# Metabolic regulation of fibroblast fate by ATP citrate lyase

> **NIH NIH F31** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $37,326

## Abstract

Project Summary
 Idiopathic Pulmonary Fibrosis (IPF) is a fibrotic lung disease characterized by progressive accumulation
of fibrotic extracellular matrix (ECM) eventually leading to extensive airway remodeling, impaired lung function
and respiratory failure. The cell type responsible for the majority of ECM production is an activated fibroblast
known as the myofibroblast, characterized by α-SMA expression and production of ECM proteins, particularly
collagen and fibronectin. Our laboratory has previously demonstrated that young mice are capable of
spontaneously resolving bleomycin induced lung fibrosis, with the myofibroblast population undergoing
apoptosis and clearance; in contrast, aged mice fail to resolve in association with a persistent myofibroblast
population that appears to be resistant to apoptosis.
 ATP Citrate Lyase (ACLY) is an enzyme which catalyzes citrate to acetyl CoA conversion, thereby
regulating acetyl-CoA bioavailability and fatty acid synthesis. Interrogation of a publicly available dataset
indicates that ACLY mRNA levels are reduced in lungs of human subjects with IPF. Our preliminary data shows
that ACLY expression in mice aged over 18 months is also deficient and that this expression decreases when
subjected to bleomycin induced fibrogenesis. ACLY siRNA knockdown in IMR90 human fibroblasts promotes
production of α-SMA, a myofibroblast marker, downregulates phosphorylation of AMPK and enhances
myofibroblast apoptosis resistance. This project proposal will test the hypothesis that ACLY deficiency drives
myofibroblast apoptosis regulation and determine whether ACLY is a therapeutic target in a mouse model of
persistent lung fibrosis. Aim 1 will investigate ACLY regulation during myofibroblast differentiation, particularly
its interaction with TGF-β1. Aim 2 will focus describing the mechanism of apoptotic regulation by ACLY,
especially on its effects on AMPK phosphorylation. Aim 3 will make use of a genetic knockout mouse model to
definitively examine whether ACLY deficiency is a key fibrotic driver capable of sustaining persistent fibrosis.
Collectively these studies will elucidate the role ACLY in fibrogenesis and non-resolving persistent lung fibrosis
while also serving as the vehicle for a solid foundation of research training for Samuel Smith (PI) under the
mentorship of Dr. Victor Thannickal, fostering his professional development and facilitating his pathway to
independent academic research.

## Key facts

- **NIH application ID:** 10234570
- **Project number:** 1F31HL158230-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Samuel R Smith
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,326
- **Award type:** 1
- **Project period:** 2021-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10234570

## Citation

> US National Institutes of Health, RePORTER application 10234570, Metabolic regulation of fibroblast fate by ATP citrate lyase (1F31HL158230-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10234570. Licensed CC0.

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