Abstract | BACKGROUND AND AIMS: 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.
|
Authors | Francesco De Chiara, Karen Louise Thomsen, Abeba Habtesion, Helen Jones, Nathan Davies, Jordi Gracia-Sancho, Nicolò Manicardi, Andrew Hall, Fausto Andreola, Hannah L Paish, Lee H Reed, Abigail A Watson, Jack Leslie, Fiona Oakley, Krista Rombouts, Rajeshwar Prosad Mookerjee, Jelena Mann, Rajiv Jalan |
Journal | Hepatology (Baltimore, Md.)
(Hepatology)
Vol. 71
Issue 3
Pg. 874-892
(03 2020)
ISSN: 1527-3350 [Electronic] United States |
PMID | 31378982
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | © 2019 by the American Association for the Study of Liver Diseases. |
Chemical References |
|
Topics |
- Ammonia
(metabolism)
- Animals
- Cells, Cultured
- Disease Models, Animal
- Disease Progression
- Female
- Humans
- Liver Cirrhosis
(prevention & control)
- Male
- Non-alcoholic Fatty Liver Disease
(complications, metabolism)
- Rats
- Rats, Sprague-Dawley
- Urea Cycle Disorders, Inborn
(etiology)
|