Generation and use of lipid emulsions to understand mechanisms of and optimally manage parenteral nutrition associated liver disease

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DESCRIPTION (provided by applicant): Parenteral Nutrition (PN) is critical for supporting growth and development in infants and children with intestinal failure. Although PN provides necessary nutritional support when there is insufficient bowel length or functionality for nutrient absorption, children on prolonged PN are at significant risk of developing parenteral nutrition-associated liver disease (PNALD), which includes a spectrum of elevated liver enzymes and cholestasis that can progress to cirrhosis, liver failure, need for transplantation, and death. Lipids are important components of PN, providing ω-3 and ω-6 polyunsaturated fatty acids (PUFA) that cannot be generated endogenously. These fatty acids are important for preventing essential fatty acid deficiency (EFAD), as well as providing a dense source of calories to decrease the carbohydrate calories required to meet caloric needs, as PN devoid of lipid can promote PNALD. Lipid emulsions currently approved in the United States for use in PN are soybean oil or soybean/olive oil lipid emulsions (SOLE), which provide essential fatty acids to avoid EFAD, but exacerbate PNALD. It has recently been shown that the fish oil-based lipid emulsion (FOLE), Omegaven, that is rich in ω-3 fatty acids, can reverse PNALD in a mouse model and in patients. The mechanisms by which FOLE protects from PNALD while SOLE exacerbates PNALD remain debated, as several differences exist between SOLE and FOLE. SOLE contains an abundance of ω-6 fatty acids that are metabolized to more pro-inflammatory than anti-inflammatory mediators while FOLE contains predominantly ω-3 fatty acids that are metabolized to more anti-inflammatory than pro-inflammatory mediators. Additionally, SOLE contains phytosterols, cholesterol-like substance unique to plants and believed to be hepatotoxic, while FOLE does not; and FOLE contains an abundance of the anti-oxidant tocopherol whereas SOLE contains markedly less. In this study we will generate highly-purified SOLE-derived (PSO) and FOLE-derived (PFO) lipid emulsions and equalize the phytosterol and α tocopherol content, so that PUFA content is the only variable between the two emulsions. Using these PFO and PSO emulsions, our first aim is to assess the role of PUFA content in a mouse model of PN-induced steatosis. For our second aim, we will vary the phytosterol content or the α tocopherol content to assess the roles of each of these variables in PN-induced steatosis in our mouse model. We will also test the effect of these variables on global metabolic parameters, using mass spectrometry to identify key mediators of fatty acid metabolism, inflammation, and oxidative stress; and quantify the expression of genes previously identified as important in the pathogenesis of PNALD. Understanding the mechanisms and causative factors in PNALD may ultimately guide methods to generate lipid emulsions tailored to minimize risk of PNALD and maximize hepato-protection in children dependent on PN for nutrition.