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（由申请人证明）：肝病的主要原因是全球的肝脏疾病和肠道肝脏的肝病紧密的连接素，增强抗菌剂防御能力，维生素D靶向骨质蛋白使用维生素D和牛奶骨桥蛋白可能的肝损伤的治疗。从肠道循环中的革兰氏阴性菌，从而降低了脂多糖水平； ，E将开发新的酒精性肝炎的体内模型，以进一步了解D或牛奶骨the的机制。 D和牛奶骨座蛋白在肠道渗透性，细菌易位和IDE的可用性中阻止etranol-甲醇。脂多糖降低了kupffer细胞的活化，以及其他硫酸含硫酸钠或脂多糖钠的生产。接下来，我们将确定维生素D和牛奶骨质蛋白是通过激活自噬途径而不是靶向细菌易位或结合脂多糖来减少脂肪的。牛奶骨桥蛋白可能是减慢降低或曲酚脂肪炎的有效治疗策略。