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

Abstract

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.

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

“…The most prominent finding in the NAFLD cohort was a negative correlation between plasma α-ketoglutarate levels and BUN (r = −0.7969, p < 0.05). This may be related to cataplerosis (loss of Krebs cycle intermediates) of α-ketoglutarate due to hyperammonemia that has been reported in preclinical models of NAFLD [38]. This is consistent with our previous report that Krebs cycle intermediate levels, including α-ketoglutarate, were significantly lower in C2C12 myotube cells during hyperammonemia [39].…”

Serum ammonia is a strong prognostic factor for patients with acute-on-chronic liver failure

“…The Kaplan-Meier survival curves further demonstrated that ammonia was still a strong prognostic factor after division of the population into subgroups. In vivo and in vitro studies showed that ornithine phenylacetate significantly decreased the cell death rate of hepatocytes and alleviated the progression of fibrosis after downregulation of serum ammonia levels 33 . Although the pathophysiology of HE is multifactorial and undetermined according to current studies, hyperammonemia, inflammation and genetic factors are three main pathways in the pathogenetic process.…”

High Protein Diet and Metabolic Plasticity in Non-Alcoholic Fatty Liver Disease: Myths and Truths

“…Animal protein-based diets contain high levels of glutamine and ornithine which are major precursors for ammoniagenesis compared with vegetarian diets [126]. Ammonia accumulation has been showed to be toxic for the body and its removal improved greatly liver zonation and functionality [127].…”