Limited role for hyperammonemia in the progression of diet‐induced nonalcoholic steatohepatitis

Objectives To determine whether hyperammonemia has a direct impact on steatohepatitis in mice fed with a high‐fat diet (HFD). Methods Male C57BL/6 mice were divided into two groups receiving either chow diet or HFD. After 12‐week NASH modeling, hyperammonemia was induced by intragastric administration of ammonium chloride solution (NH 4 Cl) or liver‐specific carbamoyl phosphate synthetase 1 ( Cps1 ) knockdown. In vitro experiments were performed in HepG2 cells induced by free fatty acid (FFA) and NH 4 Cl. Results NH 4 Cl administration led to increased levels of plasma and hepatic ammonia in NASH mice. NH 4 Cl‐induced hyperammonemia did not influence liver histological changes in mice fed with HFD; however, elevated plasma cholesterol level, and an increasing trend of liver lipid content were observed. No significant effect of hyperammonemia on hepatic inflammation and fibrosis in NASH mice was found. In vitro cell experiments showed that NH 4 Cl treatment failed to increase the lipid droplet content and the expressions of de novo lipogenesis genes in HepG2 cells induced by FFA. The knockdown of Cps1 in HFD‐fed mice resulted in elevated plasma ammonia levels but did not cause histological change in the liver. Conclusions Our study revealed a limited role of ammonia in aggravating the progression of NASH. Further studies are needed to clarify the role and mechanism of ammonia in NASH development.