatocyte rhodamine extrusion and presence of bile phosphatidylcholine in the TPN with lipid group. Conclusions: The study shows that TPN led to alterations in the function of MDR1‐ and MDR2‐expressed proteins. The changes help in the understanding of the mechanisms leading to PNALD, and suggest that fibrate administration may palliate these changes.