# Interrogating Liver Macrophage LXR Signaling in Health and Non-Alcoholic Fatty Liver Disease

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $37,997

## Abstract

Project Summary:
The mechanisms that drive the behavior of hepatic macrophages in homeostasis and disease are poorly
understood. The liver X receptor (LXR) transcription factors are highly expressed in hepatic macrophages
and hepatocytes. While in hepatocytes LXR signaling controls cholesterol metabolism, macrophage LXR
signaling regulates both cholesterol metabolism and inflammation, processes that are central to the
pathogenesis of non-alcoholic steatohepatitis (NASH). Activation of LXRs represses inflammation by
interfering with nuclear factor κ (NFκ) activation. NFκ is a downstream target of multiple NASH signaling
pathways, including toll-like-receptors, interleukin-1, and tumor-necrosis factor 
The central hypothesis of this proposal is that loss of LXR signaling in liver macrophages will block LXR
mediated inhibition of inflammatory signaling and worsen NASH progression. Prior research by the Glass
lab has demonstrated that LXR is highly expressed in Kupffer cells (the resident macrophages of the liver)
and rapidly upregulated in bone marrow derived macrophages upon entry into both healthy and NASH livers.
This led to the hypothesis that loss of LXR in Kupffer cells would worsen NASH phenotypes in mice with
metabolic disease via increased NFκ signaling. A pilot study was performed to examine the effect of
myeloid-lineage-specific LXR deletion in NASH. In this study mice lacking myeloid LXR fed a NASH-
model diet for 20 weeks demonstrated increased hepatic fibrosis, and hepatic inflammatory gene
expression. However, whether this effect is due to loss of LXR in Kupffer cells or other hepatic macrophage
populations present during NASH is unknown.
Aim 1 will test whether loss of LXR signaling in Kupffer cells increases hepatic fibrosis and worsens
NASH progression. Serum markers of inflammation, liver damage, and cholesterol metabolism and hepatic
histopathology will be used to assess the effect of myeloid-specific or Kupffer cell-specific LXR knockout
during NASH. ChIP-seq, ATAC-seq, and RNA-seq will be used on two novel mouse strains to
mechanistically assess whether loss of LXR signaling alters inflammation in different hepatic macrophage
populations during NASH. Aim 2 will test whether hepatic desmosterol is the native LXR ligand in
Kupffer cells. Studies in this aim will utilize a newly developed transgenic mouse to assess the effects of
hepatic desmosterol depletion on Kupffer cell transcription both at homeostasis and during NASH. If
successful, these studies could identify a new myeloid specific molecular target for the treatment or
prevention of NASH.

## Key facts

- **NIH application ID:** 10068922
- **Project number:** 1F30DK124980-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Hunter R. Bennett
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,997
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068922

## Citation

> US National Institutes of Health, RePORTER application 10068922, Interrogating Liver Macrophage LXR Signaling in Health and Non-Alcoholic Fatty Liver Disease (1F30DK124980-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10068922. Licensed CC0.

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