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Publication Detail
Ammonia Scavenging Prevents Progression of Fibrosis in Experimental Nonalcoholic Fatty Liver Disease
Abstract
In non-alcoholic fatty liver disease (NAFLD), fibrosis is the most important factor contributing to NAFLD-associated morbidity and mortality. Prevention of progression and reduction in fibrosis is the main aim of treatment. Even in early stages of NAFLD, hepatic and systemic hyperammonaemia is evident. This is due to reduced urea synthesis and as ammonia is known to activate hepatic stellate cells, we hypothesised that ammonia may be involved in the progression of fibrosis in NAFLD. In a high-fat high-cholesterol diet induced rodent model of NAFLD, we observed a progressive step-wise reduction in the expression and activity of urea cycle enzymes resulting in hyperammonaemia, evidence of hepatic stellate cell activation and progressive fibrosis. In primary, cultured hepatocytes and precision cut liver slices we demonstrated increased gene expression of pro-fibrogenic markers after lipid and/or ammonia exposure. Lowering of ammonia with the ammonia scavenger ornithine phenylacetate (OP) prevented hepatocyte cell death and significantly reduced the development of fibrosis both in vitro in the liver slices and also in vivo in the rodent animal 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. CONCLUSION: The results of this study suggest that hepatic steatosis results in hyperammonaemia, which is associated with progression of hepatic fibrosis. Reduction of ammonia levels prevented progression of fibrosis providing a potentially novel treatment for NAFLD. This article is protected by copyright. All rights reserved.
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Inst for Liver and Digestive Hlth
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Department of Education
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Inst for Liver and Digestive Hlth
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Inst for Liver and Digestive Hlth
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Inst for Liver and Digestive Hlth
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