# Intestinal exosomes in alcohol-induced liver injury

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $336,375

## Abstract

PROJECT SUMMARY
Although binge alcohol-induced liver injury has been studied extensively in the context of endotoxins and alcohol
itself, it was recently revealed that circulating protein and RNA factors play an essential role as well. Ethanol-
inducible cytochrome P450-2E1 (CYP2E1), a key enzyme in ethanol metabolism to generate Reactive Oxygen
Species (ROS), promotes alcohol-induced hepatic steatosis and inflammatory liver disease, at least in part by
mediating changes in intestinal permeability to endotoxins and release of extracellular proteins and RNAs into
the blood stream. Specific miRNAs, including let-7 family miRNAs, have been shown to be amplified in serum
from alcohol use disorder (AUD) cohorts having decreased liver function, suggesting that these miRNAs
contribute to ethanol-induced injury of organs such as the liver. In my published studies and preliminary
investigations, I made two key observations that contribute to my scientific premise that let-7b is released from
the intestine through exosomes upon binge alcohol: 1) I demonstrated that the RNA-binding protein AUF1 binds
mature let-7b miRNA, the ligand of Toll-like Receptor 7 (TLR7) in liver, and that this binding modulates its
existence in cytosol and exosome; 2) I showed that the Serine/Threonine kinase MST1 mediates oxidative
stress-induced phosphorylation of RNA-binding proteins such as AUF1 and is required for let-7b enrichment in
blood exosomes after alcohol binging. This latter finding suggests that ROS-mediated signaling modulates
interaction of AUF1 and miRNA through MST1-mediated phosphorylation. Based on these observations, I
hypothesize that ethanol-induced activation of MST1 kinase results in the AUF1-dependent exosomal release of
let-7b targeting hepatic TLR7, resulting in transcriptional activation of pro-inflammatory cytokines that cause liver
injury through hepatic senescence. For this project, we will focus on elucidating the critical functions of AUF1
phosphorylation by MST1 in the dissociation of let-7b from AUF1, the release of let-7b from the intestine to the
blood stream via cargo proteins QKI and hnRNP K, and subsequent hepatic injury.

## Key facts

- **NIH application ID:** 10219941
- **Project number:** 5R01AA027532-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Je-Hyun Yoon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $336,375
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219941

## Citation

> US National Institutes of Health, RePORTER application 10219941, Intestinal exosomes in alcohol-induced liver injury (5R01AA027532-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10219941. Licensed CC0.

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