Regulation and Function of Thioredoxin Interacting Protein (Txnip) in Nonalcoholic Steatohepatitis (NASH)

项目总结 非酒精性脂肪性肝病(NAFLD)的全球流行已成为对 公共卫生。目前NAFLD的治疗选择极其有限，特别是其严重的形式- 非酒精性脂肪性肝炎(NASH)，没有FDA批准的治疗方法。迫切需要找出 NASH治疗的新治疗靶点。硫氧还蛋白相互作用蛋白(TXNIP)是一种应激诱导基因， 而且它也与纳什有牵连。然而，TXNIP在NASH中的作用存在争议，这可能是由于 以下两个问题。首先，在TXNIP基因座上有两个基因：TXNIP和TXNIP反义Long 非编码RNA Gm15441。TXNIP的基因缺失也会导致Gm15441的部分缺失。第二，TXNIP播放 在其他新陈代谢器官中的关键作用，这干扰了它在肝脏中的功能。因此，以往的研究 使用TXNIP全局基因敲除的小鼠不能揭示TXNIP在NASH中的肝脏特异性作用。我们的预赛 数据表明，TXNIP蛋白在NASH小鼠肝脏中异常积聚。我们的初步研究 提示TXNIP有促进肝细胞凋亡的作用。鉴于过度的肝细胞凋亡会导致 NASH的发生，因此，我们提出了一个中心假设，即抑制肝脏TXNIP可以缓解NASH。 在目标1中，将开发一种基于反义RNA的TXNIP翻译抑制剂用于NASH治疗。在目标2中， 我们将剖析TXNIP在NASH小鼠肝脏中的功能作用和机制。在目标3中，我们将调查一个 导致TXNIP蛋白在NASH小鼠肝脏积聚的新机制。完成这项提案将 提供对TXNIP在NASH开发中的功能和机制的重要见解。这些研究将 也导致了NASH治疗的新治疗策略的发展。

PROJECT SUMMARY The worldwide epidemic of nonalcoholic fatty liver disease (NAFLD) has become a severe and costly threat to public health. The current therapeutic options for NAFLD are exceedingly limited, especially for its severe form - nonalcoholic steatohepatitis (NASH), which has no FDA-approved therapy. There is an urgent need to identify novel therapeutic targets for NASH treatment. Thioredoxin interacting protein (Txnip) is a stress-induced gene, and it has been implicated in NASH. However, the role of Txnip in NASH is controversial, which may be attributed to the following two issues. Firstly, there are two genes in the Txnip gene locus: Txnip and Txnip antisense long non-coding RNA Gm15441. Genetic deletion of Txnip also deletes part of Gm15441. Secondly, Txnip plays critical roles in other metabolic organs, which interferes with its function in the liver. Therefore, previous studies using Txnip global knockout mice were not able to reveal the liver-specific role of Txnip in NASH. Our preliminary data demonstrate that Txnip protein is abnormally accumulated in NASH mouse livers. Our preliminary studies also suggest that Txnip may promote hepatocyte apoptosis. Given that excessive hepatocyte apoptosis drives NASH development, therefore, we propose a central hypothesis that inhibition of hepatic Txnip alleviates NASH. In Aim 1, an antisense RNA based Txnip translational inhibitor will be developed for NASH treatment. In Aim 2, we will dissect the functional role and mechanism of Txnip in NASH mouse liver. In Aim 3, we will investigate a novel mechanism that causes Txnip protein accumulation in NASH mouse liver. Completion of this proposal will provide critical insights into the functions and mechanisms of Txnip in NASH development. These studies will also lead to the development of novel therapeutic strategies for NASH treatment.