Acute pancreatitis (AP) affects ? 275,000/ year in the USA, and is the commonest gastroenterological cause of hospitalization. The major morbidity and cost from AP is from the severe disease which occurs in 10-25% patients. Over the last several years, the proportion of hypertriglyceridemia (HTG) has increased from being 20% of all AP causes. Moreover HTG is now commonly noted to co-exist with AP, and this, along with HTG AP often result in sustained organ failure, and consequently severe AP. Our previous work shows that the fat stored as triglycerides (TG) in visceral adipocytes, provides a fuel for the lipases leaked from the pancreas during AP. This stored triglyceride can be hydrolyzed by the lipases into fatty acids, which then result in multi-system organ failure and severe AP. We have also learnt that this triglyceride when unsaturated causes worse AP outcomes than saturated visceral fat. In Aim 1A, we will determine if TG composition is associated with the severity of the clinical HTG AP episode. For this the clinical course of patients admitted to Mayo Clinic AZ with a diagnosis of AP will be studied in the context of their TG amounts, TG composition at admission, and lipolytically generated total, and unbound fatty acids. In Aim 1B noting that the composition of dietary fat intake affects the composition of circulating TGs, we propose to study how dietary TG composition affects circulating TG behavior during HTG AP, by comparing the severity of HTG AP in the context of its composition. In Aim 1C we will study whether genetic deletion of PNLIP will reduce the severity of HTG AP. We will also focus on the use of heparin as an agent that releases LPL, such as when used as anticoagulant for plasma exchange during the management of HTG AP. The clinical literature shows worse outcomes when heparin is used in these scenarios, and our preliminary data show that heparin accelerates fatty acid generation and worsens the outcomes of HTG when this TG is unsaturated. Aim 2 focusses on the mechanisms on why ?6 and ?9 unsaturated triglyceride is a more risky form of triglyceride during pancreatitis. In aim 1A, based on preliminary findings that ?3 and saturated fatty acids interfere with the hydrolysis of a triglyceride containing them, we propose to study the molecular basis and energetics of how a TGs composition affects its lipolysis by pancreatic triglyceride lipase (PNLIP) and lipoprotein lipase (LPL). In Aim 2B based on previous work showing that unsaturated fatty acids cause more injury than saturated fatty acids, we propose to study how the double bonds in an unsaturated fatty acid affect its behavior in an aqueous environment like ours. Lastly in Aim 2C we will determine the role of ?3 fatty acids in affecting a TG?s lipolysis vs. how the ?3 bond affects the behavior of a NEFA in cellular signaling. The results of Aim 2 will explain the role of triglyceride composition in determining the severity of HTG AP. Overall these studies will provide novel mechanisms underlying the pathogenesis and outcomes of HTG and HTG AP, along with clinically relevant, scientifically sound approaches to improve these outcomes.
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