title: Contribution of Cyclooxygenase End Products and Oxidative Stress to Intrahepatic Endothelial Dysfunction in Early Non-Alcoholic Fatty Liver Disease.
abstract: BACKGROUND
  Metabolic syndrome induces endothelial dysfunction, a surrogate marker of cardiovascular disease. In parallel, metabolic syndrome is frequently associated with non-alcoholic fatty liver disease (NAFLD), which may progress to cirrhosis. The aim of the present study was to evaluate intrahepatic endothelial dysfunction related to cyclooxygenase end products and oxidative stress as possible mechanisms involved in the pathophysiology of NAFLD.
  
  
  METHODS
  Sprague-Dawley rats were fed standard diet (control-diet, CD) or high-fat-diet (HFD) for 6 weeks. Metabolic syndrome was assessed by recording arterial pressure, lipids, glycemia and rat body weight. Splanchnic hemodynamics were measured, and endothelial dysfunction was evaluated using concentration-effect curves to acetylcholine. Response was assessed with either vehicle, L-NG-Nitroarginine (L-NNA), indomethacin, tempol, or a thromboxane receptor antagonist, SQ 29548. We quantified inflammation, fibrosis, oxidative stress, nitric oxide (NO) bioavailability and thromboxane B2 levels.
  
  
  RESULTS
  HFD rats exhibited metabolic syndrome together with the presence of NAFLD. Compared to control-diet livers, HFD livers showed increased hepatic vascular resistance unrelated to inflammation or fibrosis, but with decreased NO activity and increased oxidative stress. Endothelial dysfunction was observed in HFD livers compared with CD rats and improved after cyclooxygenase inhibition or tempol pre-incubation. However, pre-incubation with SQ 29548 did not modify acetylcholine response.
  
  
  CONCLUSIONS
  Our study provides evidence that endothelial dysfunction at an early stage of NAFLD is associated with reduced NO bioavailability together with increased cyclooxygenase end products and oxidative stress, which suggests that both pathways are involved in the pathophysiology and may be worth exploring as therapeutic targets to prevent progression of the disease.
authors.affiliation: Institute of Biomedical Technologies and Center of Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna, La Laguna, Tenerife, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gonzalez-Paredes
authors.affiliation: Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain.
authors.forename: Goretti
authors.initials: G
authors.lastname: Hernández Mesa
authors.affiliation: Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain.
authors.forename: Dalia
authors.initials: D
authors.lastname: Morales Arraez
authors.affiliation: Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Marcelino Reyes
authors.affiliation: Institute of Biomedical Technologies and Center of Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna, La Laguna, Tenerife, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Abrante
authors.affiliation: Central Laboratory, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Diaz-Flores
authors.affiliation: Institute of Biomedical Technologies and Center of Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna, La Laguna, Tenerife, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
authors.affiliation: Institute of Biomedical Technologies and Center of Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna, La Laguna, Tenerife, Spain.|Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain.|Department of Medicine and Psychiatry, University of La Laguna, La Laguna, Tenerife, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Quintero
authors.affiliation: Institute of Biomedical Technologies and Center of Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna, La Laguna, Tenerife, Spain.|Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain.|Department of Medicine and Psychiatry, University of La Laguna, La Laguna, Tenerife, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hernández-Guerra
mesh_terms: D000109:Acetylcholine / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides / Q000493:pharmacokinetics / Q000494:pharmacology; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000493:pharmacokinetics / Q000494:pharmacology; D007213:Indomethacin / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000097:blood*; D019335:Nitroarginine / Q000493:pharmacokinetics / Q000494:pharmacology; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013152:Splanchnic Circulation; D013929:Thromboxane B2 / Q000097:blood*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D004041:Dietary Fats; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D013113:Spin Labels; D019335:Nitroarginine; D009569:Nitric Oxide; D013929:Thromboxane B2; C045749:SQ 29548; D000109:Acetylcholine; C001803:tempol; D007213:Indomethacin