RIP3-mediated necroptosis and ethanol-induced liver injury

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DESCRIPTION (provided by applicant): Although apoptosis has been associated with the progression of alcohol-induced liver injury, no direct evidence demonstrates that inhibition of apoptosis actually prevents alcoholic liver damage. We found that inhibition of apoptosis did not, in fact, attenuate ethanol-induced hepatocyte injury, expression of pro- inflammatory cytokines/chemokines or oxidative stress in Bid-deficient mice. Recently, a newly described mode of cell death, called necroptosis, has been implicated in caspase-independent cell injury in a variety of cell types. Necroptosis is activated in a fashion similar to apoptosis, but morphologically, the process resembles necrosis. Signaling mechanisms involving receptor-interacting protein kinases (RIP), including RIP1 and RIP3, mediate necroptosis induced by the activation of death ligands, including TNFa or Fas. In preliminary studies, we find, for the first time, that expression of RIP3, a central mediator of necroptosis, is increased in mouse livers following chronic ethanol feeding in parallel to the markers of hepatocyte injury. RIP3 is also induced in mouse liver in other models of hepatic injury including carbon tetrachloride (CCl4)- and ischemia/reperfusion-induced liver damage. Moreover, in pilot experiments we now show that RIP3-deficient mouse are protected from ethanol-induced liver injury and inflammation. Here we hypothesize that hepatocyte injury following chronic ethanol feeding is regulated by RIP3-driven caspase-independent cell death. To test our hypothesis, we will use mice deficient in RIP3 as well as treatment with necrostatin-1, a necroptosis inhibitor, during ethanol feeding. We will also use mice deficient in CYP2E1, TNFR1, and TLR4 to determine upstream activators of the RIP3-signaling pathway in response to ethanol feeding. This study will explore new pathways of cell death in mouse liver following ethanol feeding. The proposed work will help us to determine new molecular targets for better therapeutic management of alcoholic liver disease (ALD).