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

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Francesco De ChiaraRajiv Jalan

Abstract

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. 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 a...Continue Reading

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Citations

Jan 26, 2020·Journal of Clinical Medicine·Yana SandlersSrinivasan Dasarathy
Nov 16, 2019·Current Opinion in Pharmacology·Fiona OakleyLee A Borthwick
Feb 13, 2021·Journal of Clinical Medicine·Kristoffer KjærgaardKaren Louise Thomsen
Aug 8, 2020·Neurochemistry International·Yun ZhouNiels Christian Danbolt
Mar 7, 2021·Hepatology Research : the Official Journal of the Japan Society of Hepatology·Yasushi Imamura Akio Ido
Apr 27, 2021·Liver International : Official Journal of the International Association for the Study of the Liver·Sharon DeMorrowChristopher F Rose
Oct 23, 2021·Hepatology Research : the Official Journal of the Japan Society of Hepatology·Kazuhiro Katayama
Sep 30, 2021·American Journal of Physiology. Gastrointestinal and Liver Physiology·Erica LafozJuan Carlos García-Pagán

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