# LXRs Link Lipid Metabolism and Inflammation

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $377,403

## Abstract

Project Summary:
 Inflammation plays a role in the response to pathogens and in the etiology of chronic diseases including
atherosclerosis, diabetes and Alzheimer’s disease. Not surprisingly, strategies to inhibit the inflammatory
response and promote resolution of inflammation are being explored for therapeutic benefit. Recent studies
have demonstrated that the response of immune cells to pro- and anti-inflammatory signals is associated with
changes in lipid metabolism. Activation of toll-like receptor 4 (TLR4) in macrophages leads to a rapid and
transient inhibition of fatty acid synthesis that is followed by a later increase in the synthesis of long chain
unsaturated fatty acids. Importantly, fatty acid synthesis at later stages of the inflammatory response has been
suggested to play a role in resolving inflammation. The signaling pathways that couple lipid metabolism to
inflammation, however, are still being defined.
 The liver X receptors LXR and LXR are members of the nuclear hormone receptor superfamily of
ligand activated transcription factors that control genetic networks involved in fatty acid and cholesterol
metabolism. We have uncovered a previously unexplored link between LXR activity and inflammatory
signaling. Our data indicates that TLR activation leads to up-regulation of LXR expression in a type I interferon-
dependent manner at relatively late stages of the inflammatory response. Signal transducer and activator of
transcription 1 (STAT1), an interferon stimulated transcription factor, appears to be necessary for the LXR
induction. LXRs are subsequently required for the proper shutdown of type I interferon stimulated gene
expression. We hypothesize that LXRs interfere with STAT1 transcriptional activity and contribute to a
negative feedback loop that plays a role in resolution of the inflammatory response. Concurrently there
is an LXR-dependent increase in gene expression associated with the generation of long chain unsaturated
fatty acids with reported anti-inflammatory activity. We propose that the effect of LXRs on fatty acid
synthesis requires cooperation with sterol regulatory element binding protein 1 (SREBP1), a second
transcriptional regulator of fatty acid synthesis. Furthermore we propose that SREBP1 activity can be regulated
via interferon-dependent control of the mammalian target of rapamycin (mTOR). Thus type I interferons
integrate LXR and mTOR signaling pathways to establish a specific gene expression network that contributes
to resolution of the inflammatory response. The goals of the proposed studies are to define the pathway that
controls the inflammation-dependent activation of fatty acid synthesis and to determine the LXR-dependent
pathway that shuts down type I interferon signaling. We anticipate that these studies will define a novel
interface between lipid metabolism and the inflammatory response and may provide new approaches to
promote the resolution of inflammation.

## Key facts

- **NIH application ID:** 9980385
- **Project number:** 5R01DK119182-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Ira G Schulman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,403
- **Award type:** 5
- **Project period:** 2019-07-18 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980385

## Citation

> US National Institutes of Health, RePORTER application 9980385, LXRs Link Lipid Metabolism and Inflammation (5R01DK119182-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980385. Licensed CC0.

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