Innate immune regulation of hepatic insulin sensitivity and metabolism

非酒精性脂肪性肝病（NAFLD）是美国最常见的慢性肝病。 目前还没有FDA批准的治疗方法。而 NAFLD的病理生理学是复杂的，越来越多的证据支持 慢性炎症破坏胰岛素信号传导和正常的肝脏代谢功能。 然而，我们对炎症的转录机制的理解， 代谢功能障碍的触发因素仍然不完全。干扰素调节因子 是几乎涉及免疫系统所有方面的转录因子， 功能我们的实验室已经确定并表征了许多串扰点 IRFs和营养过剩的代谢效应之间的关系，包括发现， IRF3控制脂肪组织炎症和产热。在这里，我们展示了 脂肪饮食激活肝脏IRF3，而全身IRF3的缺乏可以保护肝脏和肝脏。 肝胰岛素抵抗和脂肪变性。通过产生携带floxed或 组成型活性Irf3等位基因，我们证明肥胖诱导的肝脏IRF3激活， 在2细胞模型中运行，其中肝细胞IRF3建立胰岛素抵抗， 巨噬细胞IRF3促进脂肪变性。我们假设IRF3位于一个关键的 肝脏代谢和炎症反应之间的结合，并发挥因果作用 在肝胰岛素抵抗的发展中作为转录调节因子的作用， NAFLD中的脂肪变性。本K08的科学目的是1）确定肝细胞如何 IRF3调节胰岛素信号传导，和2）确定库普弗细胞IRF3在胰岛素分泌中的确切作用。 促进脂肪变性。这些研究的长期目标是改善代谢 通过操纵炎症通路和转录程序来改善患者的健康 在肝脏中。

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and currently has no FDA-approved therapies for treatment. While the pathophysiology of NAFLD is complex, mounting evidence supports a central role for chronic inflammation in disrupting insulin signaling and normal liver metabolic function. Our understanding, however, of the transcriptional mechanisms by which inflammation triggers metabolic dysfunction remains incomplete. Interferon regulatory factors (IRFs) are transcription factors that have been implicated in nearly all aspect of immune function. Our laboratory has identified and characterized numerous points of crosstalk between IRFs and the metabolic effects of overnutrition, including the discovery that IRF3 controls adipose tissue inflammation and thermogenesis. Here, we show that high fat diet activates liver IRF3, and that whole body deficiency in IRF3 protects against both hepatic insulin resistance and steatosis. By generating mice carrying a floxed or constitutively active Irf3 allele, we demonstrate that obesity-induced liver IRF3 activation operates in a 2-cell model, where hepatocyte IRF3 establishes insulin resistance and macrophage IRF3 promotes steatosis. We hypothesize that IRF3 sits at a critical junction between metabolic and inflammatory responses in the liver, and plays a causal role as a transcriptional regulator in the development of hepatic insulin resistance and steatosis in NAFLD. The scientific aims of this K08 are to 1) identify how hepatocyte IRF3 regulates insulin signaling, and 2) to define the precise role of Kupffer cell IRF3 in promoting steatosis. The long-term goal of these studies is to improve the metabolic health of patients by manipulating inflammatory pathways and transcriptional programs in the liver.