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American Liver Foundation
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New York, New York 10006
Alexander M. White, III Postdoctoral Research Fellowship
Texas Children's Hospital / Baylor College of Medicine
Project Title: The Role of Phytosterols in TPN Cholestasis
Total parenteral nutrition (TPN) is a life-saving nutritional modality that is received by more than 500,000 children annually. However, it is known that prolonged use of TPN can be harmful to the pediatric liver. Although lipid is an essential component of parenteral nutrition, it has also emerged as a potential cause of parenteral nutrition associated liver disease. Dr. Ng utilizes a unique neonatal pig model of TPN-induced liver disease to study the negative effects of soybean oil-based lipid emulsions. His central hypothesis is that phytosterols found in soybean oil-emulsions antagonize hepatic FXR function leading to bile acid homeostatic dysregulation.
In Aim 1, he will test whether or not the three principal phytosterols in soy lipid emulsions, beta-sitosterol, campesterol, and stigmasterol, suppress FXR target gene expression in premature pig hepatocytes. Dr. Ng will harvest viable hepatocytes from premature pigs and incubate the cells with an FXR agonist plus each of the three principal phytosterols found in Intralipid as well as Intralipid itself. He will measure FXR target gene expressions via PCR to identify possible negative effects. In Aim 2, Dr. Ng will test whether parenteral phytosterol inhibits hepatic FXR function (in contrast to the stimulating effects of an FXR agonist). He will study premature pigs given TPN in combination with different lipid formulations for 14 days. After 14 days of treatment, he will quantify endpoints of cholestasis and liver injury (serum biomarkers and histo-pathologic markers of inflammation). Dr. Ng will also quantify expressions of hepatic and intestinal FXR target genes related to bile acid homeostasis.
Dr. Ng anticipates this project will elucidate important molecular mechanisms explaining how Intralipid and new generation parenteral lipid emulsions affect specific bile acid homeostasis. Dr. Ng’s data may ultimately lead to major changes in lipid emulsion design which in turn will minimize future patients’ risk for parenteral nutrition associated liver disease.
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