title: Ornithine phenylacetate targets alterations in the expression and activity of glutamine synthase and glutaminase to reduce ammonia levels in bile duct ligated rats.
abstract: OBJECTIVE
  In liver failure, ammonia homeostasis is dependent upon the function of the ammonia metabolising enzymes, glutamine synthetase (GS) and glutaminase (GA) but data about their protein expression and activity are lacking. The aims of this study were to determine the protein expression and activity of GS and GA in individual organs in a rat model of chronic liver disease and to test whether the treatment with the ammonia-lowering agent ornithine phenylacetate (OP) modulates their activities.
  
  
  METHODS
  49 SD rats were studied 35 days after sham-operation or bile duct ligation (BDL). The BDL group received: L-ornithine (0.6 mg/kg/day), Phenylacetate (0.6 mg/kg/day), OP (0.6 mg/kg/day) or placebo (saline) for 5 days prior to sacrifice. Arterial ammonia, amino acids and liver biochemistry were measured. Expressions of GS and GA were determined by Western-blotting and activities by end-point methods in liver, muscle, gut, kidney, lung, and frontal cortex.
  
  
  RESULTS
  In BDL rats, hepatic GS enzyme activity was reduced by more than 80% compared to sham rats. Further, in BDL rats GA activity was reduced in liver but increased in the gut, muscle and frontal cortex compared to sham rats. OP treatment resulted in a reduction in hyperammonemia in BDL rats, associated with increased GS activity in the muscle and reduced gut GA activity.
  
  
  CONCLUSIONS
  In a rat model of chronic liver failure, hyperammonemia is associated with inadequate compensation by liver and muscle GS activity and increased gut GA activity. OP reduces plasma ammonia by increasing GS in the muscle and reducing GA activity in the gut providing additional insights into its mechanism of its action. GS and GA may serve as important future therapeutic targets for hyperammonemia in liver failure.
authors: Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom.
authors: M
authors: M
authors: Jover-Cobos
authors: Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom; COMPLEX CoMPLEX, UCL, Gower Street, London WC1E 6BT, United Kingdom.
authors: L
authors: L
authors: Noiret
authors: Royal Veterinary College, Hatfield, Hertfordshire AL9 7TA, United Kingdom.
authors: K
authors: K
authors: Lee
authors: Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom.
authors: V
authors: V
authors: Sharma
authors: Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom.
authors: A
authors: A
authors: Habtesion
authors: CIBEREHD, UCM Digestive Diseases, Valme University Hospital, Seville, Spain.
authors: M
authors: M
authors: Romero-Gomez
authors: Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom.
authors: N
authors: N
authors: Davies
authors: Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom. Electronic address: r.jalan@ucl.ac.uk.
authors: R
authors: R
authors: Jalan
mesh_terms: D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D004195:Disease Models, Animal; D058625:End Stage Liver Disease / Q000188:drug therapy* / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D005972:Glutaminase / Q000378:metabolism*; D008026:Ligation; D008099:Liver / Q000503:physiopathology; D008297:Male; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000641:Ammonia; C572232:ornithine phenylacetate; D009952:Ornithine; D005972:Glutaminase; D005974:Glutamate-Ammonia Ligase
keywords: ALF; Acute liver failure; Amino acids; Ammonia; BDL; CLF; Chronic liver failure; Cirrhosis; GA; GS; Gln; Glu; Glutamate; Glutaminase; Glutamine; Glutamine synthetase; HE; Hepatic encephalopathy; O; OP; Ornithine; Ornithine phenylacetate; Ornithinephenylacetate; P; PAGN; Phenylacetate; Phosphate-activated glutaminase; bile duct ligation; phenylacetylglutamine (PAGN)