Autophagy is a genetically programmed, evolutionarily conserved process that degrades long-lived cellular proteins and damaged organelles, including mitochondria, as a critical cell survival mechanism in response to stress. We recently reported that ethanol induces autophagy, which reduces ethanol-induced liver injury (Ding et al., 2010a). This is an important finding because alcohol abuse is a major cause of liver disease and a major health problem in the United States. Oxidative stress and mitochondrial damage play important roles in alcohol-induced hepatotoxicity. Cells may protect themselves by removing damaged mitochondria by mechanisms such as autophagy. Therefore modulating the autophagy process could offer new therapeutic treatments for alcoholic liver diseases. However, the mechanisms by which ethanol induces autophagy and how autophagy protects against ethanol-induced liver pathogenesis are not clear. Without such understanding, the potential to ultimately use autophagy in the treatment of alcohol-related liver disease will be limited. Our preliminary studies suggest that the forkhead transcription factor FoxO3a could play a major role in ethanol- induced autophagy. Therefore, the central hypothesis is that ethanol induces autophagy by activating FoxO3a, and autophagic removal of ethanol-induced damaged mitochondria is crucial to protect against ethanol- induced liver pathogenesis. To examine our hypothesis, three specific aims are proposed: 1) determine the mechanisms by which ethanol activates FoxO3a in hepatocytes, 2) determine how ethanol-activated FoxO3a induces autophagy in hepatocytes, and 3) determine the mechanisms by which removal of damaged mitochondria protects against ethanol-induced hepatotoxicity. The research proposed in this application is innovative in the concept that ethanol can activate autophagy as a protective mechanism against its known detrimental effects on the liver. Moreover, we will utilize novel genetic animal models such as GFP-LC3 transgenic and Atg5 liver-specific knockout mice to specifically study the role of autophagy in alcohol-induced liver injury. Furthermore, it focuses on the role of FoxO3a-mediated autophagy pathway in alcoholic liver disease, which has not been studied. The proposed research is significant because the results from this study will lead to the understanding of mechanisms and roles of autophagy in alcohol-induced liver pathogenesis. Ultimately, such knowledge has the potential of offering novel therapeutic approaches for treating alcoholic liver pathogenesis by modulating autophagy.

Public Health Relevance

Alcohol abuse and consumption are major causes of liver disease and is a major health problem in the United States and around the world. Autophagy has been shown to be able to regulate mitochondria homeostasis and cell death, which are important in alcoholic liver disease. Elucidating the molecular mechanisms of how autophagy, mitochondria homeostasis and cell death are integrated in alcoholic liver disease will help to generate novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020518-04
Application #
8702053
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Gao, Peter
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Kansas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Ni, Hong-Min; McGill, Mitchell R; Chao, Xiaojuan et al. (2016) Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice. J Hepatol 65:354-62
Yang, Hua; Ni, Hong-Min; Guo, Fengli et al. (2016) Sequestosome 1/p62 Protein Is Associated with Autophagic Removal of Excess Hepatic Endoplasmic Reticulum in Mice. J Biol Chem 291:18663-74
Nagy, Laura E; Ding, Wen-Xing; Cresci, Gail et al. (2016) Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes. Gastroenterology 150:1756-68
Li, Yuan; Ding, Wen-Xing (2016) A Gene Transcription Program Decides the Differential Regulation of Autophagy by Acute Versus Chronic Ethanol? Alcohol Clin Exp Res 40:47-9
Li, Yuan; McGreal, Steven; Zhao, Jean et al. (2016) A cell-based quantitative high-throughput image screening identified novel autophagy modulators. Pharmacol Res 110:35-49
Ding, Wen-Xing; Jaeschke, Hartmut (2016) Autophagy in macrophages regulates the inflammasome and protects against liver injury. J Hepatol 64:16-8
Williams, Jessica A; Ni, Hong-Min; Ding, Yifeng et al. (2015) Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice. Am J Physiol Gastrointest Liver Physiol 309:G324-40
Williams, Jessica A; Ding, Wen-Xing (2015) A Mechanistic Review of Mitophagy and Its Role in Protection against Alcoholic Liver Disease. Biomolecules 5:2619-42
Yang, Hua; Peng, Yuan-Fei; Ni, Hong-Min et al. (2015) Basal Autophagy and Feedback Activation of Akt Are Associated with Resistance to Metformin-Induced Inhibition of Hepatic Tumor Cell Growth. PLoS One 10:e0130953
Ni, Hong-Min; Williams, Jessica A; Ding, Wen-Xing (2015) Mitochondrial dynamics and mitochondrial quality control. Redox Biol 4:6-13

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