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Title: Rifampicin, not vitamin E, suppresses parenteral nutrition-associated liver disease development through pregnane X receptor pathway in piglets

Author
item GUTHRIE, GREGORY - BAYLOR COLLEGE OF MEDICINE
item STOLL, BARBARA - BAYLOR COLLEGE OF MEDICINE
item CHAKO, STAJI - BAYLOR COLLEGE OF MEDICINE
item LAURIDSEN, CHARLOTTE - AARHUS UNIVERSITY
item PLAT, JOGCHUM - MAASTRICHT UNIVERSITY
item Burrin, Douglas - Doug

Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/7/2019
Publication Date: 10/11/2019
Citation: Guthrie, G.J., Stoll, B., Chako, S., Lauridsen, C., Plat, J., Burrin, D.G. 2019. Rifampicin, not vitamin E, suppresses parenteral nutrition-associated liver disease development through pregnane X receptor pathway in piglets. American Journal of Physiology - Gastrointestinal and Liver Physiology. 318:G41-G52. https://doi.org/10.1152/ajpgi.00193.2019.
DOI: https://doi.org/10.1152/ajpgi.00193.2019

Interpretive Summary: Intravenous nutrition support is a life saving intervention for many infants who are unable to consume foods by mouth. This intravenous support is comprised of an emulsion of fluid, electrolytes, amino acids, glucose, fats, vitamins and minerals and collectively referred to as total parenteral nutrition TPN. While TPN is life saving, there are some negative long term effects observed in infants, including the development of liver disease while receiving TPN. This liver disease is associated with the fat component of TPN, and in particular soy oil-based fat emulsions. Fat emulsions that contain fish oil or a mixture of oils that have been supplemented with vitamin E do not tend to cause liver disease. Our previous studies showed that TPN fed piglets receiving soy oil based fat emulsions were healthier when the fat emulsion was supplemented with vitamin E. We conducted a follow-up experiment to determine how the vitamin E improved liver disease outcomes. We hypothesized that vitamin E will activate genes in the liver that promote clearance of bile acids, which are believed to contribute to the cause of liver injury, through the same mechanisms the body removes drug compounds. To test this we gave neonatal piglets TPN with soy-lipid emulsion, soy-lipid emulsion supplemented with vitamin E, or soy-lipid emulsion and a daily antibiotic, rifampicin, which is known to activate genes that help the liver metabolize drugs. We found that rifampicin reduced the severity of liver disease in the piglets receiving TPN, but vitamin E did not activate any genes associated with drug clearance. The results of this study represent a potential approach to minimize the effect of TPN on liver disease through the use of rifampicin.

Technical Abstract: Infants receiving long-term parenteral nutrition (PN) develop PN associated liver disease (PNALD). We previously showed that PN containing soy-based lipid supplemented with vitamin E (a-tocopherol) prevents the development of PNALD. We hypothesize that this occurs via vitamin E-activation of pregnane X receptor (PXR) mediated pathways involved in bile acid metabolism. Neonatal piglets received PN for 14 d containing Intralipid (IL, soy based lipid emulsion), IL supplemented with 12.6 mg/kg^d-1 vitamin E (VITE), or IL with 10 mg/kg^d-1 Rifadin IV (RIF) a PXR agonist. Pigs treated with IL and VITE, but not RIF, developed cholestasis and hyperbilirubinemia, markers of liver disease. The hepatic PXR target genes CYP3A29 and UGT1A6 increased during RIF treatment. RIF also modestly increased metabolism of chenodeoxycholic acid to the more hydrophilic bile acid, hyocholic acid. Serum fibroblast growth factor (FGF)-19, a key regulator in suppressing hepatic bile acid synthesis significantly increased in the RIF group. We conclude rifampicin modified markers of PNALD development by increased metabolism of bile acids and potentially suppressed bile acid synthesis. Vitamin E was ineffective at high lipid doses in preventing PNALD.