Alcohol abuse and consumption are major causes of liver disease and is a major health problem in the United States. The characteristics of this disease are fatty liver, hepatitis, fibrosis, and cirrhosis. Cirrhosis is the eleventh leading cause of death in the United States. Alcohol abuse and alcoholism accounts for approximately 50 % of all death induced by liver cirrhosis. However, the pathogenesis of alcoholic liver diseases (ALD) is not completely understood although recent researches suggest that oxidative stress- induced mitochondrial damage and apoptosis are involved in the development of ALD. It is estimated that 28% of the adult population has a high-risk drinking pattern, such as binge drinking (1). Although there are large number of studies regarding the hepatotoxicity due to excessive drinking, the effects of drinking too much and too fast (binge drinking) on the liver have been sparingly studied. Autophagy is a genetically programmed, evolutionarily conserved process that degrades long-lived cellular proteins and damaged organelles including mitochondria. Whether ethanol can induce autophagy, or whether autophagy plays a role in alcohol-induced liver pathogenesis is not known. We have obtained evidence that ethanol treatment of hepatocytes can lead to the accumulation of autophagosomes. We hypothesize that ethanol can induce autophagy which is important for the removal of damaged mitochondria caused by ethanol;and that autophagy can modulate ethanol-induced cell death. It is anticipated that this work will generate novel finding regarding the role of autophagy in alcoholic pathogenesis. Public Health Relevance: Alcohol abuse and consumption are major causes of liver disease and is a major health problem in the United States. Autophagy has been shown to be able to regulate cell death and organelle turn over including mitochondria, which is an important mechanism in alcoholic liver disease. Elucidating the molecular mechanisms of how autophagy 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
Exploratory/Developmental Grants (R21)
Project #
7R21AA017421-02
Application #
7980289
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Radaeva, Svetlana
Project Start
2009-08-20
Project End
2011-07-31
Budget Start
2010-01-15
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$187,500
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
Ni, Hong-Min; Woolbright, Benjamin L; Williams, Jessica et al. (2014) Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. J Hepatol 61:617-25
Ding, Wen-Xing; Guo, Fengli; Ni, Hong-Min et al. (2012) Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. J Biol Chem 287:42379-88
Ding, Wen-Xing; Li, Min; Biazik, Joanna M et al. (2012) Electron microscopic analysis of a spherical mitochondrial structure. J Biol Chem 287:42373-8
Ding, Wen-Xing; Yin, Xiao-Ming (2012) Mitophagy: mechanisms, pathophysiological roles, and analysis. Biol Chem 393:547-64
Dolganiuc, Angela; Thomes, Paul G; Ding, Wen-Xing et al. (2012) Autophagy in alcohol-induced liver diseases. Alcohol Clin Exp Res 36:1301-8
Ni, Hong-Min; Boggess, Nikki; McGill, Mitchell R et al. (2012) Liver-specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury. Toxicol Sci 127:438-50
Ni, Hong-Min; Bockus, Abigail; Boggess, Nikki et al. (2012) Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology 55:222-32
Ni, Hong-Min; Williams, Jessica A; Yang, Hua et al. (2012) Targeting autophagy for the treatment of liver diseases. Pharmacol Res 66:463-74
Ni, Hong-Min; Bockus, Abigail; Wozniak, Ann L et al. (2011) Dissecting the dynamic turnover of GFP-LC3 in the autolysosome. Autophagy 7:188-204
Mei, Shuang; Ni, Hong-Min; Manley, Sharon et al. (2011) Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. J Pharmacol Exp Ther 339:487-98

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