Ammonia Scavenging Prevents Progression of Fibrosis in Experimental Nonalcoholic Fatty Liver Disease

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  • Francesco De Chiara, Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom.
  • ,
  • Karen Louise Thomsen
  • Abeba Habtesion, Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom.
  • ,
  • Helen Jones, Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom.
  • ,
  • Nathan Davies, Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom.
  • ,
  • Jordi Gracia-Sancho, Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute & CIBEREHD, Barcelona, Spain.
  • ,
  • Nicolò Manicardi, Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute & CIBEREHD, Barcelona, Spain.
  • ,
  • Andrew Hall, Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom.
  • ,
  • Fausto Andreola, Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom.
  • ,
  • Hannah L Paish, Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • ,
  • Lee H Reed, Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • ,
  • Abigail A Watson, Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • ,
  • Jack Leslie, Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • ,
  • Fiona Oakley, Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • ,
  • Krista Rombouts, Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom.
  • ,
  • Rajeshwar Prosad Mookerjee, Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom.
  • ,
  • Jelena Mann, Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • ,
  • Rajiv Jalan, Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom.

BACKGROUND AND AIMS: In nonalcoholic fatty liver disease (NAFLD), fibrosis is the most important factor contributing to NAFLD-associated morbidity and mortality. Prevention of progression and reduction in fibrosis are the main aims of treatment. Even in early stages of NAFLD, hepatic and systemic hyperammonemia is evident. This is due to reduced urea synthesis; and as ammonia is known to activate hepatic stellate cells, we hypothesized that ammonia may be involved in the progression of fibrosis in NAFLD.

APPROACH AND RESULTS: In a high-fat, high-cholesterol diet-induced rodent model of NAFLD, we observed a progressive stepwise reduction in the expression and activity of urea cycle enzymes resulting in hyperammonemia, evidence of hepatic stellate cell activation, and progressive fibrosis. In primary, cultured hepatocytes and precision-cut liver slices we demonstrated increased gene expression of profibrogenic markers after lipid and/or ammonia exposure. Lowering of ammonia with the ammonia scavenger ornithine phenylacetate prevented hepatocyte cell death and significantly reduced the development of fibrosis both in vitro in the liver slices and in vivo in a rodent model. The prevention of fibrosis in the rodent model was associated with restoration of urea cycle enzyme activity and function, reduced hepatic ammonia, and markers of inflammation.

CONCLUSIONS: The results of this study suggest that hepatic steatosis results in hyperammonemia, which is associated with progression of hepatic fibrosis. Reduction of ammonia levels prevented progression of fibrosis, providing a potential treatment for NAFLD.

OriginalsprogEngelsk
TidsskriftHepatology
Vol/bind71
Nummer3
Sider (fra-til)874-892
Antal sider19
ISSN0270-9139
DOI
StatusUdgivet - 2020

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© 2019 by the American Association for the Study of Liver Diseases.

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