Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Arteel, Gavin Edward
Liver; Oxidative stress; Aldehyde dehydrogenase 2; Alda-1; Hepatocyte; Partial hepatectomy
Liver--Cirrhosis; Oxidative stress
Alcoholic liver disease (ALD) ranks among the major causes of morbidity and mortality in the world and effects millions of patients each year. Progression of ALD is well characterized and is actually a spectrum of liver diseases, which progresses from steatosis, to inflammation and necrosis, to finally fibrosis and cirrhosis. However, the underlying mechanism(s) of ALD are not as well understood, and as a result there is no FDA-approved therapy to prevent or reverse the disease. With a better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of ALD, a targeted therapy can be developed to treat or prevent it. The regenerative capacity of the liver is inhibited in fibrosis and cirrhosis. By enhancing the regenerative ability of the liver we may be able to reverse the effects of ALD. Indeed, recent in vivo studies by this group indicate that activating Aldehyde Dehydrogenase 2 (ALDH2) with Alda-1 (a novel ALDH2 activator) or Ethanol (EtOH) protects against oxidative stress and damage to the liver, as result enhancing regeneration. Because ALDH2 can protect mitochondria from oxidative stress that results from partial hepatectomy, oxidative stress from other sources should be protected against as well. To test this hypothesis, primary hepatocytes were isolated from mice and plated on 96-well plates for analysis via Cellomics High Content Screening. Some mice were administered EtOH for 3 days prior to hepatocyte isolation or exposed to Alda-1 to activate ALDH2. Cells were exposed to 4-Hydroxynonenal (4-HNE; 0-1000 µM) for 0-24 H. Activation of ALDH2, by pretreatment with EtOH or Alda-1 preexposure, clearly protected isolated hepatocytes from 4-HNE toxicity. Mitochondrial membrane potential was significantly increased in cells with activated ALDH2 and membrane permeability was decreased in these cells as well. These changes in hepatocyte viability indicate that activation of ALDH2 protects cells from oxidative stress.
Baldauf, Keegan J. 1982-, "Acetaldehyde dehydrogenase 2 (ALDH2) activation protects hepatocytes from mitochondrial damage and death caused by 4-hydroxynonenal." (2012). Electronic Theses and Dissertations. Paper 63.