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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020518-07
Application #
9474092
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Gao, Peter
Project Start
2011-08-01
Project End
2022-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kansas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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