Innate immune regulation of hepatic insulin sensitivity and metabolism

肝脏胰岛素敏感性和代谢的先天免疫调节

基本信息

批准号：
10654806
负责人：
Suraj J Patel
金额：
$ 16.47万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654806
关键词：
Adipose tissue Alleles Binding Body Weight Cell model Cells Ceramides ChIP-seq Chronic Coculture Techniques Complex Data Data Set Dedications Development Endocrinology Ensure Environment FDA approved Fatty Liver Fatty acid glycerol esters Foundations Functional disorder Gastroenterology Genes Genetic Transcription Genomics Glucose Clamp Goals Health Hepatic Hepatocyte Hepatology High Fat Diet Hyperinsulinism IRF3 gene ISG15 gene Inflammation Inflammatory Inflammatory Response Insulin Resistance Interferons Joints Kupffer Cells Laboratories Link Liver Liver diseases LoxP-flanked allele Macrophage Mediating Metabolic Metabolic Control Metabolic dysfunction Metabolism Mus Natural Immunity Obesity Overnutrition Pathway interactions Patients Phenocopy Phosphorylation Phosphotransferases Physiological Physiology Play Protein Phosphatase 2A Regulatory Subunit PR53 Proto-Oncogene Proteins c-akt Research Research Personnel Resources Role System TBK1 gene Techniques Testing Thermogenesis Tracer Transcriptional Regulation Work career career development chronic liver disease epigenomics gain of function genomic locus immune function immunoregulation improved in vitro Model insulin sensitivity insulin signaling interest loss of function non-alcoholic fatty liver disease novel strategies programs success transcription factor transcriptome

项目摘要

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.

非酒精性脂肪肝病（NAFLD）是最常见的慢性肝病世界范围内，目前尚无 FDA 批准的治疗方法。虽然 NAFLD 的病理生理学很复杂，越来越多的证据支持 NAFLD 的核心作用慢性炎症会破坏胰岛素信号传导和正常的肝脏代谢功能。然而，我们对炎症转录机制的理解引发代谢功能障碍的机制仍然不完全。干扰素调节因子 (IRF) 是与免疫的几乎所有方面有关的转录因子功能。我们的实验室已识别并表征了许多串扰点 IRF 与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生热作用。在这里，我们展示了高脂肪饮食会激活肝脏 IRF3，而全身缺乏 IRF3 可以预防这两种疾病肝脏胰岛素抵抗和脂肪变性。通过产生携带 flox 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 建立胰岛素抵抗并巨噬细胞IRF3促进脂肪变性。我们假设 IRF3 处于临界状态肝脏代谢和炎症反应之间的联系，并起着因果作用作为转录调节剂在肝胰岛素抵抗的发展中的作用 NAFLD 中的脂肪变性。 K08 的科学目标是 1) 确定肝细胞如何 IRF3 调节胰岛素信号传导，2) 定义库普弗细胞 IRF3 在胰岛素信号传导中的精确作用促进脂肪变性。这些研究的长期目标是改善新陈代谢通过操纵炎症途径和转录程序来保证患者的健康在肝脏中。