# Project 3: CYP2E1 Regulation of Ethanol-Induced miRNAs in Intestinal Epithelial Cells

> **NIH NIH P20** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $224,250

## Abstract

Project 3 – Project Summary
While binge alcohol-induced gut leakage has been studied extensively in the context of reactive oxygen species
(ROS)-mediated signaling, it was recently revealed that post-transcriptional regulation plays an essential role as
well. Ethanol-inducible cytochrome P450-2E1 (CYP2E1) is a key enzyme in ethanol metabolism, and promotes
alcohol-induced hepatic steatosis and inflammatory liver disease at least in part by mediating changes in
intestinal permeability. For instance, gut leakage and elevated intestinal permeability to endotoxins have been
shown to be regulated by enhancing CYP2E1 mRNA and CYP2E1 protein levels. Although it is understood that
ethanol promotes CYP2E1 induction and activation, the mechanisms by which CYP2E1 expression is regulated
in the context of intestinal damage remain poorly defined. Specific miRNAs, including miR-132, miR-212, miR-
378, and miR-552, have been shown to repress the expression of CYP2E1, suggesting that these miRNAs
contribute to ethanol-induced intestinal injury. In my published studies and preliminary investigations, I made two
key observations that contribute to my scientific premise that CYP2E1 expression is regulated post-
transcriptionally through miRNA-mediated degradation: 1) I demonstrated that the RNA-binding protein AUF1
binds mature miRNAs, including CYP2E1-targeting miRNAs, and that this binding modulates the degradation of
corresponding target mRNAs; 2) I showed that the Serine/Threonine kinase MST1 mediates oxidative stress-
induced phosphorylation of RNA-binding proteins such as AUF1. This finding suggests that ROS-mediated
signaling modulates AUF1/miRNA interaction through MST1-mediated phosphorylation. Based on these
observations, I hypothesize that ethanol-induced activation of the MST1 kinase results in the AUF1-dependent
destabilization of miRNAs targeting CYP2E1 mRNA, resulting in transcript stabilization and increased levels of
CYP2E1 protein which cause intestinal injury through damage to the epithelial barrier. For this project in the
COBRE for Digestive & Liver Disease, we will focus on elucidating the critical functions of AUF1 phosphorylation
by MST1 in the decay of miRNAs targeting CYP2E1, the stabilization of CYP2E1 mRNA in the presence of
ethanol, and subsequent intestinal injury.

## Key facts

- **NIH application ID:** 9853391
- **Project number:** 1P20GM130457-01A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Je-Hyun Yoon
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $224,250
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853391

## Citation

> US National Institutes of Health, RePORTER application 9853391, Project 3: CYP2E1 Regulation of Ethanol-Induced miRNAs in Intestinal Epithelial Cells (1P20GM130457-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9853391. Licensed CC0.

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