Neutrophil elastase in obesity-related fatty liver diseases

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Summary Obesity is the primary factor that contributes to the development of nonalcoholic fatty liver diseases (NAFLD), including steatosis and nonalcoholic steatohepatitis (NASH), and fibrosis in the liver. However, the molecular and cellular events that initiate and propagate obesity-related steatosis, inflammatory damage, and fibrotic remodeling in the liver remain unclear. We observed that a fat- and fructose-enriched diet increases pro- inflammatory neutrophil production preceding leukocyte infiltration, lipid deposition, and inflammatory damage in the liver. However, neutrophil elastase (NE) knockout (KO) mice or mice treated with an NE inhibitor are resistant to obesogenic diet-induced inflammation, lipid deposition, and fibrosis in the liver. Based on our preliminary data, we hypothesize that inhibition of NE prevents obesity-induced proinflammatory neutrophil production via altering NAD-dependent deacetylase Sirtuin 1 (Sirt1) signaling pathway in neutrophils. Deletion of NE also activates AMP-kinase (AMPK), increases the expression of peroxisome proliferator-activated receptor alpha (PPARα), and enhances mitochondrial gene expression and fatty acid oxidation, attenuating obesogenic diet- induced steatosis in the liver. Furthermore, inhibition or deletion of NE mitigates obesogenic diet-induced accumulation of inflammatory macrophages and T-helper 17 cells, inflammatory damage, and collagen deposition in the liver. In this proposal, we will evaluate if Sirt1 in neutrophils, and if PPARα and AMPKα in the liver are required for the beneficial effects of NE inhibition on diet-induced NASH. To understand how NE inhibition regulates diet-induced liver fibrotic remodeling, we will also explore the molecular basis by which neutrophils interact with other immune and non-immune cells in the liver. Successful completion of this project will shed new light on molecular and cellular mechanisms by which inhibition of NE as a potential therapeutic approach for obesity-related fatty liver diseases.