# Functional characters of non-coding RNAs in alcoholic liver injury

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2021 · —

## Abstract

Alcoholic liver disease (ALD) is one of the most common forms of chronic liver injury in the United States.
Chronic ethanol consumption results in toxic metabolites in the liver and increases endothelial senescence
and dysfunction leading to inflammation and liver damage. Aging is linked with the severity and poor
prognosis of various liver diseases including alcoholic liver diseases and is associated gradual alteration of
structure and function in liver tissues and cells including liver sinusoidal endothelial cells. Endothelial
dysfunction is an early pathophysiological hallmark in the development of liver disease. Senescence, the
cellular equivalent of aging, was proposed to be involved in endothelial dysfunction. Indeed, enhanced
cellular senescence was associated with a poor outcome in alcohol-related fatty liver disease, while
increased hepatic senescence mediators such as p21 and TNF-α that were related to liver/endothelial
dysfunction in ALD cirrhosis. Increasing evidence supports that non-coding RNAs (ncRNAs) play a central
role in various cellular pathways by regulating gene expression. Indeed, there is a strong link between
ethanol metabolism and endotoxin/lipopolysaccharide (LPS) induced cellular senescence and endothelial
dysfunction in ALDs. Hepatic sinusoids, connected directly to the portal circulation, serve as the first barrier
against these inflammatory and noxious stimuli. We have novel preliminary data showing that selective
ncRNA/microRNA genes are aberrantly expressed in liver specimens from ALD animals and are regulated
and involved in ethanol metabolism. In particular, we have found: (a) intra-gastric ethanol feeding
significantly increased the expression of cellular senescence initiators EGR1, PAI-1 and Id1 and silenced
p53 effectors E2F1 and IGFBP3; (b) ethanol enhanced microRNA-34a and p53 expressions and altered
their target genes such as SIRT1, PPARα and HNF4α, which leads to senescence phenotypes in liver
sinusoidal endothelial cells (LSECs); (c) Inhibition of miR-34a/p53/TLR4 by anti-miR-34a/p53 Morpholino
and CRISPR/cas9 approaches has successfully recovered alcoholic liver injury in ethanol treated mice in
vivo. Although the combined evidence supports a link between ncRNAs and alcoholic liver disease, there
is a critical need to determine the underlying mechanism whereby ethanol-dependent miRNAs promote
alcoholic liver injury. Our long-term goal is to determine underlying mechanisms contributing to alcohol-
induced liver disease so that new mechanism-based, clinically effective prevention or treatment strategies
can be developed. The objective for this proposal is to determine how ethanol- dependent ncRNAs mediate
endothelial dysfunction and senescence in the progression of alcoholic liver diseases. Our central
hypothesis is that ethanol-dependent miRNAs contribute to alcoholic liver injury through regulation of
cellular senescence and dysfunction in endothelial cells. This hypothesis was formulated based upon the...

## Key facts

- **NIH application ID:** 10044417
- **Project number:** 5I01BX001724-10
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** FANYIN MENG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-07-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044417

## Citation

> US National Institutes of Health, RePORTER application 10044417, Functional characters of non-coding RNAs in alcoholic liver injury (5I01BX001724-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10044417. Licensed CC0.

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