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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Roger L. Jenkins, MD Postdoctoral Research Fellowship
University of North Carolina at Greensboro
Project Title: Dysregulation of aldehyde dehydrogenase in the pathogenesis of alcoholic liver disease
Alcoholic liver disease (ALD) is a major health problem. Dr. Zhong’s long-term goal is to understand the mechanisms of pathogenesis and develop effective therapies for treatment of ALD. Alcohol metabolism in the liver generates aldehydes including acetaldehyde and lipid aldehydes such as 4-hydroxynonenol and malondialdehyde which are detoxified by aldehyde dehydrogenases (ALDH). However, aldehyde accumulation has been documented in patients with ALD, suggesting a dysregulation of aldehyde detoxification. Dr. Zhong’s preliminary studies have shown that chronic alcohol exposure induces aldehyde accumulation and liver damage, but surprisingly, hepatic ALDH was not induced. She also found that zinc supplementation up-regulated ALDH and attenuated aldehyde accumulation in association with restoring zinc finger transcription factors, hepatocyte nuclear factor-4α (HNF-4α) and peroxisome proliferation-α (PPAR-α). These data suggest that ALDH dysregulation due to HNF-4α and PPAR-α inactivation may account for aldehyde hepatoxicity in ALD. Dr. Zhong thus proposes to investigate the molecular mechanisms of aldehyde detoxification in the pathogenesis of ALD. She will first determine if aldehyde detoxification critically impacts alcohol-induced hepatic lipid accumulation and inflammation. Her hypothesis is that activation of ALDH by ALDH activator, will speed up aldehyde clearance, thereby attenuating aldehyde accumulation and liver damage. Dr. Zhong will then define the molecular mechanism by which hepatic ALDH genes are not up-regulated despite aldehyde generation. Her hypothesis is that the aldehydes form adducts with hepatic transcription factors including HNF-4α and PPAR-α, thereby inactivating these transcription factors and preventing ALDH transactivation.
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