Mechanisms underlying hepatic immune cell recruitment in nonalcoholic fatty liver disease

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PROJECT SUMMARY/ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a spectrum of progressive conditions ranging from nonalcoholic fatty liver (NAFL) or hepatic steatosis to the more severe nonalcoholic steatohepatitis (NASH) characterized by excessive inflammation and varying degrees of fibrosis. NASH-related cirrhosis is the second leading cause of liver transplantation in the United States and NASH patients face an increased risk of developing hepatocellular carcinoma. The incidence of NASH and NASH-related cirrhosis continues to rise; there, are no FDA-approved therapies as we lack a clear understanding of the cellular and molecular mechanisms driving the progression of NAFL to NASH and the subsequent development of cirrhosis. While there is mounting evidence that inflammation is central to the initiation and progression of NAFLD, the specific immune pathways that drive inflammation in this setting are not well understood. The objective of this proposal is to improve our functional understanding of the mechanisms by which immune cells contribute to NASH-related hepatic inflammation, and to identify the key molecules underlying recruitment of immune cells to the liver. Our published findings and preliminary data have demonstrated that the heterodimeric integrin receptor α4β7 and its ligand, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), play a pivotal role in NASH-related hepatic inflammation and fibrosis by promoting the recruitment of inflammatory monocytes and CD4 T cells to the liver. These data provide the scientific rationale for our central hypothesis that the α4β7/MAdCAM-1 axis drives hepatic inflammation and fibrosis in NASH by promoting recruitment of proinflammatory monocytes and CD4 T cells to the liver. We will test this hypothesis in both a mouse model of progressive NAFLD and in human liver tissue from NASH patients according to the following integrated Specific Aims. Aim 1 will investigate the contribution of α4β7+ monocytes and CD4 T cells in promoting hepatic inflammation in NASH. Aim 2 focuses on the role of hepatic stellate cells in the regulation of immune cell recruitment to the NASH liver. Lastly, Aim 3 investigates the mechanisms regulating the α4β7/MAdCAM-1 axis in NASH. The results of our investigations will provide comprehensive and mechanistic insights into the inflammatory events crucial to the pathogenesis of NASH, and may lead to the identification of viable therapeutic targets for regulating hepatic inflammation. Given the importance of immune cells in governing metabolic inflammation and the therapeutic potential of targeting immune cells, this proposal addresses significant and clinically relevant issues in NASH.