# Mechanisms regulating autophagy in alcohol-induced liver injury

> **NIH NIH R37** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $348,750

## Abstract

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.
RELEVANCE (See instructions):
Alcohol abuse and consumption are major causes of alcoholic liver disease, which has high morbidity and
mortality and no specific treatment is available. Alcohol consumption impairs lysosomal biogenesis results
in insufficient autophagy and alcoholic steatosis and liver injury. Elucidating the molecular mechanisms of
how activating TFEB to improve lysosomal biogenesis and autophagy that are impaired by alcohol will help
to develop novel therapeutic strategies for treating alcoholic liver disease.

## Key facts

- **NIH application ID:** 10832042
- **Project number:** 5R37AA020518-13
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Wen-Xing Ding
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $348,750
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832042

## Citation

> US National Institutes of Health, RePORTER application 10832042, Mechanisms regulating autophagy in alcohol-induced liver injury (5R37AA020518-13). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10832042. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*