# Investigating Mechanisms of Acetyl-CoA Sensing and Its Implications in Non-Alcoholic Fatty Liver Disease

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2020 · $50,520

## Abstract

PROJECT SUMMARY
Nutrient sensing (i.e. the ability of cells and organisms to sense, report on, and respond to nutrient availability)
is a fundamental mechanism that is essential to life and health, but often dysregulated in the context of
diseases. While the discovery of sensing mechanisms for some nutrients, such as amino acids and ATP, have
yielded critical insight into their implications for disease, the mechanisms other essential metabolites may be
sensed remains unexplored. Acetyl-CoA is a metabolite at the intersection of several catabolic, anabolic, and
signaling pathways, and therefore, may be uniquely positioned to report on nutrient availability. Indeed, data
from our lab and others indicates that acetyl-CoA availability is sensed. Specifically, our lab has previously
shown that upon deletion or inhibition of ATP-citrate lyase (ACLY), cells and tissues upregulate Acetyl-CoA
synthetase short chain family member 2 (ACSS2) in order to maintain nuclear-cytosolic pools of acetyl-CoA.
However, we have a very limited understanding of the mechanisms by which cells sense acetyl-CoA and how
this sensing pathway can subsequently engage adaptive responses when acetyl-CoA production via ACLY is
compromised. Notably, a liver-specific inhibitor against ACLY is currently in phase 3 clinical trials for the
treatment of hypercholesterolemia. Despite this clinical therapeutic and the potential for the inhibitor to be
widely used in individuals with metabolic diseases, studies with genetic models of hepatic ACLY deficiency are
lacking, and in particular, no studies have investigated the implications of ACLY loss and subsequent
compensatory ACSS2 upregulation in metabolic liver disease, such as non-alcoholic fatty liver disease
(NAFLD). Based on my preliminary data, I hypothesize i) that the sensitivity of the mevalonate and cholesterol
pathway to ACLY loss mediates ACSS2 upregulation via activation of SREBP transcription factors and ii) that
suppression of lipogenic acetyl-CoA production and activation of this sensing mechanism has implications in
the pathogenesis of NAFLD by causing a defect in mitochondrial function and fatty acid oxidation. I will test this
hypothesis, first (aim 1) through quantification of cholesterol pathway metabolites and assessment of SREBP
transcriptional activity, using both an in vitro and in vivo model of ACLY deficiency. Further, I will characterize
(aim 2) the effect of suppressing lipogenic acetyl-CoA production an in vivo model of hepatic steatosis.
Specifically, I will investigate how a deficit in lipogenic acetyl-CoA production alters fatty acid oxidation and
mitochondrial function, and determine whether these changes are dependent on alterations in levels of the
mevalonate pathway product, ubiquinone. Overall, I expect the results of this study to address an essential
mechanism in acetyl-CoA sensing, as well as the functional consequences of targeting acetyl-CoA metabolism
in NAFLD, with the potential to impact treatmen...

## Key facts

- **NIH application ID:** 10067172
- **Project number:** 1F30DK126353-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Joyce Ying Liu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 1
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067172

## Citation

> US National Institutes of Health, RePORTER application 10067172, Investigating Mechanisms of Acetyl-CoA Sensing and Its Implications in Non-Alcoholic Fatty Liver Disease (1F30DK126353-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10067172. Licensed CC0.

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