title: Comparative effects of the renin-angiotensin system blockers on nonalcoholic fatty liver disease and insulin resistance in C57BL/6 mice.
abstract: BACKGROUND
  The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. The current study evaluated the effects of RAS blockers in a model of diet-induced insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD).
  
  
  METHODS
  Male C57BL/6 mice were fed a standard chow (SC; 10% lipids, n=15) diet or a high-fat (HF; 50% lipids, n=60) diet for 8 weeks and then treated with aliskiren (HF-A; 50 mg/kg per day, n=15), enalapril (HF-E; 30 mg/kg per day, n=15), or losartan (HF-L; 10 mg/kg per day, n=15) for an additional 6 weeks. We assessed glucose and lipid metabolism, hepatic histopathology, the expression profile of genes and proteins affecting hepatic gluconeogenesis, RAS and insulin signaling, and lipid beta-oxidation and accumulation. The differences between the groups were tested via analysis of variance (ANOVA) and the post hoc Holm-Sidak test.
  
  
  RESULTS
  All treatments restored the up-regulation of hepatic RAS. The enalapril treatment, but not aliskiren or losartan, was effective in improving leptin, glucose intolerance, IR, hepatic steatosis, and triglycerides and in preventing increased hepatic protein levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and glucose transporter-2 (GLUT-2). Furthermore, enalapril improved the response to the deleterious effects of the HF diet by upregulating signal transduction through the insulin receptor substrate (IRS) 1/protein kinase B (Akt) pathway, as well as downregulating the protein levels and mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1c (SREBP-1c), and fatty acid synthase (FAS).
  
  
  CONCLUSIONS
  Enalapril was the most successful treatment in protecting against hepatic IR and NAFLD by enhancing hepatic insulin action, leptin, and gluconeogenesis and by reducing the lipogenic pathway and lipid accumulation in the liver.
authors: Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro , Rio de Janeiro, Brazil .
authors: Eliete Dalla Corte
authors: ED
authors: Frantz
authors: Aline
authors: A
authors: Penna-de-Carvalho
authors: Thais de Medeiros
authors: Tde M
authors: Batista
authors: Marcia Barbosa
authors: MB
authors: Aguila
authors: Carlos Alberto
authors: CA
authors: Mandarim-de-Lacerda
mesh_terms: D000273:Adipose Tissue; D000577:Amides / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004656:Enalapril / Q000494:pharmacology; D005650:Fumarates / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005943:Gluconeogenesis; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D050356:Lipid Metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy*; D012084:Renin-Angiotensin System / Q000502:physiology*
chemical_list: D000577:Amides; D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D005650:Fumarates; D020738:Leptin; C446481:aliskiren; D004656:Enalapril; D019808:Losartan