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Scientists at the UA make critical end-stage liver disease discovery
Date:4/25/2014

late in the cell," explained Zhang, who is also a member of the UA BIO5 Institute. "Nrf2 then activates the cellular antioxidant response. That is how antioxidants work." According to conventional wisdom, our bodies turn on their Nrf2-mediated protection pathway when subjected to high oxidative stress to limit the damage from the destructive oxygen compounds. During liver cirrhosis, Nrf2 should be induced by oxidative stress, but for reasons unclear until this study, this does not happen.

"This was a puzzle before we did our study," she said. "Somehow the protective mechanism mediated by Nrf2 is compromised by another factor, other than Keap1, in liver cirrhosis." Adding to the mystery is the fact that drugs aimed at inhibiting Keap1 from chewing up Nrf2 have proven ineffective in a cirrhotic liver.

When Zhang and her colleagues studied tissue samples from a human cirrhotic liver, they discovered the reason behind the inexplicably low Nrf2 levels in the face of rampant oxidative stress.

It turned out that another enzyme chews up Nrf2 and prevents the much-needed antioxidant response, exacerbating the disease process. That protein, Hrd1, is part of the cells' garbage disposal it specializes in destroying misfolded proteins before they can accumulate and damage cell components.

Under normal conditions, Hrd1 levels are low, so it does not interfere much with Nrf2, explained Zhang. As liver cirrhosis progresses, excessive inflammation triggers the garbage-mediated stress response and Hrd1 becomes very abundant and begins chewing up Nrf2.

The study is published in the April 1 issue of the journal Genes and Development. The first author of the report is Tongde Wu, a graduate of the UA Department of Pharmacology and Toxicology, who developed the project as part of her dissertation research. Fei Zhao and Eli Chapman, in the same department, also contributed to the research. The work resulted from a collaboration betwe
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Contact: Daniel Stolte
stolte@email.arizona.edu
520-626-4402
University of Arizona
Source:Eurekalert  

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