title: Aliskiren attenuates steatohepatitis and increases turnover of hepatic fat in mice fed with a methionine and choline deficient diet.
abstract: OBJECTIVE
  Activation of the renin-angiotensin-system is known to play a role in nonalcoholic steatohepatitis. Renin knockout mice manifest decreased hepatic steatosis. Aliskiren is the first direct renin inhibitor to be approved for clinical use. Our study aims to evaluate the possible therapeutic effects and mechanism of the chronic administration of aliskiren in a dietary steatohepatitis murine model.
  
  
  METHODS
  Male C57BL/6 mice were fed with a methionine and choline-deficient (MCD) diet to induce steatohepatitis. After 8 weeks of feeding, the injured mice were randomly assigned to receive aliskiren (50 mg·kg(-1) per day) or vehicle administration for 4 weeks. Normal controls were also administered aliskiren (50 mg·kg(-1) per day) or a vehicle for 4 weeks.
  
  
  RESULTS
  In the MCD mice, aliskiren attenuated hepatic steatosis, inflammation and fibrosis. Aliskiren did not change expression of lipogenic genes but increase turnover of hepatic fat by up-regulating peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1a, cytochrome P450-4A14 and phosphorylated AMP-activated protein kinase. Furthermore, aliskiren decreased the hepatic expression of angiotensin II and nuclear factor κB. The levels of oxidative stress, hepatocyte apoptosis, activation of Kupffer cells and hepatic stellate cells, and pro-fibrotic markers were also reduced in the livers of the MCD mice receiving aliskiren.
  
  
  CONCLUSIONS
  Aliskiren attenuates steatohepatitis and fibrosis in mice fed with a MCD diet. Thus, the noted therapeutic effects might come from not only the reduction of angiotensin II but also the up-regulation of fatty acid oxidation-related genes.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan ; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan ; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Kuei-Chuan
authors.initials: KC
authors.lastname: Lee
authors.forename: Che-Chang
authors.initials: CC
authors.lastname: Chan
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Yang
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Yi-Hsiang
authors.initials: YH
authors.lastname: Huang
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
mesh_terms: D000577:Amides / Q000627:therapeutic use*; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002794:Choline / Q000378:metabolism*; D004032:Diet; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005650:Fumarates / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000804:Angiotensin II; D002794:Choline; D005650:Fumarates; D007328:Insulin; D008715:Methionine; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D014280:Triglycerides; D000092502:Renin Inhibitors; C446481:aliskiren