Dimethylarginine Dimethylaminohydrolase 1 Protects Against High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance in Mice.

AIMS: mice to investigate the effects of the ADMA/DDAH1 pathway on high-fat diet (HFD)-induced hepatic steatosis. RESULTS: 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 and steatosis, whereas overexpression of DDAH1 attenuated palmitic acid-induced steatosis, oxidative stress, and inflammation. Innovation and Conclusion: Our results provide the first direct evidence that the ADMA/DDAH1 pathway has a marked effect on hepatic lipogenesis and steatosis induced by HFD feeding. Our findings suggest that strategies to increase DDAH1 activity in hepatocytes may provide a novel approach to attenuate NAFLD development. Antioxid. Redox Signal. 26, 598-609.

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