Milk osteopontin, a nutritional therapeutic intervention for alcoholic hepatitis

牛奶骨桥蛋白，酒精性肝炎的营养治疗干预措施

• 批准号: 9025179
• 负责人: Natalia Nieto
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9025179
• 关键词: Milk; osteopontin; nutritional; therapeutic; intervention

DESCRIPTION (provided by applicant): Alcoholic hepatitis is a leading cause of liver disease and death worldwide; thus, there is an urgent need to develop novel therapeutic interventions. Key events for the onset and progression of alcoholic hepatitis result from the gut-to-liver interaction. Vitamin D deficiency is highly prevalent in patients with alcoholic hepatitis. VitaminD supplementation regulates the expression of tight junction proteins, enhances antimicrobial defenses and reduces proinflammatory cytokines in the gut. Vitamin D targets osteopontin via a vitamin D-responsive element in the osteopontin promoter. Milk osteopontin protects the gut by maintaining the epithelial barrier function, providing mucosal defense, preventing sepsis and the inflammatory response. So far, a link between vitamin D and osteopontin in protecting from alcoholic hepatitis has not been established. We believe that nutritional therapy using vitamin D and milk osteopontin could protect from alcohol-induced liver injury. In this Application we will focus on testing the Central Hypothesis "Dietary supplementation with vitamin D or milk osteopontin could prevent alcoholic hepatitis due to the gut protective and antisteatotic actions of osteopontin". In particular, we hypothesize that vitamin D and milk osteopontin will: 1) Target the gut-liver axis protecting the intestinal mucosal barrier and blocking the translocation of Gram-negative bacteria from the gut into the portal circulation thus lowering lipopolysaccharide levels; 2) Prevent steatosis and liver injury by targeting fatty acid metabolism and decreasing lipopolysaccharide-mediated Kupffer cell activation and TNF� production; and 3) Avert hepatic steatosis, inflammation and liver injury by increasing autophagy, a recently identified pathway regulating steatosis. We will develop new in vivo models of alcoholic hepatitis to further our understanding of the mechanisms of liver injury. Using these models, mice will be treated with vitamin D or milk osteopontin to assess their therapeutic potential. To prove our hypothesis we plan three Specific Aims. In Aim 1, we will analyze if vitamin D and milk osteopontin block the ethanol-mediated increase in gut permeability, bacterial translocation and lipopolysaccharide availability. The chronic Lieber-DeCarli model along with dextran sodium sulfate treatment will be used. In Aim 2, first, we will determine whether vitamin D and milk osteopontin blunt steatosis by targeting fatty acid metabolism; and second, we will dissect if the ability of osteopontin to bind lipopolysaccharide lowers Kupffer cell activation, TNF� production as well as other pro-inflammatory cytokines. The chronic Lieber-DeCarli model along with dextran sodium sulfate or lipopolysaccharide treatment will be used. In Aim 3, a new model of alcoholic hepatitis based on autophagy blockade will be developed. Next, we will identify if vitamin D and milk osteopontin reduce steatosis by activating the autophagy pathway independent of targeting bacterial translocation or binding lipopolysaccharide. Thus, the Overall Goal of this Application is to investigate whether dietary administration of vitamin D and milk osteopontin could be an efficient low-cost therapeutic strategy for slowing down or preventing the progression of alcoholic hepatitis.

描述（由申请人提供）：酒精性肝炎是全世界肝病和死亡的主要原因；因此，迫切需要开发新的治疗干预措施，以应对酒精性肝炎从肠道到肝脏的发病和进展。维生素 D 缺乏症在酒精性肝炎患者中非常普遍，补充维生素 D 可调节紧密连接蛋白的表达，增强抗菌防御并减少肠道内促炎性细胞因子。通过骨桥蛋白启动子中的维生素 D 反应元件，牛奶骨桥蛋白通过维持上皮屏障功能、提供粘膜防御、预防败血症和炎症反应来保护肠道。迄今为止，维生素 D 和骨桥蛋白在预防酒精性肝炎方面存在联系。我们相信使用维生素 D 和牛奶骨桥蛋白的营养疗法可以预防酒精引起的肝损伤。在本申请中，我们将重点测试中心假设“饮食”。由于骨桥蛋白具有肠道保护和抗脂肪变性作用，补充维生素 D 或牛奶骨桥蛋白可以预防酒精性肝炎。特别是，我们发现维生素 D 和牛奶骨桥蛋白将： 1) 靶向肠肝轴，保护肠粘膜屏障和阻止革兰氏阴性菌从肠道转移到门静脉循环，从而降低脂多糖水平 2) 通过靶向脂肪酸代谢和减少脂多糖水平来预防脂肪变性和肝损伤；脂多糖介导的 Kupffer 细胞激活和 TNFα 产生；3) 通过增加自噬（最近发现的调节脂肪变性的途径）避免肝脏脂肪变性、炎症和肝损伤。我们将开发新的酒精性肝炎体内模型，以进一步了解其机制。为了证明我们的假设，我们在目标 1 中计划了三个具体目标。将分析维生素 D 和牛奶骨桥蛋白是否会阻断乙醇介导的肠道通透性、细菌易位和脂多糖可用性的增加。在目标 2 中，我们将首先确定是否使用慢性 Lieber-DeCarli 模型和葡聚糖硫酸钠治疗。维生素D和牛奶骨桥蛋白通过靶向脂肪酸代谢来钝化脂肪变性；其次，我们将剖析骨桥蛋白结合脂多糖的能力是否降低；在目标 3 中，将使用基于自噬阻断的慢性 Lieber-DeCarli 模型以及葡聚糖硫酸钠或脂多糖治疗。接下来，我们将确定维生素 D 和乳骨桥蛋白是否通过激活自噬途径来减少脂肪变性，而与靶向细菌易位或结合无关。因此，本申请的总体目标是研究通过饮食摄入维生素 D 和牛奶骨桥蛋白是否可以成为减缓或预防酒精性肝炎进展的有效低成本治疗策略。