# MicroRNAs in Alcoholic Liver Disease

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $577,696

## Abstract

PROJECT ABSTRACT
Alcoholic liver disease (ALD) and alcoholic hepatitis (AH) are the leading causes of liver cirrhosis and liver-
related death worldwide. MicroRNAs modulate the pathogenesis of ALD by regulating hepatocyte function,
inflammatory cell activation and liver fibrosis. Our research revealed that alcohol-induced increase in miR-155
interferes with key elements in the pathogenesis of ALD including steatosis, liver damage and inflammation.
Based on these data we hypothesize that miR-155 plays a cell-specific role in ALD both in hepatocytes and
immune cells and represents a potential therapeutic target in ALD. We also discovered that circulating miR-155
is packaged in exosomes and that alcohol increases exosome release and our novel data show that alcohol-
induced exosome production is attenuated in miR-155 deficient mice. We found that alcohol-induced
upregulation of miR-155 promotes autophagy, both in macrophages and hepatocytes, by targeting key
molecules in the autophagy pathway. Thus, we propose that exosome production is linked to impaired
autophagy flux and it may represent a mechanism to maintain cellular homeostasis in alcohol exposed cells.
The specific aims of this proposal will! 1) delineate the cell-specific role of miR-155 in ALD in hepatocytes and
innate immune cells using hepatocyte- and bone marrow-derived cell-specific deletion of miR-155 (cre-lox
recombination based) in vivo after chronic alcohol feeding (ALD) and acute binge on chronic alcohol (AH) in
mice; 2) test the role of miR-155 in alcohol-induced exosome cargo and the biological effect of exosome-
mediated transfer of miR-155 on hepatocyte-macrophage crosstalk; 3) investigate the effect of alcohol and
miR-155 on the mechanistic inter-relationship between impaired autophagy flux and exosome
production/biogenesis in hepatocytes and immune cells; and 4) evaluate the effect of inhibition of miR-155 on
autophagy, exosome production and liver injury in a mouse model of ALD and AH using an AAV8-mediated
miR-155 tough decoy to inhibit miR-155, in vivo. Our experiments will provide novel insights into key
intracellular processes by which miR-155 regulates autophagy and exosome production for better
understanding of the pathophysiology of alcoholic liver disease and alcoholic hepatitis.

## Key facts

- **NIH application ID:** 10456995
- **Project number:** 5R01AA020744-09
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Gyongyi Szabo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $577,696
- **Award type:** 5
- **Project period:** 2011-09-10 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456995

## Citation

> US National Institutes of Health, RePORTER application 10456995, MicroRNAs in Alcoholic Liver Disease (5R01AA020744-09). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10456995. Licensed CC0.

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