# Acetyl CoA Carboxylase in the Metabolic Control of Inflammation

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $621,038

## Abstract

SUMMARY - Acetyl CoA Carboxylase in the Metabolic Control of Inflammation
Metabolic adaptation is central to both the induction and resolution of inflammation, and immune cells such as
macrophages must rapidly rewire their cellular metabolism to successfully carry out effector functions. Signaling
through pattern recognition receptors, such as Toll-like and interferon receptors, results in a switch to aerobic
glycolysis and increased glucose demand, with concomitant downregulation of oxidative phosphorylation and
lipid beta-oxidation. Paradoxically, there is also an increase in lipid biosynthesis in response to pathogens, which
results in accumulation of excess lipid in macrophages. Metabolic dysregulation in macrophages results in either
compromised or overshooting immune responses, resulting in devastating outcomes in resolution of infections.
Patients with preexisting conditions such as obesity and diabetes are particularly at risk to inadequately respond
to and resolve viral and bacterial infections. Despite major advances in our understanding of immunometabolism,
the role of de novo lipogenesis and the etiology of metabolic dysregulation in inflammatory macrophages remains
unclear. Our preliminary studies unexpectedly identify Acetyl CoA Carboxylase (ACC) as a key enzyme
regulating the inflammatory response in macrophages, providing an opportunity to investigate the link between
lipid metabolism and inflammatory responses in immune cells. ACC is a central enzyme directly regulating de
novo lipogenesis as well as indirectly affecting transcriptional capacity by regulating acetyl-CoA levels and thus
histone acetylation and chromatin accessibility. ACC inhibitors (Firsocostat) are used in clinical trials against
non-alcoholic steatohepatitis (NASH), however, a role for ACC in the control of the inflammatory response has
not been reported. To test the overall hypothesis that ACC activity is essential for the immune cell-intrinsic
metabolic and transcriptional adaptations required for the induction and resolution of acute inflammation, we
propose two specific aims: In Specific Aim 1 we will test the hypothesis that ACC activity regulates induction and
resolution of the acute inflammatory response in mice, using genetic and pharmacologic approaches including
novel macrophage-specific ACCDKO mice, and by creating macrophage-specific Acacb and Acacb deficient mice.
Specific Aim 2 will identify the conserved transcriptional, metabolic, and functional mechanisms underlying ACC-
dependent induction and resolution of inflammation. Successful completion of these studies will identify a novel
role for ACC in controlling inflammation and resolution during innate immune responses and discover
evolutionarily conserved and individual functions of ACC1 and ACC2 isoforms.

## Key facts

- **NIH application ID:** 10897206
- **Project number:** 5R01AI168194-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** NORBERT LEITINGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $621,038
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897206

## Citation

> US National Institutes of Health, RePORTER application 10897206, Acetyl CoA Carboxylase in the Metabolic Control of Inflammation (5R01AI168194-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10897206. Licensed CC0.

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