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

非酒精性脂肪性肝病（NAFLD）是由于脂肪沉积到肝脏（脂肪变性）引起的。 除酒精外，其他因素也会影响NAFLD;而且，NAFLD现在是西方发达国家最常见的肝病。 国家如果不治疗或发生另一种损伤（“两次打击”假设），NAFLD可发展为NASH。 虽然肝细胞被认为是参与NAFLD的主要细胞，但新的研究表明， 胆管细胞和肥大细胞（MC）均促进NAFLD进展，并可能导致NAFLD？NASH 过渡此外，受损的胆管细胞经历衰老，并呈现衰老相关的凋亡。 分泌表型（SASP），这也可能有助于NASH中观察到的炎症环境。MCS 在肥胖患者的脂肪组织中发现，并且在NAFLD患者中组胺水平增加， NASH和终末期肝病。迄今为止，还没有成功的治疗NAFLD的方法， 除了改变饮食和生活方式之外;而且，还没有研究来检查潜在的 NAFLD模型中胆管细胞和MC之间的旁分泌相互作用。此外，协同 MC、胆管细胞、肝星状细胞（HSC）和枯否细胞之间的关系尚未完全阐明， 考察这项研究的前提是支持：（i）以前的工作表明，胆管细胞， 和MC导致NAFLD;（ii）PI的工作表明MC导致肝损伤， 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 影响肝损伤、枯否细胞活化/炎症和 NAFLD期间HSC驱动的纤维化。在SA 1中，PI将使用小鼠检查胆汁诱导的MC迁移 进行HFD/HFCS和Vivo-Morpholino处理以抑制胆汁衰老。这一目标将侧重于 主要是胆管细胞和MC之间的相互作用。SA 2将重点关注MC对以下方面的贡献： 通过使用MC耗竭和MC再引入的遗传模型的NAFLD进展。这些研究 使我们能够检查失去MC的影响，但也可以确定MC是否使NAFLD进展永久化， 潜在的NAFLD向NASH的转变（以增强的肝脏炎症为标志）。最后，在SA 3中，PI将 专注于抑制MC衍生的组胺和TGF-β 1使用药物抑制直接靶向 这种炎症分子。初步数据和以前的出版物显示，TGF-β 1可能是一个关键， NAFLD和肝损伤（包括纤维化）的调节剂; MC衍生的组胺调节TGF-β 1 表达和分泌。在所有提出的目标中，PI将评价西方饮食诱导的NAFLD (HFD/HFCS）和蛋氨酸-胆碱缺乏（MCD）饮食。此外，代谢综合征的特征 包括胰岛素抵抗、甘油三酯升高、脂蛋白异常和葡萄糖耐受不良， 评估。靶向MC介质可能是管理NAFLD的有益治疗方法 进步！

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.!