Alcoholic liver disease (ALD) is characterized by steatosis, inflammation and fibrosis, which can lead to end stage cirrhosis and multiple complications. Ethanol has very broad biological effects affecting multiple cellular processes. While significant progresses have been made regarding the understanding of the pathogenesis of ethanol induced liver injury, much has yet to be learnt about the cellular defense against the detrimental effects of ethanol. We recently find that macroautophagy is induced by acute ethanol treatment and has significant protective effects against ethanol-induced apoptosis and liver injury. Macroautophagy is an evolutionarily conserved intracellular degradation mechanism involved in diverse biological activities and in the pathogenesis of many diseases. It would thus be important to understand how and why macroautophagy can counteract the toxicity of ethanol in the liver, which could lead to a further understanding of the pathogenesis of ALD, and, more importantly, novel approaches to treat the disease. We have found that ethanol-induced autophagy is characterized by its selectivity toward damaged mitochondria and lipid droplets, but not general proteins. We thus hypothesize that this feature must be related to how autophagy affects ethanol-induced toxicity.
Aim 1 of this project will investigate the mechanisms involved in the recognition of the damaged mitochondria and lipid droplets by the autophagosome in the ethanol conditions, and the dynamics of autophagy during a prolonged ethanol treatment to determine whether and how the function of autophagy may change during this course, thus providing important information for forge a possible therapeutic strategy to enhancing autophagy function.
Aim 2 of this project will examine the hypothesis that autophagy reduces ethanol-induced cell death and liver injury by removing damaged mitochondria and reducing total cellular lipid content, culminating in decreased ROS generation, lipid peroxidation, and ER stress. We anticipate that this study will result in important and systemic findings of how autophagy may function in ethanol-induced pathogenesis. The subject of whether and how autophagy may affect the progression of ALD is novel, critical, but insufficiently studied, despite the wide recognition of the importance of both the disease (ALD) and the mechanism (autophagy in the liver). This project could thus yield important information for the development of a novel approach toward the treatment of ALD.

Public Health Relevance

Alcohol liver disease (ALD) is a serious world wild health concern with very limited options of treatment. We have recently discovered that a novel cellular defensive mechanism, called autophagy, can protect against acute ethanol-induced liver injury and hepatocyte death possibly by regulating mitochondria and lipid homeostasis in hepatocytes, which constitutes the base of this proposal.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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Health Services Research Review Subcommittee (AA)
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Orosz, Andras
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Khambu, Bilon; Li, Tiangang; Yan, Shengmin et al. (2018) Hepatic Autophagy Deficiency Compromises FXR Functionality and Causes Cholestatic Injury. Hepatology :
Khambu, Bilon; Huda, Nazmul; Chen, Xiaoyun et al. (2018) HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers. J Clin Invest 128:2419-2435
Wang, Lin; Zhou, Jun; Yan, Shengmin et al. (2017) Ethanol-triggered Lipophagy Requires SQSTM1 in AML12 Hepatic Cells. Sci Rep 7:12307
Yan, Shengmin; Huda, Nazmul; Khambu, Bilon et al. (2017) Relevance of autophagy to fatty liver diseases and potential therapeutic applications. Amino Acids 49:1965-1979
Yu, Changshun; Yan, Shengmin; Khambu, Bilon et al. (2016) Gene Expression Analysis Indicates Divergent Mechanisms in DEN-Induced Carcinogenesis in Wild Type and Bid-Deficient Livers. PLoS One 11:e0155211
Kwon, Jason J; Willy, Jeffrey A; Quirin, Kayla A et al. (2016) Novel role of miR-29a in pancreatic cancer autophagy and its therapeutic potential. Oncotarget 7:71635-71650
Wang, Lin; Khambu, Bilon; Zhang, Hao et al. (2015) Autophagy in alcoholic liver disease, self-eating triggered by drinking. Clin Res Hepatol Gastroenterol 39 Suppl 1:S2-6