# Innate immune regulation of hepatic insulin sensitivity and metabolism

> **NIH NIH K08** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $166,524

## Abstract

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.

## Key facts

- **NIH application ID:** 10039392
- **Project number:** 1K08DK125762-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Suraj J Patel
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $166,524
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10039392

## Citation

> US National Institutes of Health, RePORTER application 10039392, Innate immune regulation of hepatic insulin sensitivity and metabolism (1K08DK125762-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10039392. Licensed CC0.

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