Knockout of neutrophil elastase protects against western diet induced nonalcoholic steatohepatitis in mice by regulating hepatic ceramides metabolism.

Previous studies reported increased expression and activity of neutrophil elastase (NE) in NASH. However, the role of NE in nonalcoholic steatohepatitis (NASH) remained unclear. Wild type (WT) and NE knockout (NE KO) mice were fed with western diet (WD) for 24 weeks to establish NASH model. The severity of liver injury in NASH mice was assessed by biochemical analysis, liver triglyceride (TG) quantitation and histological scoring. The gene and protein expression was detected by quantitative real-time PCR, immunohistochemical and immunofluorescence staining (IHC/IF) and western blot analysis. After 24 weeks, WD induced WT (WD-WT) mice had significantly up-regulated NE protein in the liver. Moreover, body weight, liver/body weight, serum and hepatic TG, liver histological score, and hepatic inflammatory factors expression were significantly higher in WD-WT mice than those in low fat diet (LFD) induced WT mice, and these effects were markedly improved by NE KO. In addition, we found incereased expression of ceramides and serine palmitoyltransferase subunit 2 (SPT2) in WD-WT mice could be reversed by NE KO. Up-regulating expression of ceramides and SPT2 by active NE treatment was also found in mice primary hepatocytes. Collectively, these findings indicated that NE KO ameliorated WD induced NASH, and this beneficial effect was due, at least in part, to the potential of NE in regulating hepatic ceramides metabolism.