1853-P: Neutrophils Play a Pivotal Role in Obesogenic Diet-Induced Nonalcoholic Steatohepatitis

Abstract

Lipid deposition, inflammatory damage, and fibrotic remodel are the hallmarks of nonalcoholic steatohepatitis (NASH). However, the molecular and cellular mechanisms by which obesogenic diet-induced progression from steatosis to NASH remains elusive. Here, we report that neutrophils play a significant role in mediating NASH in the liver. Remarkably, high-fat high-fructose diet (HFHFD) feeding increased expression of chemokines in the liver leading to a dramatic upsurge of neutrophil infiltration into the liver with a concomitant increase of macrophages and Th17 cell accumulation and collagen deposition in the liver. In contrast, inhibition or deletion of neutrophil elastase (NE) significantly reduced lipid deposition, metabolic stress, and inflammation in the liver in mice fed obesogenic diets. Inhibition of NE dramatically reduced the expression of chemokines, accumulation of neutrophils, macrophages, and Th17 cells, and progress of fibrosis in the liver. Together, our data suggest that NE contributes to NASH progression through regulating metabolic signaling and inflammatory damage in the liver. Disclosure Q.L. Zhou: None. S. Khan: None. M. Rigor: None. I. Beeram: None. Z.Y. Jiang: None. Funding National Institutes of Health (1R56DK121142)