Dimethylarginine dimethylaminohydrolase 1 protects against high fat diet induced hepatic steatosis and insulin resistance in mice.

Abstract Aims: High plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are associated with hepatic dysfunction in patients with nonalcoholic fatty liver disease (NAFLD). However, it is unknown whether ADMA is involved in the pathogenesis of NAFLD. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an enzyme that degrades ADMA. In this study, we used Ddah1−/− mice to investigate the effects of the ADMA/DDAH1 pathway on high-fat diet (HFD)-induced hepatic steatosis. Results: After HFD feeding for 20 weeks, Ddah1−/− mice were more obese and had developed more severe hepatic steatosis and worse insulin resistance compared with wild-type (WT) mice. In the livers of HFD-fed mice, loss of DDAH1 resulted in higher levels of lipogenic genes, lower expression of β-oxidation genes, and greater induction of oxidative stress, endoplasmic reticulum stress, and inflammation than in the WT livers. Furthermore, ADMA treatment in HepG2 cells led to oxidative stress...