Molecular Regulation of Hepatic Transporters

肝脏对炎症反应的中心特征之一是抑制一系列广泛的 核心生理功能，包括维持胆汁酸的肝胆运输所必需的功能。在……里面 除了对转运蛋白膜表达和功能的翻译后调节外， 基于炎症的细胞信号通路作用于核靶点，从转录上抑制 胆汁酸转运蛋白Ntcp和Bsep的表达中央型NR超家族 成员和异源二聚体伙伴RXRA是这两个基因的主要转录激活因子，其 以炎症为基础的细胞信号会迅速抑制核活动。RXRA靶基因缺失 表达可导致多种功能损害和肝细胞损伤。细胞信号如何 抑制RXRA功能的途径尚不清楚，并形成了探索和干预的基础 在本申请中提出的。总体的统一假设是炎性细胞信号通路 通过翻译后修饰、核出口的协调级联来降低RXRA的核活性 和蛋白酶体的降解。以下四个目标将决定潜在的生理学，以及 炎症介导的胆汁淤积的病理生理学和探索新的治疗方法。 目的1：明确IL-1(3)诱导RXRA核输出的分子机制。 目的2：确定IL-1IB-1对RXRA泛素化和蛋白酶体降解的影响。 诱导的信号通路。 目的3：探讨胆汁酸和IL-1p介导的调节RXRA功能的信号通路之间的串扰。 目的4：探讨抗炎药物对血管转运蛋白基因和蛋白表达的影响。 肝脏炎症的IPS模型。 它是通过体外和体内相结合的方法，我们可以探索机制，介体和 旨在恢复RXRA功能、肝胆转运体功能的潜在治疗干预措施 胆汁流动，在肝脏炎症介导的细胞信号传递的背景下。这些研究的最终目标是 提供合理的分子靶点，用于测试专门设计的干扰 炎症介导的途径的破坏性后果，这些途径参与了几乎所有形式的急性 和慢性肝病。

One of the central features of the hepatic response to inflammation is the suppression of a broad array of core physiological functions, including those essential to maintaining hepatobiliary transport of bile acids. In addition to post-translational regulation of transporter protein membrane expression and function, inflammation-based cell signaling pathways act on nuclear targets to transcriptionally suppress the expression of the essential bile acid transporters Ntcp and Bsep. The central Type II NR superfamily member and heterodimer partner RXRa is a major transcriptional activator of these two genes, and its nuclear activity is rapidly suppressed by inflammation-based cell signaling. Reduced RXRa target gene expression leads to multiple functional impairments and damage to hepatocytes. How cell signaling pathways suppress RXRa function is unknown, and forms the basis for the explorations and interventions proposed in this application. The overall unifying hypothesis is that inflammatory cell signaling pathways reduce nuclear activity of RXRa via a coordinated cascade of post-translational modification, nuclear export and proteasomal degradation. The following four Aims will determine the underlying physiology, and pathophysiology of inflammation-mediated cholestasis and explore novel therapeutics. Aim 1: Define the molecular mechanisms mediating IL-1(3-induced nuclear export of RXRa. Aim 2: Determine roles for ubiquitination and proteasomal degradation of RXRa in response to IL-1 IB- induced signaling pathways. Aim 3: Explore crosstalk between bile acid and IL-1p-mediated pathways that modify RXRa function. Aim 4: Investigate the effects of anti-inflammatory agents on transporter gene and protein expression in the IPS model of hepatic inflammation. It is through a combined in vitro and in vivo approach that we can explore the mechanisms, mediators, and potential therapeutic interventions aimed at restoring RXRa function, hepatobiliary transporter function, and bile flow, in the setting of inflammation-mediated cell signaling in liver. The ultimate goal of these studies is to provide rational molecular targets for the testing of therapies specifically designed to interfere with the damaging consequences of inflammation-mediated pathways, which are engaged in nearly all forms of acute and chronic liver diseases.