Role of Early Growth Response Factor-1 in Cholestatic Liver Injury

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The overall goal of this proposal is to elucidate the mechanism by which cholestasis triggers production of proinflammatory mediators in the liver. Cholestatic liver disease arises when excretion of bile acids from the liver is interrupted. This results in the accumulation of bile acids in the liver, hepatic inflammation, and hepatocyte injury. The pathogenesis of hepatocyte injury during cholestasis depends in part on the release of proinflammatory mediators that cause neutrophils to accumulate in the liver and become activated to damage hepatocytes. Interestingly, inflammation associated with cholestasis occurs independently of tumor necrosis factor-a or interteukin-1, suggesting that this process is regulated by a novel, previously undescribed mechanism. Our preliminary studies indicate that the transcription factor, early growth response factor-1 (Egr-1), is critical for this process. Egr-1 is rapidly upregulated in hepatocytes during cholestasis. Upregulation of Egr-1 appears to be mediated directly by bile acids, since exposure of primary mouse hepatocytes to pathological concentrations of bile acids upregulates Egr-1. Our studies show further that upregulation of macrophage inflammatory protein-2, intercellular adhesion molecule-1, neutrophil accumulation, and hepatocyte injury are dramatically reduced in Egr-1 knockout mice with cholestasis. These preliminary results suggest that upregulation of Egr-1 in hepatocytes is vital for the development of neutrophil-dependent inflammatory liver injury. Furthermore, these studies indicate that Egr-1 provides the critical link between elevated concentrations of bile acids and the production of proinflammatory mediators in liver. Therefore, the main hypothesis of this proposal is that during early stages of cholestasis, elevated concentrations of bile acids upregulate Egr-1 in hepatocytes, which increases expression of proinflammatory mediators that cause neutrophils to accumulate in the liver and become activated to damage hepatocytes. The studies in this proposal aim to test this hypothesis by: (1) elucidating the molecular mechanism(s) by which bile acids upregulate Egr-1 in hepatocytes, (2) determining whether Egr-1 regulates proinflammatory mediator expression by hepatocytes, and (3) determining whether bile acids increase proinflammatory mediator expression by hepatocytes through Egr-1-dependent mechanisms. A greater understanding of the molecular mechanism(s) by which Egr-1 mediates hepatocellular injury during cholestasis could provide insight into ways to treat this disease in humans. Furthermore, since bile acid concentrations are increased in several types of liver disease in humans, this pathway could also prove to be an important, general mechanism of inflammatory injury in the liver.