Ethanol-induced hepatic fibrosis is a severe form of liver disease. Although great strides have been made in understanding the mechanisms by which fibrosis is established and how it resolves, these discoveries have not yet lead to improved therapeutic strategies. Egr-1 is a transcription factor that regulates a broad array of genes involved in inflammation and the wound-healing response. Egr-1 is a critical modulator of ethanolinduced fatty liver and acute hepatic inflammation in mice. Due to the ability of Egr-1 to regulate genes that modulate fibrosis, we hypothesize that Egr-1 is an important contributor to liver fibrosis after toxin-mediated liver injury. Indeed, recently published work completed during the K99 portion of this award revealed that carbon tetrachloride (CCI4)-induced liver fibrosis is enhanced in mice deficient in Egr-1. Enhanced fibrosis was associated with reduced hepatoprotection, more severe liver injury and a delay in hepatocyte entrance into and progression through the cell cycle in egr-1-/- mice after acute CCI4 exposure. Activation of the oval cell response in egr-1-/- mice after chronic CCW exposure is consistent with these findings. Collectively, our studies suggest novel roles for Egr-1 as a critical modulator the liver's response to hepatotoxins and the fibrogenic process. Ethanol feeding to mice produces limited fibrosis necessitating the use of hepatotoxicants such as CCi4 to explore mechanisms of fibrosis. To better understand the effects of ethanol exposure on fibrogenesis, we developed a new model with which we can 'accelerate'fibrosis using low-level ethanol (2% v/v ethanol for 5 days to 2 weeks) in combination with acute or chronic CCW exposure. Importantly, CYP2E1, the enzyme required for CCW bioactivation and induced in liver after chronic ethanol exposure, is not different between control and ethanol-fed mice exposed to this dose of ethanol. Using this model, as well as primary hepatic stellate cell cultures, we will continue to dissect the molecular mechanisms by which Egr-1 contributes to fibrosis through completion of the three Specific Aims as originally described.

Public Health Relevance

Hepatic fibrosis is a significant health problem in the United States. Regardless of the causative agent, the outcome is the same: patients with fibrosis are likely to progress to cirrhosis and later succumb to their disease. Liver transplantation is the only real 'cure', but the supply of donor livers is limited. Our studies will help define new therapeutic strategies to attenuate, halt and reverse fibrosis and, thus, limit need for liver transplantation.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Radaeva, Svetlana
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Case Western Reserve University
Internal Medicine/Medicine
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United States
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