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. ALD is the result of long-term alcohol consumption. It is also not clear how ethanol may affect the function of autophagy during the long exposure, which in turn can affect the disease. It would be important to understand how and why macroautophagy can counteract the toxicity of ethanol in the liver and the dynamics of this process, which could lead to a further understanding of the pathogenesis of ALD, and, more importantly, novel approaches to treat the disease. Toward that end, we have developed the following aims.
Aim 1 will investigate the dynamics of autophagy and its signaling environment during a prolonged ethanol treatment to determine the function status of autophagy during this course, thus providing a deeper understanding of the ethanol-induced pathogenesis regarding the impact on a cellular defensive mechanism.
Aim 2 will examine the hypothesis that autophagy ameliorates oxidative stress, lipotoxicity and ER stress to protect against cell death and liver injury. This is based on the observation that ethanol-induced autophagy is characterized by its selectivity toward damaged mitochondria and lipid droplets. Our studies should provide the essential knowledge of how autophagy can impact the development of alcoholic liver injury. In couple with the studies of Aim 2, Aim 3 will dissect the mechanisms of selective autophagy in hepatocytes by exploring the participation of a conserved molecular pathway in both in vivo and in vitro systems. This study in this aim will provide the basis for future intervention at a specific site to control ethanol-induced liver pathology. Overall, the exploration of autophagy in ALD represents a novel direction in the field and will generate novel information regarding the pathogenesis and therapy.
Alcohol liver disease (ALD) is a serious world wild health concern, for which there are very limited ways 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. We propose that autophagy is important in regulating ethanol-induced liver injury in hepatocytes, which could be the basis of its protection against ethanol toxicity in the liver.
|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|
|Li, M; Fu, Y; Yang, Z et al. (2017) Measurement of the Activity of the Atg4 Cysteine Proteases. Methods Enzymol 587:207-225|
|Huang, Tianzhi; Kim, Chung Kwon; Alvarez, Angel A et al. (2017) MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma. Cancer Cell 32:840-855.e8|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|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|
|Bronner, Denise N; Abuaita, Basel H; Chen, Xiaoyun et al. (2015) Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage. Immunity 43:451-62|
|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|