Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 446, Issue 2, Pages 111-118Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2005.12.011
Keywords
Nrf2; liver; fibrosis; stellate cell; antioxidant; oxidative stress; NADPH : quinone oxidoreductase; tert-butylhydroquinone; extracellular signal-regulated kinase; phosphatidyositol 3-kinase
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Funding
- NIAAA NIH HHS [AA05578-03, AA09300] Funding Source: Medline
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Liver fibrogenesis is dependant upon transdifferentiation of hepatic stellate cells to a profibrogenic phenotype. Prooxidant stress purportedly stimulates both an antioxidant response and myofibroblastic transdifferentiation with fibrogenic gene expression; however, mechanisms by which oxidative stress mediates stellate cell activation remain unclear. To this end, stellate cells were treated with tert-butylhydroquinone (tBHQ), a known inducer of antioxidant response genes. As anticipated, tBHQ induced expression of antioxidant response element (ARE)regulated genes via the transcription factor Nrf2. Further, tBHQ promoted transdifferentiation of quiescent stellate cells cultured on Engelbreth-Holm Swarm extracellular matrix. Pretreatment of cultured stellate cells with a phosphatidyositol 3-kinase (PI3K) inhibitor blocked tBHQ-mediated ARE-dependent gene induction as well as stellate cell transdifferentiation. In contrast, extracellular signal-regulated kinase, which was demonstrated to be prominently phosphorylated following tBHQ treatment, was not found to affect either induction of the antioxidant response nor stellate cell transdifferentiation. These data implicate involvement of PI3K pathways in tBHQ-mediated stellate cell activation and demonstrate a requirement for PI3K in the antioxidant response of hepatic stellate cells. (c) 2005 Elsevier Inc. All rights reserved.
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