# The role of PDK4 in alcohol-associated liver disease

> **NIH NIH K01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $187,444

## Abstract

ABSTRACT
Alcohol-associated liver disease (ALD) is a major health problem and can lead to liver failure, liver cancer, and
death, incurring enormous healthcare expenditures annually in the US. Few specific treatments are available for
patients with ALD. Abstinence is difficult to achieve in many patients and cannot prevent the progression at later
stages of ALD. Deciphering molecular mechanisms and identifying novel markers of ALD can lead to new
therapeutic avenues and is of substantial interest to public health and welfare. Mitochondria, the central location
for alcohol-metabolizing enzymes, are active mediators in response to alcohol toxicity. Mitochondrial alterations
induced by alcohol are a hallmark of ALD, which have profound impacts on cell metabolism and associate with
activation of inflammation, underlying the pathogenesis of ALD. Pyruvate dehydrogenase kinase 4 (PDK4)
inactivates pyruvate dehydrogenase complex (PDC) in the mitochondrial matrix, thus suppressing the conversion
of pyruvate to acetyl-CoA. PDK4 maintains mitochondrial homeostasis and has been implicated in the
development of non-alcoholic fatty liver disease and apoptotic liver injury. However, little is known about the role
of PDK4 in ALD. This proposal is to reveal how PDK4 coordinates mitochondrial dysfunction with activation of
inflammation in the face of ethanol-induced liver injury. Our central hypothesis is that loss of PDK4 function
impairs alcohol metabolism/detoxification and enhances pro-inflammatory response to promote the development
of ALD. We aim to: (1) define the role PDK4 in liver injury in mouse models of ethanol feeding; (2) unravel the
molecular mechanisms of PDK4 in ethanol-induced liver injury. Our proposed studies will conceptually and
mechanistically reveal the connection between mitochondrial ethanol metabolism and inflammasome activation,
which helps to open novel therapeutic avenues for the treatment of ALD. This K01 application will allow the
applicant to acquire advanced knowledge and research skills in ALD by integrating interdisciplinary resources.
The applicant has assembled an advisory committee composed of outstanding members, including Drs. Laura
Nagy (mentor), Srinivasan Dasarathy, and Xiaoxia Li, who are renowned hepatologists or well-recognized
scientists in fields of alcohol metabolism, inflammation, mitochondrial biology, gene expression and regulation,
immunology, etc., with a formidable record of training junior scientists to be independent and successful in
academia. They will direct the applicant's academic career development and provide full support to the
implementation of proposed experiments.

## Key facts

- **NIH application ID:** 10914149
- **Project number:** 5K01AA029474-04
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** JIANGUO WU
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $187,444
- **Award type:** 5
- **Project period:** 2021-09-22 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914149

## Citation

> US National Institutes of Health, RePORTER application 10914149, The role of PDK4 in alcohol-associated liver disease (5K01AA029474-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10914149. Licensed CC0.

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