Neutrophil elastase in obesity-related fatty liver diseases

Boston University Medical Campus, Boston MA

Investigators

Linked publications, trials & patents

Abstract

Liver inflammation and steatosis are fundamental pathological changes that contribute to the development of systemic insulin resistance in obesity. However, the molecular and cellular events that initiate and propagate obesity-related non-alcoholic fatty liver disease (NAFLD) remain unclear. We reported that neutrophil elastase (NE) knockout (KO) mice are resistant to a high-fat diet (HFD)-induced systemic inflammation, fatty liver, and insulin resistance. HFD feeding of WT mice for only a few days increases proinflammatory neutrophil production preceding vascular leakage, leukocyte infiltration and steatosis in the liver. Based on our preliminary data, we hypothesize that inhibition of NE prevents HFD-induced proinflammatory neutrophil production via altering NAD-dependent deacetylase Sirtuin 1 (Sirt1) signaling pathway in neutrophils. Inhibition of NE also increases the levels of high-molecular-weight adiponectin that activates AMP-kinase (AMPK) and fatty acid oxidation, thus attenuating HFD-induced steatosis in the liver. In addition, inhibition of NE also ameliorated high-fat high-carb diet (HFHCD)- induced steatosis, nonalcoholic steatohepatitis (NASH) and collagen deposition in the liver. In this proposal, we will evaluate if Sirt1 in neutrophils and the adiponectin ? AMPK pathway in the liver are required for the beneficial effects of NE inhibition on diet-induced neutrophil phenotypic changes, inflammatory liver damage and steatosis. Successful completion of this project will shed new light on molecular and cellular mechanisms by which inhibition of NE prevent obesity-related NAFLD and insulin resistance.