Figure 1.

Overview of hepatic nitrogen metabolism homeostasis and disrupted gut-liver nitrogen metabolism in Fatty Liver Disease. (A) Both ammonia and glutamine hepatic metabolism are highly zonated processes. Hepatic ammonia enters in the liver from the gut where it can be eliminated by the urea cycle activity. In alternative, periportal hepatic glutaminase can convert glutamine to ammonia. Glutaminase and gut-derived ammonia that is not excreted in the periportal urea cycle, escapes to the pericentral region where is further eliminated by means of the glutamine synthetase (GS) enzyme. This enzyme converts ammonia back to glutamine and closing the glutamine cycle in order to maintain glutamine homeostasis. (B) Nitrogen metabolism homeostasis is disrupted in Fatty Liver Disease. Overall, inflamed gut in Fatty Liver Disease is characterized by the accumulation of proteobacteria Escherichia coli, very active in the production of ammonia. Gut-derived ammonia efflux through the portal vein can damage the liver directly or in alternative can exert detrimental effects on gut permeability and might indirectly contribute to NAFLD facilitating toxic molecules drainage into the portal blood. Additionally, it is possible that endotoxin and inflammation may contribute to increased uptake of ammonia from the gut into the bloodstream and thereby contribute to the latter’s toxic effect on the liver. In addition, Fatty liver Disease is characterized by diminished hepatic urea cycle activity and a switch from the low activity GLS2 to the high activity glutaminase, GLS, that together induce the accumulation of ammonia content in the liver. Ammonia can further drive fibrosis by promoting hepatic stellate cells activation, the main fibrogenic cell type. (Created by Biorender.com).