| dc.description.abstract | Chronic alcohol consumption can lead to an aberrant wound healing response of the liver, or hepatic fibrosis. Egr-1 is an essential regulator of many genes involved in the orchestration of tissue injury and repair, yet the implications of Egr-1 in different models of liver disease remain unclear. Previously, we demonstrated that carbon tetrachloride (CCl4)-induced hepatic fibrosis is enhanced in Egr-1 deficient mice. In this study, we investigated the role of Egr-1 in the attenuation of early markers of hepatic fibrosis using a model of ethanol-accelerated, CCl4-induced liver injury in wild-type and Egr-1 deficient mice. Whereas Egr-1 mRNA was induced 100-fold in livers from wild-type mice 48h after CCl4 exposure, ethanol feeding reduced Egr-1 expression by 50 percent. Seventy-two hours after CCl4 exposure, hepatic mRNA accumulation of type I collagen and αSMA, markers of fibrogenesis expressed by activated hepatic stellate cells (HSC), were increased 22-fold and 20-fold, respectively, in both wild-type and Egr-1 -/- mice; levels of these transcripts were greater in ethanol-fed, Egr-1 -/- mice. Consistently, plate-induced activation of HSC from Egr-1 deficient mice was increased relative to HSC from wild-type mice. Previous use of an oxidant stress, antioxidant defense pathway array identified genes differentially expressed in ethanol-fed, Egr-1 -/- mice compared to ethanol-fed, wild-type mice after CCl4 exposure. We examined one of these genes, NAD(P)H dehydrogenase, quinone 1 (Nqo1), and found that Nqo1 mRNA and protein was reduced in Egr-1 -/- mice relative to wild-type mice 72h after CCl4 exposure, and ethanol feeding exacerbated this reduction. Consistently, chromatin from livers of wild-type, CCl4-treated mice confirmed association between Egr-1 and the Nqo1 promoter upon immunoprecipitation with an Egr-1 antibody. Although Egr-1 deficient mice did not demonstrate inhibited oxidation of NADH after CCl4 via loss of Nqo1, β-lapachone-mediated stimulation of Nqo1 activity suppressed CCl4-induced liver injury and fibrogenic changes. Collectively, these data support the hypothesis that Egr-1 attenuates early markers of hepatic fibrosis, and here we propose that Nqo1, a previously unrecognized target of Egr-1, is a contributing factor | |
