# Role of Arginine Methylation in Alcohol Pathogenesis

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2021 · $416,686

## Abstract

PROJECT SUMMARY
Alcoholic liver disease is a major clinical problem with unknown susceptibility factors. It displays marked
variability in disease phenotype. Only about 15% of heavy drinkers develop disease while 85% appear to be
protected, suggesting that there are mechanisms of adaptation to alcohol in majority of individuals. Arginine
methylation is a common posttranslational modification (PTM) that regulates hundreds of proteins directly and
many more via histone arginine methylation (epigenetic regulation). Protein arginine methyltransferase 1
(PRMT1) is the main enzyme responsible for about 90% of cellular arginine methylation. JMJD6 is the only
known arginine demethylase
Preliminary data indicate that patients with alcoholic liver disease have extremely low levels of PRMT1 protein
compared other patient groups suggesting that PRMT1 might be involved in disease progression of these
patients. Using hepatocyte specific knockout mouse model, we found that PRMT1 knockout in alcohol fed mice
results in dramatic increase in hepatocyte death, steatosis, inflammation and fibrosis; and increased serum
ALT levels suggesting that PRMT1 is protective against alcohol induced liver injury. This function of PRMT1 is
specific to alcohol, and preliminary data suggests that it is mediated by alcohol induced dephosphorylation of
PRMT1. We thus hypothesize that alcohol induced changes in PRMT1 activity are necessary for liver
adaptation to alcohol. This project will specifically examine this hypothesis with the following specific aims:
Specific Aim 1. To study the mechanism of PRMT1 mediated alcohol sensitivity. We will study non-
histone targets and promoter arginine methylation and define the major pathways. Specific Aim 2. To define
the role of PRMT1 phosphorylation in protection from alcohol induced liver injury. We hypothesize that
dephosphorylated form is particularly protective from alcohol induced injury. Inhibiting the upstream kinase in
this case is a promising future therapeutic strategy. Specific Aim 3. To define the role of arginine
demethylation enzyme JMJD6 in susceptibility to alcohol induced liver injury. JMJD6 is another
promising target. JMJD6 inhibition reverts the phenotype of PRMT1 knockout mice. We will study the
mechanism of this regulation.
Results of the proposed project will provide novel insights into the nature of the arginine methylation defects in
alcoholic liver disease. It should determine whether PRMT1 and JMJD6 are essential regulators of the
hepatocyte adaptation to alcohol and identify the primary targets. The project will set the stage for further
studies to understand the alcohol susceptibility in patients and explore the potential targets for therapy. The
ultimate goal is to use this information to develop clinical strategies to treat alcohol associated liver disease.

## Key facts

- **NIH application ID:** 10165425
- **Project number:** 5R01AA027586-03
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Irina Tikhanovich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $416,686
- **Award type:** 5
- **Project period:** 2019-06-05 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165425

## Citation

> US National Institutes of Health, RePORTER application 10165425, Role of Arginine Methylation in Alcohol Pathogenesis (5R01AA027586-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10165425. Licensed CC0.

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