Innate immune regulation of hepatic insulin sensitivity and metabolism

非酒精性脂肪肝(NAFLD)是中国最常见的慢性肝病 目前还没有FDA批准的治疗方法。而当 NAFLD的病理生理学是复杂的，越来越多的证据支持 破坏胰岛素信号和正常肝脏代谢功能的慢性炎症。 然而，我们对炎症的转录机制的理解 引发代谢功能障碍仍不完全。干扰素调节因子(IRF) 转录因子几乎涉及免疫的方方面面 功能。我们的实验室已经确定并表征了许多串扰点 IRFs和营养过剩的代谢影响之间的关系，包括发现 IRF3控制脂肪组织炎症和产热。在这里，我们展示了它的高度 脂肪饮食激活肝脏IRF3，而IRF3全身缺陷对两者都有保护作用 肝脏胰岛素抵抗和脂肪变性。通过产生携带牙线或牙线的老鼠 我们证明了肥胖诱导肝脏IRF3激活 在2-细胞模型中工作，其中肝细胞IRF3建立胰岛素抵抗和 巨噬细胞IRF3促进脂肪变性。我们假设IRF3处于临界状态 肝脏中代谢反应和炎症反应之间的连接，并起到因果作用 作为转录调节因子在肝脏胰岛素抵抗的发生和发展中的作用 非酒精性脂肪肝的脂肪变性。K08的科学目的是1)确定肝细胞如何 IRF3调节胰岛素信号转导；2)确定Kupffer细胞IRF3在胰岛素信号传导中的确切作用。 促进脂肪变性。这些研究的长期目标是改善新陈代谢 通过操纵炎症通路和转录程序来保护患者的健康 在肝脏里。

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.