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: 10543802
• 负责人: Vijay Prem Singh
• 金额: $ 47.98万
• 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/10543802
• 关键词: Acceleration; Adipocytes; Admission activity; Affect; Anticoagulants; Behavior; Biological; Citrates; Clinic; Clinical; Data; Diagnosis; Dietary Fats; Disease; Environment; Fatty Acids; Fatty acid glycerol esters; Gastroenterology; Generations; Genetic; Heparin; Heterogeneity; Hospitalization; Human; Hydrolysis; Hypertriglyceridemia; Inflammation; Injury; Intake; Lipase; Lipolysis; Literature; Membrane; Methods; Molecular; Morbidity - disease rate; Mus; Nonesterified Fatty Acids; Organ failure; Outcome; Pancreas; Pancreatitis; Pathogenesis; Patient Admission; Patients; Plasma Exchange; Prevalence; Recommendation; 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; body system; 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.

在美国，急性胰腺炎（AP）影响≈275,000/年，是最常见的胃肠病因 住院。 AP的主要发病率和成本来自严重疾病，发生在10-25％ 患者。在过去的几年中，高甘油三酯血症（HTG）的比例因 <5％，有时>所有AP原因的20％。此外，现在通常注意到HTG与AP共存，并且 这与HTG AP一起通常会导致持续的器官衰竭，因此是严重的AP。我们的先前 工作表明，在内脏脂肪细胞中存储为甘油三酸酯（TG）的脂肪为脂肪酶提供燃料 在AP期间从胰腺泄漏。该储存的甘油三酸酯可以用脂肪酶水解为脂肪酸， 然后导致多系统器官衰竭和严重的AP。我们还了解到，这种甘油三酸酯 与饱和的内脏脂肪相比，不饱和导致AP结果差。在AIM 1A中，我们将确定TG是否 组成与临床HTG AP发作的严重程度有关。为此，临床课程 接受AP诊断的梅奥诊所AZ的患者将在TG数量的情况下进行研究， 入院时TG组成，脂解产生的总和未结合的脂肪酸。在AIM 1B中指出 饮食脂肪摄入的组成会影响循环TG的组成，我们建议研究如何研究 饮食TG组成通过比较HTG AP的严重程度来影响HTG AP期间循环TG行为 在AIM 1C中，我们将研究PNLIP的遗传缺失是否会减少 HTG AP的严重程度。我们还将专注于将肝素用作释放LPL的代理，例如 在HTG AP的管理过程中，用作血浆交换的抗凝剂。临床文献显示 在这些情况下使用肝素时的结果更糟，我们的初步数据表明肝素 加速脂肪酸的产生，并在此TG不饱和时会恶化HTG的结果。目标2 重点关注机制，为什么ω6和ω9不饱和甘油三酸酯是甘油三酸酯的风险更大的形式 在胰腺炎期间。在AIM 1A中，基于初步发现，ω3和饱和脂肪酸干扰了 我们提议研究含甘油三酸酯的水解，我们建议研究分子基础和能量学 TGS组成会影响胰甘油三酸酯脂肪酶（PNLIP）和脂蛋白脂肪酶（LPL）的脂解。在 AIM 2B基于以前的工作表明，不饱和脂肪酸比饱和脂肪造成更多的伤害 酸，我们建议研究不饱和脂肪酸中的双键如何影响其在水中的行为 像我们一样的环境。最后，在AIM 2C中，我们将确定ω3脂肪酸在影响TG脂解中的作用 与ω3键在细胞信号传导中如何影响NEFA的行为。 AIM 2的结果将解释 甘油三酸酯组成在确定HTG AP的严重程度中的作用。总的来说，这些研究将提供新颖 HTG和HTG AP的发病机理和结果的基础机制，以及临床相关的， 从科学上讲是改善这些结果的方法。