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)
Type
Research Project (R01)
Project #
5R01AA020518-04
Application #
8702053
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Gao, Peter
Project Start
Project End
Budget Start
Budget End
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
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Ding, Wen-Xing (2014) Induction of autophagy, a promising approach for treating liver injury. Hepatology 59:340-3
Williams, Jessica A; Manley, Sharon; Ding, Wen-Xing (2014) New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases. World J Gastroenterol 20:12908-33
Li, Yuan; Wang, Shaogui; Ni, Hong-Min et al. (2014) Autophagy in alcohol-induced multiorgan injury: mechanisms and potential therapeutic targets. Biomed Res Int 2014:498491
Ding, Wen-Xing (2014) Drinking coffee burns hepatic fat by inducing lipophagy coupled with mitochondrial *-oxidation. Hepatology 59:1235-8
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Williams, Jessica A; Hou, Yifeng; Ni, Hong-Min et al. (2013) Role of intracellular calcium in proteasome inhibitor-induced endoplasmic reticulum stress, autophagy, and cell death. Pharm Res 30:2279-89
Manley, Sharon; Williams, Jessica A; Ding, Wen-Xing (2013) Role of p62/SQSTM1 in liver physiology and pathogenesis. Exp Biol Med (Maywood) 238:525-38
Bi, Lipeng; Chiang, John Y L; Ding, Wen-Xing et al. (2013) Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice. J Lipid Res 54:2754-62

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