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

Lookup NU author(s): Hannah Paish, Lee Reed, Abi Watson, Dr Jack Leslie, Professor Fiona Oakley, Professor Jelena Mann

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Abstract

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


Publication metadata

Author(s): De Chiara F, Thomsen KL, Habtesion A, Jones H, Davies N, Gracia-Sancho J, Manicardi N, Hall A, Andreola F, Paish HL, Reed LH, Watson AA, Leslie J, Oakley F, Rombouts K, Mookerjee RP, Mann J, Jalan R

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2019

Issue: ePub ahead of Print

Online publication date: 05/08/2019

Acceptance date: 07/07/2019

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1002/hep.30890

DOI: 10.1002/hep.30890

PubMed id: 31378982


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