# Hepatocyte-derived extracellular vesicles in alcoholic liver disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $594,593

## Abstract

Alcoholic liver disease (ALD) continues to be a devastating disease in the United States and many
other countries with the global mortality estimated to exceed 0.7 million per year. Chronic ethanol
consumption results in lipid accumulation in hepatocytes and their organelle stress leading to
inflammation and fibrosis in the progression of ALD. The crosstalk between hepatocytes and non-
parenchymal cells - including hepatic macrophages (HMs) and hepatic stellate cells (HSCs) - is
crucial to this process. However, the molecular mechanisms and signaling pathways involved in
the crosstalk between lipid overloaded hepatocytes and non-parenchymal cells, remain
incompletely understood. In particular, the mechanisms by which this crosstalk facilitates or
regulates a transition from chronic asymptomatic alcoholic steatohepatitis (ASH) to fatal alcoholic
hepatitis (AH) is a central issue for designing efficacious novel treatments for this devastating
disease. While focused on the investigation of cell-to-cell communication we recently revealed
that damaged hepatocytes release extracellular vesicles (EVs) and these EVs circulate in the
blood in mouse models of ALD. EVs are efficiently internalized into target cells and transfer their
cargo including miRNAs. The later is a key mechanism by which encapsulated miRNAs in EVs
(EV-miRNAs) serve as “functional extracellular RNAs” to regulate protein translation in target
cells. EVs also contain sterile danger signal known as damage-associated molecular patterns
(DAMPs). We found that EVs derived from hepatocytes from AH mice are enriched in
mitochondrial DNA (mtDNA) that contribute to activation of an inflammatory process. Further, our
pathway analysis of RNA-seq data comparing AH vs. preceding chronic (c)ASH mouse livers,
identifies EV as one of the most significantly upregulated pathways. Based on these results, we
propose the central hypothesis that EVs with a quantitatively and qualitatively distinct cargo are
released from damaged hepatocytes in AH vs. preceding cASH to induce unique cellular crosstalk
in the genesis of the AH pathologic phenotype. We also hypothesize that plasma EV analysis
serves as a liquid liver biopsy providing a barcode for diagnosis and staging of ALD severity. To
investigate these hypotheses our proposal has the following SPECIFIC AIMS. 1) Determine the
role of EVs and their cargo derived from hepatocytes as barcodes for a transition from
asymptomatic cASH to AH in murine models and human ALD. 2) Dissect the mechanisms
involved in EV-mediated cell-to-cell communication in the cASH to AH transition. To address
these central issues, we have put together a MPI investigative team with expertise in EV biology,
ALD pathology, development of unique animal models, human ALD, and RNA therapeutics.

## Key facts

- **NIH application ID:** 9877419
- **Project number:** 1R01AA028134-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ariel Feldstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $594,593
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877419

## Citation

> US National Institutes of Health, RePORTER application 9877419, Hepatocyte-derived extracellular vesicles in alcoholic liver disease (1R01AA028134-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9877419. Licensed CC0.

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