Plasma membrane rupture in alcohol-associated hepatitis

Tulane University Of Louisiana, New Orleans LA

Investigators

Abstract

Project Summary Alcohol-associated hepatitis (AH) is a severe, potentially life-threatening form of alcohol-associated liver disease (ALD) with limited therapeutic options. Cholestasis and biliary dysfunction are common in AH patients and can worsen AH prognosis. Plasma membrane integrity usually determines whether a form of cell death is pro-inflammatory. Lytic cell death pathways can cause plasma membrane changes and eventually lead to plasma membrane rupture (PMR), which releases intracellular contents that stimulate the immune response. The role of PMR in ALD remains unknown. There is a critical need to determine the role of cholestasis in promoting PMR in ALD and the therapeutic potential of targeting PMR in AH. The long-term goal is to contribute toward the development of clinically useful, mechanism-based diagnostic and therapeutic interventions to improve outcomes in patients with advanced ALD. The overall objectives for this proposal are to 1) determine the role of PMR in ALD, and 2) investigate the mechanism by which cholestasis promotes hepatocellular PMR in the setting of ALD. The central hypothesis is that cholestasis promotes PMR in hepatocytes, thereby enhancing alcohol-associated liver damage. The rationale for the proposed research is based on the identification of cholestatic injury in a preclinical model of AH. The overall objectives of this application will be attained by pursuing two specific aims: (1) Determine the role of PMR in ALD; (2) Investigate the mechanism by which cholestasis promotes hepatocellular PMR in ALD. Under the first aim, the working hypothesis will be determined in mice and in vitro cell or organoid cultures with a key PMR contributor knocked down by vivo- morpholinos. For the second aim, the working hypothesis will be tested in liver tissues from ALD patients and in in vitro cell or organoid cultures to understand the role of bile acid-mediated pathways in PMR. The contribution of this proposal will be to determine the role of PMR during the progression of ALD and begin to clarify the mechanisms underlying hepatocellular PMR in ALD. Upon completion of the proposed project, there is the promise that a significant advance in understanding the mechanism of AH will have been made, and a mechanistic link will have been established between cholestasis and hepatocellular PMR in ALD. The successful completion of the proposed studies will be significant because they are expected to offer novel therapeutic targets for ALD.