Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Pharmacology and Toxicology, MS
Committee Co-Chair (if applicable)
Acrolein; Alcoholic liver diseases; Alcohol--Physiological effect
Alcohol is the most socially accepted addictive drug, and it can cause alcoholic liver disease (ALD), which is a major cause of morbidity and mortality in the United States and worldwide. Animal and human studies demonstrate that chronic alcohol consumption causes a pro-oxidant environment in the liver and increases hepatic lipid peroxidation and the accumulation of by-products such as acrolein and 4-hydroxynonenal. Acrolein is the most reactive and toxic aldehyde generated through lipid peroxidation. Also, acrolein is a major component of cigarette smoke, and there is increasing evidence that smoking negatively impacts the incidence, severity, and clinical course of chronic liver disease. Acrolein is known to form protein adducts, and can trigger endoplasmic reticulum (ER) stress. Notably, alcohol-induced perturbations in the ER have emerged as an important etiologic factor in alcoholic liver disease. This study investigated the role of acrolein as a mediator of hepatic ER stress and injury during alcohol consumption. Acrolein accumulation, activation of pro-apoptotic stress kinase JNK ( the mitogen activated protein kinase c-jun N-terminal kinase) , ER stress, and apoptotic cell death was examined in vitro in alcohol-exposed rat hepatic cells (H4IIEC), and in vivo in a mouse model of alcohol consumption. Exposure to alcohol led to substantial accumulation of acrolein adducts both in vitro and in vivo. This was accompanied by phospho-activation of JNK and upregulation of ER stress transcription factors ATF3 and ATF4, and the pro-apoptotic protein, GADD153/CHOP. This study demonstrates that acrolein is likely to be a major culprit in the ER stress and hepatotoxicity associated with alcohol consumption. Also, the data show that acrolein removal protects against alcohol-induced ER stress and injury, suggesting that acrolein scavengers may have therapeutic potential in alleviating the adverse effects of alcohol consumption.
Chen, Wei-Yang (Jeremy) 1980-, "Pathogenic role of acrolein in alcoholic liver disease." (2014). Electronic Theses and Dissertations. Paper 1722.