# The effects of alcohol metabolism on hepatic and cardiac energy state and function

> **NIH NIH K01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $140,850

## Abstract

Project Summary/Abstract
Alcohol is the most commonly used drug in the United States and its use is on the rise. Alcohol abuse can
result in alcoholic fatty liver disease, and even cirrhosis, as the majority of alcohol is metabolized by the liver
during first pass metabolism. Alcohol is primarily metabolized in the liver through two enzymatic reactions
(alcohol dehydrogenase and aldehyde dehydrogenase 2) that each reduce an NAD+ to NADH, contributing to a
reduced redox state. Alcohol consumption reduces the redox state (greater NADH/ NAD+ ratio) which may
impair β-oxidation and the TCA cycle. These factors may result in a reduction in fatty acid oxidation and the
accumulation of lipids. Metabolic mechanisms in the liver may also use acetate as substrate to contribute to de
novo lipogenesis, further contributing to alcoholic fatty liver disease. However, as much as 80% of the acetate
produced during alcohol metabolism escapes the liver and can be used by peripheral tissues or organs such
as the heart. The heart is also severely affected by alcohol abuse, which can lead to cardiac dysfunction and
the development of various cardiovascular diseases, such as alcoholic cardiomyopathy. In the heart, acetate
interferes with fatty acid oxidation, which results in lower ATP concentrations, as well as the accumulation of
triglycerides. Acetate may impair the oxidation of free fatty acids (FFAs) as fuel, not through the inhibition of
CPT via malonyl-CoA production, but by metabolic mechanisms outcompeting CPT for free CoAs therefore
resulting in the limitation of FFAs entry into the mitochondria for oxidation. Administering acetate in in vitro
(heart perfusions) and in vivo infusion experiments results in an energy deficit through a mechanism that has
yet to be elucidated. It is possible that this energy deficit, and lipid accumulation, in the heart are contributing to
cardiac dysfunction. The aim of this proposal is to examine these particular metabolic mechanisms and
determine whether they are responsible for the alcohol induced energy deficit in the heart. This proposal will
also determine whether these mechanisms are responsible for mediating alcohol induced cardiac dysfunction.
A secondary aim is to determine, through the use of tracers, how chronic alcohol consumption changes
overtime and how the liver and heart metabolize and use alcohol metabolites.

## Key facts

- **NIH application ID:** 10908544
- **Project number:** 5K01AA030327-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Justin Fletcher
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $140,850
- **Award type:** 5
- **Project period:** 2022-08-10 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908544

## Citation

> US National Institutes of Health, RePORTER application 10908544, The effects of alcohol metabolism on hepatic and cardiac energy state and function (5K01AA030327-03). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10908544. Licensed CC0.

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