The long-term objectives of this research project are to characterize the signaling pathways that control the hepatic regenerative response in liver injury and disease. Clinical experience suggests that derangement of this regenerative response in chronic liver disease can lead to cirrhosis or neoplasia. Studies using the partial hepatectomy (PH) model system have led to the elucidation of a number of important coordinated signaling events involved in the initiation of hepatic regeneration. These include the production of cytokines and growth factors, generation of mitochondrial reactive oxygen species (ROS), activation of stress- and mitogen-activated-protein (MAP) kinases, and induction of transcription factors. We have shown that prostaglandin synthesis is also required for initiation of this regenerative response. Inhibition of prostaglandin synthesis with non-steroidal anti-inflammatory drugs (NSAIDs) augments TNFalpha-IL-6-STAT3 signaling, prolongs MAP kinase activation, and impairs activation of Jun nuclear kinase (Jnk) during liver regeneration. These changes are remarkably similar to alterations that occur in mouse models of steatohepatitis. In steatohepatitis models, altered production of ROS occurs in response to augmented cytokine signaling, and leads to subsequent alterations in MAP kinase and Jnk activation and inhibition of liver regeneration. This suggests that changes in cytokine-regulated ROS production may be involved in the mechanism by which inhibition of prostaglandin synthesis leads to impaired liver regeneration. Therefore, we hypothesize that prostaglandin synthesis is essential for appropriate regulation of cytokine-stimulated ROS production after PH and that changes in ROS metabolism are a fundamental component of the mechanism by which inhibition of prostaglandin synthesis leads to impaired liver regeneration. This could have important implications with respect to the clinical use of NSAIDs in patients with liver disease. In this grant we propose to determine the effects of prostaglandins on ROS synthesis, expression of genes regulating ROS metabolism, and expression and activity of negative regulators of cytokine signaling during liver regeneration.
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| Shteyer, Eyal; Liao, Yunjun; Muglia, Louis J et al. (2004) Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice. Hepatology 40:1322-32 |
