Parenteral nutrition (PN) has been credited with saving the lives of countless patients with a variety of intestinal failure syndromes since the 1960s. Despite its life-saving properties, PN is not without complications, including PN-associated liver disease (PNALD). Recent studies have demonstrated that the composition of the lipid emulsion administered in combination with PN plays a pivotal role in the development of PNALD. Commonly used lipid emulsions are rich in soybean oil, which contain large quantities of pro-inflammatory omega-6 fatty acids and hepatotoxic phytosterols;these emulsions have been shown to cause liver injury in both in vitro and in vivo studies. Previous studies in our laboratory have demonstrated that an omega-3 FA rich fish oil-based lipid emulsion is protective against PNALD. Omega-3 FAs are metabolized to eicosapenaenoic acid (EPA) and docosahexaenoic acid (DHA), which increase the anti-inflammatory cytokines PGE3 and LTB5, and are suggested to contribute to the prevention of PNALD. A second mechanism which has recently been proposed to characterize the anti-inflammatory effects of omega-3 FAs involves the binding of a G-protein coupled receptor 120 (GPR120) with resultant inhibition of TNF-a and lipopolysaccharide-mediated inflammatory cascades. The purpose of this study is to determine whether the protective effect of fish oil-based lipid emulsions is mediated via the downstream metabolites of omega-3 FAs, or whether it results from the GPR120 receptor mediated pathway, or a combination of both mechanisms. To evaluate this further, two specific aims will be addressed. The first specific aim is to characterize the differences in insulin resistance, peripheral fat and liver inflammatory profiles, hepatosteatosis, and degree of liver injury within a PN fed murine model. To achieve this goal, GPR120 knockout (KO) mice and their wild-type (WT) littermates will be randomized to four groups. KO and WT control groups (KO control and WT control, respectively) will receive standard rodent chow. A third group will be comprised of KO mice receiving high-carbohydrate PN solution (HCD) with saline (KO HCD), and a fourth group will be comprised of WT mice receiving HCD (WT HCD). Serum inflammatory markers, adipose tissue and liver will be assessed among the four groups. The second specific aim is to determine if the GPR120 receptor is required for the reduction of tissue inflammation, hepatosteatosis and/or liver injury in a PN fed model. To achieve this goal, KO and WT mice will be randomized into six groups to receive saline, fish oil (FO) or soybean oil (SO) via tail injection concomitantly with HCD (KO control, KO HCD+FO, KO HCD+SO, WT control, WT HCD+FO, and WT HCD+SO). Markers of insulin resistance, peripheral fat inflammation and liver injury will be compared between groups.

Public Health Relevance

In recent years, omega-3 fatty acids (FAs) have been shown to have a variety of health benefits in humans. With respect to the liver, previous studies have identified liver-protective and anti-inflammatory effects of omega-3 FAs when given to individuals who depend on intravenous nutrition for their daily caloric needs. The goal of this study is to characterize the molecular basis underlying the beneficial effects of omega-3 FAs and elucidate the mechanism in order to better diagnose, prevent, and treat tissue inflammation and liver disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F06-S (20))
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Grave, Gilman D
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Children's Hospital Boston
United States
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Carlson, Sarah J; Nandivada, Prathima; Chang, Melissa I et al. (2015) The addition of medium-chain triglycerides to a purified fish oil-based diet alters inflammatory profiles in mice. Metabolism 64:274-82
Nandivada, Prathima; Chang, Melissa I; Potemkin, Alexis K et al. (2015) The natural history of cirrhosis from parenteral nutrition-associated liver disease after resolution of cholestasis with parenteral fish oil therapy. Ann Surg 261:172-9
Nandivada, Prathima; Carlson, Sarah J; Chang, Melissa I et al. (2013) Treatment of parenteral nutrition-associated liver disease: the role of lipid emulsions. Adv Nutr 4:711-7