Eighteen million Americans abuse alcohol, with alcoholic liver disease (ALD) affecting over 10 million people. The development of ALD is a complex process involving both parenchymal and non-parenchymal cells in liver. The impact of ethanol on hepatocytes is characterized as a condition of ?organelle stress? with multi-factorial changes in hepatocellular function accumulating, ultimately leading to hepatocellular death by both apoptosis and necrosis/necroptosis. Enhanced inflammation in the liver during ethanol exposure is also an important contributor to injury. Accumulating evidence indicates a strong relationship between cell death, inflammation and progression of ALD. However, the contribution of specific programmed cell death pathways in parenchymal and non-parenchymal cells to ALD is not well understood. Apoptosis is considered to be a less inflammatory mode of cell death, while death by necrosis/necroptosis releases multiple pro-inflammatory mediators into the local environment. Importantly, programmed cell death has key homeostatic functions; for example, activation-induced death of macrophages is a key element in the resolution of inflammation. Hepatocyte death via apoptosis is associated with the progression of ALD. Recently, we reported that RIP3- mediated necroptotic cell death drives ethanol-induced liver injury in a murine model and that RIP3 expression is increased in liver of ALD patients. Taken together, our data indicate that RIP3-dependent necrosome formation is critical to the progression of ethanol-induced liver injury. In order to leverage this new mechanistic understanding for the development of ALD into therapeutic strategies for treatment or prevention of ALD, here we will make use of both in vivo and cell culture models to identify the mechanisms for RIP3-necrosome formation during ethanol exposure, as well determine the specific down-stream effector pathways which mediate ethanol-induced necroptotic cell death. Our three specific aims are to: 1) Identify the ethanol-induced pathways of RIP3/MLKL necrosome formation, 2) Determine the mechanism of necroptotic cell death in hepatocytes during chronic ethanol exposure and 3) Understand the differential contribution of RIP3- dependent necroptosis in hepatocytes vs myeloid cells in the development ALD. The elucidation of detailed mechanisms for ethanol-induced programmed cell death in the liver will provide insight into future hepatocellular homeostasis and anti-inflammatory drug design and discovery, particularly related to ALD, as well as advance our knowledge of programmed cell death in the liver in general. Importantly, our studies will target a neglected therapeutic approach for preventing ethanol-induced inflammation and hepatocellular death.
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