Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression

肥大细胞/胆管细胞对非酒精性脂肪肝疾病进展的调节机制

• 批准号: 10410390
• 负责人: Heather L Francis
• 金额: $ 35.23万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410390
• 关键词: Adipose tissue; Alcohols; Automobile Driving; Bile fluid; Biliary; Cells; Cholangiocarcinoma; Cholestasis; Cholesterol; Chymase; Cicatrix; Complication; Consumption; Coupled; Cromolyn Sodium; Data; Deposition; Developed Countries; Diet; Disease; Disease Progression; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Fructose; Genetic Models; Glucose Intolerance; Hepatic; Hepatic Stellate Cell; Hepatitis; Hepatocyte; High Fat Diet; Histamine; Histamine Receptor; Hypertriglyceridemia; IgE; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Knock-out; Kupffer Cells; Left; Life Style; Lipoproteins; Liver; Liver Fibrosis; Liver diseases; Mediator of activation protein; Metabolic syndrome; Methionine; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Pharmacologic Substance; Phenotype; Plasma; Play; Publications; Reaction; Receptor Activation; Regulation; Risk; Role; Signal Transduction; Steatohepatitis; Therapeutic; Triglycerides; Wild Type Mouse; Work; bile duct; cell motility; cholangiocyte; choline deficient diet; chronic liver disease; diabetic; end stage liver disease; in vivo; inflammatory milieu; lipidomics; liver inflammation; liver injury; mast cell; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obese patients; paracrine; primary sclerosing cholangitis; protease E; recruit; senescence; western diet

Non-alcoholic fatty liver disease (NAFLD) develops as a result of fat deposited into the liver (steatosis) caused by other factors aside from alcohol; and, NAFLD is now the most common liver disease in Western developed countries. If left untreated or if another insult occurs (“two-hit” hypothesis), NAFLD can develop into NASH. While hepatocytes are believed to be the primary cell involved in NAFLD, new studies have demonstrated that both cholangiocytes and mast cells (MCs) contribute to NAFLD progression and potentially to NAFLDèNASH transition. Further, damaged cholangiocytes undergo senescence and take on a senescence-associated secretory phenotype (SASP), which may also contribute to the inflammatory environment seen in NASH. MCs are found in adipose tissue of obese patients and histamine levels are increased in patients with NAFLD, NASH and end-stage liver disease. To date, no successful treatments have been developed for NAFLD, aside from altering diet and lifestyle; and, there have been no studies to examine the potential paracrine interaction between cholangiocytes and MCs in models of NAFLD. Further, the synergistic relationship between MCs, cholangiocytes, hepatic stellate cells (HSCs) and Kupffer cells has not been fully examined. The premise of the study is supported by: (i) previous work demonstrating that both cholangiocytes and MCs contribute to NAFLD; (ii) work from the PI demonstrating that MCs contribute to liver damage and are critical regulators of disease progression; and, (iii) preliminary data showing that there is a direct interaction between cholangiocytes and MCs that influences hepatic damage, Kupffer cell activation/inflammation and HSC-driven fibrosis during NAFLD. In SA1, the PI will examine biliary-induced MC migration using mice subjected to HFD/HFCS and Vivo-Morpholino treatments to inhibit biliary senescence. This aim will focus primarily on the interactions between cholangiocytes and MCs. SA2 will focus on the contribution of MCs to NAFLD progression by using a genetic model of MC depletion and also reintroduction of MCs. These studies allow us to examine the effects of losing MCs, but also to determine if MCs perpetuate NAFLD progression and potentially NAFLD to NASH transition (marked by enhanced liver inflammation). Finally, in SA3, the PI will focus on the inhibition of MC-derived histamine and TGF-b1 using pharmaceutical inhibition to directly target this inflammatory molecule. Preliminary data and previous publications reveal that TGF-b1 may be a key modulator of NAFLD and liver damage (including fibrosis); and, MC-derived histamine regulates TGF-b1 expression and secretion. In all of proposed aims, the PI will evaluate NAFLD induced by both Western Diet (HFD/HFCS) and the methionine-choline deficient (MCD) diet. In addition, features of metabolic syndrome including insulin resistance, elevated triglycerides, lipoprotein abnormalities, and glucose intolerance will be evaluated. Targeting MC mediators may be a beneficial therapeutic approach to managing NAFLD progression.!

非酒精性脂肪肝病（NAFLD）由于沉积在肝脏中（脂肪变性）而形成 除了酒精外，其他因素；而且，NAFLD现在是西方最常见的肝病 国家。如果未经治疗或发生其他伤害（“两击”假设），则NAFLD可以发展为NASH。 虽然认为肝细胞是NAFLD涉及的主要细胞，但新研究表明， 胆管细胞和肥大细胞（MC）都有助于NAFLD进展，并有可能促进Nafldènash 过渡。此外，受损受损的胆管细胞会受到感应并进行感应相关的 秘书表型（SASP）也可能有助于纳什（Nash）中看到的炎症环境。 MCS 在肥胖患者的脂肪组织中发现，NAFLD患者的组胺水平有所增加， 纳什和终末期肝病。迄今为止，尚未为NAFLD开发成功的治疗方法 除了改变饮食和生活方式；而且，没有研究来检查潜力 NAFLD模型中胆管细胞和MC之间的旁分泌相互作用。此外，协同作用 MC，胆管细胞，肝星状细胞（HSC）和库普弗细胞之间的关系尚未完全 检查。该研究的前提得到：（i）以前的工作证明了这两个胆管细胞 MC为NAFLD做出了贡献； （ii）PI的工作表明MC有助于肝脏损害，并且是 疾病进展的关键调节因子；以及（iii）初步数据，显示存在直接相互作用 在影响肝炎损伤的胆管细胞和MC之间，库普弗细胞激活/炎症和 NAFLD期间HSC驱动的纤维化。在SA1中，PI将使用小鼠检查胆道诱导的MC迁移 经过HFD/HFC和体内 - 多球治疗以抑制胆道的感应。这个目标将集中 首先是胆管细胞与MC之间的相互作用。 SA2将专注于MC对 NAFLD通过使用MC部署的遗传模型以及重新引入MC的进展。这些研究 允许我们检查失去MC的影响，也可以确定MC是否会延续NAFLD的进展和 可能是NAFLD到NASH过渡（以增强的肝脏注射为标志）。最后，在SA3中，PI将 使用药物抑制直接靶向MC衍生的组胺和TGF-B1抑制MC衍生的组胺和TGF-B1 这种炎症分子。初步数据和以前的出版物表明，TGF-B1可能是关键 NAFLD和肝损伤的调节剂（包括纤维化）；并且，MC衍生的组胺调节TGF-B1 表达和分泌。在所有拟议的目标中，PI将评估两种西方饮食诱导的NAFLD （HFD/HFC）和胆碱缺乏（MCD）饮食。此外，代谢综合征的特征 包括胰岛素抵抗，甘油三酸酯升高，脂蛋白异常和葡萄糖耐药性 评估。针对MC调解人可能是管理NAFLD的一种有益的疗法 进展。！