title: Dimethylarginine Dimethylaminohydrolase 1 Protects Against High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance in Mice.
abstract: 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.
  
  
  
  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 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.
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Tianhe
authors: T
authors: Li
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Run
authors: R
authors: Feng
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Chenyang
authors: C
authors: Zhao
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Yue
authors: Y
authors: Wang
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Jian
authors: J
authors: Wang
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Shasha
authors: S
authors: Liu
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Jianwei
authors: J
authors: Cao
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Hongyun
authors: H
authors: Wang
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Ting
authors: T
authors: Wang
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Yuting
authors: Y
authors: Guo
authors: College of Life Science, University of Chinese Academy of Sciences , Beijing, China .
authors: Zhongbing
authors: Z
authors: Lu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D005227:Fatty Acids; D055372:AMP-Activated Protein Kinases; D000581:Amidohydrolases; C059999:dimethylargininase; D005947:Glucose
keywords: ADMA; AMPK; DDAH1; hepatic steatosis