Fat in Pancreatitis - a Focus on Hypertriglyceridemic Pancreatitis

胰腺炎中的脂肪——关注高甘油三酯血症性胰腺炎

• 批准号: 10211952
• 负责人: Vijay Prem Singh
• 金额: $ 50.63万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-06 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10211952
• 关键词: Adipocytes; Admission activity; Affect; Anticoagulants; Behavior; Biological; Citrates; Cleaved cell; Clinic; Clinical; Data; Diagnosis; Dietary Fats; Disease; Environment; Fatty Acids; Fatty acid glycerol esters; Generations; Genetic; Heparin; Heterogeneity; Hospitalization; Hydrolysis; Hypertriglyceridemia; Inflammation; Injury; Intake; Lipase; Lipolysis; Literature; Membrane; Methods; Molecular; Morbidity - disease rate; Mus; Organ failure; Outcome; Pancreas; Pancreatitis; Pathogenesis; Patients; Plasma Exchange; Prevalence; Reporting; Risk; Role; Saturated Fatty Acids; Serum; Severities; Signal Transduction; Time; Toxic effect; Transcription Factor AP-1; Triglycerides; Unsaturated Fatty Acids; Visceral; Visceral fat; Work; acute pancreatitis; aqueous; base; cell injury; clinically relevant; cost; dietary; enhancer-binding protein AP-2; hazard; improved outcome; lipoprotein lipase; mortality; novel; pi bond; response; saturated fat; sound; treatment response; uptake

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 <5%, to sometimes >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 ω6 and ω9 unsaturated triglyceride is a more risky form of triglyceride during pancreatitis. In aim 1A, based on preliminary findings that ω3 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 ω3 fatty acids in affecting a TG’s lipolysis vs. how the ω3 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.

急性胰腺炎（AP）在美国每年影响275，000人，是胰腺炎最常见的胃肠病原因。 住院AP的主要发病率和费用来自于10-25%的重症疾病 患者在过去的几年里，高甘油三酯血症（HTG）的比例已经从 <5%，有时>20%的所有AP原因。此外，HTG现在通常与AP共存， 这沿着HTG AP通常导致持续的器官衰竭，并因此导致严重的AP。我们以前的 研究表明，脂肪以甘油三酯（TG）的形式储存在内脏脂肪细胞中，为脂肪酶提供燃料 胰腺出血这种储存的甘油三酯可以被脂肪酶水解成脂肪酸， 然后导致多系统器官衰竭和严重的AP。我们还了解到，这种甘油三酯， 不饱和内脏脂肪比饱和内脏脂肪导致更差的AP结果。在目标1A中，我们将确定TG是否 在某些实施方案中，HTG AP组合物与临床HTG AP发作的严重程度相关。因此， 在马约诊所AZ住院的诊断为AP的患者将在其TG量的背景下进行研究， 入院时的TG组成，以及脂肪分解产生的总脂肪酸和未结合脂肪酸。在目标1B中指出， 膳食脂肪摄入的组成影响循环TG的组成，我们建议研究如何 通过比较HTG AP的严重程度，饮食TG组成影响HTG AP期间循环TG行为 就其组成而言。在目标1C中，我们将研究PNLIP的基因缺失是否会减少 HTG AP的严重程度。我们还将关注肝素作为释放LPL的试剂的使用，例如当 在HTG AP管理期间用作血浆置换的抗凝剂。临床文献显示 在这些情况下使用肝素的结果更糟，我们的初步数据显示肝素 当TG不饱和时，加速脂肪酸生成并抑制HTG的结果。目的2 重点是关于为什么ω6和ω9不饱和甘油三酯是一种更危险的甘油三酯形式的机制 在胰腺炎期间。在目的1A中，基于ω3和饱和脂肪酸干扰细胞增殖的初步发现， 水解的甘油三酯含有他们，我们建议研究的分子基础和能量学如何 TG的组成影响其通过胰甘油三酯脂肪酶（PNLIP）和脂蛋白脂肪酶（LPL）的脂解作用。在 目的2B基于先前的工作表明，不饱和脂肪酸比饱和脂肪酸造成更多的伤害， 酸，我们建议研究不饱和脂肪酸中的双键如何影响其在水溶液中的行为。 像我们这样的环境。最后，在目标2C中，我们将确定ω3脂肪酸在影响TG脂解中的作用 vs.ω3键如何影响NEFA在细胞信号传导中的行为。目标2的结果将解释 甘油三酯组成在确定HTG AP严重程度中的作用。总体而言，这些研究将提供新的 HTG和HTG AP的发病机制和结局，沿着临床相关， 科学合理的方法来改善这些结果。