# Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH

> **NIH NIH R00** · UNIVERSITY OF LOUISVILLE · 2024 · $248,999

## Abstract

Project Summary/Abstract:
Alcohol-associated hepatitis (AH) is a clinical manifestation of alcohol-associated liver disease (ALD) that has a
very poor prognosis. Current treatments are ineffective and liver transplantation is the only long-term solution.
The liver has the unique ability to regenerate post-injury but in ALD/AH this process becomes compromised.
Mitochondria dysfunction is a hallmark of ALD and AH that can contribute to compromised liver regeneration.
Mitochondria enriched with cardiolipin maintain the energy requirements (e.g., ATP) necessary for hepatocyte
proliferation and liver regeneration. Preliminary data demonstrate that hepatic cardiolipin synthesis is
compromised in clinical AH and experimental AH. Cardiolipin is required to maintain mitochondrial bioenergetics
and undergoes oxidation and depletion in ALD compromising liver regeneration. However, treatment with
cardiolipin or elamipretide (drug that prevents cardiolipin oxidation) can restore hepatocyte mitochondrial function
and proliferation. The aim of this study is to determine if cardiolipin supplementation and preservation will
promote liver regeneration via maintenance of ATP synthesis and prevention of hepatocyte apoptosis alleviating
hepatic insufficiency in AH. This study uses pre-clinical animal models and human in vitro models of AH to
assess the treatment efficacy of cardiolipin supplementation and preservation. Aim 1 will determine if mice with
cardiolipin deficient hepatocytes have compromised liver regeneration due to loss of mitochondrial ATP
synthesis in a model of AH. Aim 2 will test whether treatment with cardiolipin and elamipretide will enhance
hepatic mitochondrial function, liver regeneration, and proliferating hepatocyte populations in an experimental
animal model of AH. Aim 3 will identify cardiolipin species in human AH liver and plasma and assess their effect
on hepatocyte proliferation and inflammatory responses in immune cells. The K99-phase (Aim 1) will provide
training in assaying liver regeneration and mitochondrial function, sc-RNASeq analysis, and use of a mouse
deficient in hepatocyte cardiolipin. This MOSAIC K99/R00 proposal will provide the training necessary (K99) to
build a solid research foundation providing a pathway to independence as an independent researcher in the field
of ALD and liver regeneration (R00). Findings from this study will identify a therapeutic strategy to treat AH via
enhanced liver regeneration which could replace the only long-term treatment alternative, liver transplantation.

## Key facts

- **NIH application ID:** 10903086
- **Project number:** 4R00AA030627-03
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Josiah E Hardesty
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $248,999
- **Award type:** 4N
- **Project period:** 2022-09-21 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903086

## Citation

> US National Institutes of Health, RePORTER application 10903086, Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH (4R00AA030627-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10903086. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*