# Mechanisms regulating autophagy in alcohol-induced liver injury

> **NIH NIH R37** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2021 · $344,250

## Abstract

Project Summary 
Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. Currently no successful
treatment for ALD is available. The pathogenesis of alcohol-induced liver injury is characterized by hepatic
steatosis, inflammation, and fibrosis, which can progress to cirrhosis and liver cancer. Cells can adapt and
protect themselves in response to stress by activating cellular protective mechanisms such as autophagy and
lysosomal and mitochondrial biogenesis. However, these protective mechanisms are impaired after chronic
alcohol consumption. The underlying molecular mechanisms by which chronic alcohol impairs autophagy are
not known. In our preliminary studies, we found that chronic plus acute alcohol binge (“Gao-binge”)
inactivates transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, resulting in impaired
lysosomal biogenesis and insufficient autophagy. Overexpression of TFEB protects against but knockdown of
TFEB exacerbates Gao-binge alcohol-induced liver injury in mice. Our long-term goal is to understand the
molecular mechanisms for how alcohol impairs lysosomal biogenesis in hepatocytes, in order to identify steps
in the protective pathway that are points for intervention in alcoholic liver disease. The objective of this
proposal is to understand how alcohol metabolism activates mTOR results in TFEB inactivation and how
genetic and pharmacological activation of TFEB protects against alcohol-induced liver injury. The two specific
aims that we propose are: 1) to determine the mechanisms by which Gao-binge alcohol inactivates TFEB in
hepatocytes; and 2) to determine the mechanism(s) by which TFEB protects against alcohol-induced liver
injury. Understanding the mechanisms by which alcohol impairs TFEB-mediated autophagy as well as
lysosomal and mitochondrial biogenesis may ultimately help to develop novel interventions on the
improvement of the pathogenesis of ALD.

## Key facts

- **NIH application ID:** 10187463
- **Project number:** 5R37AA020518-10
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Wen-Xing Ding
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,250
- **Award type:** 5
- **Project period:** 2011-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187463

## Citation

> US National Institutes of Health, RePORTER application 10187463, Mechanisms regulating autophagy in alcohol-induced liver injury (5R37AA020518-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10187463. Licensed CC0.

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