Innate immune regulation of hepatic insulin sensitivity and metabolism

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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.