# Nuclear ATP citrate lyase and ischemia/reperfusion injury in steatotic liver

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $575,339

## Abstract

Abstract
 Non-alcoholic fatty liver disease represents a group of conditions associated with excessive lipid
accumulation in hepatocytes because of long-term energy surplus. This disease increases morbidity and
mortality associated with injury or physiological stress, and thus is a concern for all medical disciplines. Our
preliminary studies have identified a novel molecular mechanism that couples cellular energy metabolism to
hepatocellular protection.
 Our studies demonstrate that ATP citrate lyase (ACLY), one of the two enzymes responsible for the synthesis
of cytosolic acetyl-CoA, can translocate to the nuclei in hepatocytes. Impairment of ACLY nuclear translocation
increases the vulnerability of hepatocytes to injury. AMP-activated protein kinase (AMPK)-mediated
phosphorylation of ACLY is essential for its nuclear translocation. Our preliminary data also indicate that R-
spondin 1 and 3, the endogenous ligands for leucine-rich repeat-containing G-protein-coupled receptors (LGR)
secreted by hepatocytes, promote the ACLY nuclear translocation which subsequently ameliorates the
vulnerability to injury associated with liver steatosis.
 We propose four Aims to investigate the function of ACLY in hepatic protection using cell biological and
transgenic techniques. Aim 1 will define ACLY nuclear translocation as a novel mechanism accountable for the
protection of hepatocytes from injury. Aim 2 will determine the epigenetic mechanism responsible for the hepatic
protection of nuclear ACLY. Aim 3 will demonstrate that AMPK is critical for the phosphorylation of ACLY and its
subsequent nuclear translocation. Aim 4 will examine whether R-spondin1/3-LGR4 signaling, identified as an
endogenous system critical for hepatocellular protection by our previous studies, restores the impairment of
ACLY nuclear translocation in steatotic liver. Completion of this proposal will advance a completely new area of
hepatic physiology and will provide novel insights into liver injury.

## Key facts

- **NIH application ID:** 10932653
- **Project number:** 1R01DK139942-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** RANDY J SEELEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $575,339
- **Award type:** 1
- **Project period:** 2024-09-20 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932653

## Citation

> US National Institutes of Health, RePORTER application 10932653, Nuclear ATP citrate lyase and ischemia/reperfusion injury in steatotic liver (1R01DK139942-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10932653. Licensed CC0.

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