Ammonia: A novel target for the treatment of non-alcoholic steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases ranging from steatosis, through non-alcoholic steatohepatitis (NASH) to cirrhosis. The development of fibrosis is the most important factor contributing to NASH-associated morbidity and mortality. Hepatic stellate cells (HSCs) are responsible for extracellular matrix deposition in conditions of frank hepatocellular injury and are key cells involved in the development of fibrosis. In experimental models and patients with NASH, urea cycle enzyme gene and protein expression is reduced resulting in functional reduction in the in vivo capacity for ureagenesis and subsequent hyperammonemia at a pre-cirrhotic stage. Ammonia has been shown to activate HSCs in vivo and in vitro. Hyperammonemia in the context of NASH may therefore favour the progression of fibrosis and the disease. We therefore hypothesise that ammonia is a potential target for prevention of fibrosis progression of patients with NASH.

l-Ornithine l-Aspartate (LOLA) as a Novel Approach for Therapy of Non-alcoholic Fatty Liver Disease

“…In acute, acute-on-chronic and chronic liver failure, ammonia accumulates through diminished activity of the urea cycle. High serum concentrations of ammonia are associated with hepatic encephalopathy (HE), hepatocyte apoptosis, inflammation, liver function impairment, and high mortality [13, 14]. …”

“…Another possible mechanism might be reduced flux through the GS pathway by up to 50%, as demonstrated in liver biopsy samples from patients with histologically proven steatosis and raised serum transaminases [20]. Ammonia has thus been suggested as possible target for NAFLD treatment [14]. In a recent study, hypermethylation of urea cycle gene as well as reduced expression and activity of urea a cycle enzymes have been demonstrated in human NASH and a rat model of NASH [21].…”

Different types of hyperammonemia in clinical practice

“…Гипераммониемия в контексте НАСГ может поэтому способствовать развитию фиброза. Таким образом, аммиак является потенциальной мишенью для профилактики развития фиброза у пациентов с НАСГ [35]. Аналогичные данные были получены на экспериментальных моделях Jalan R. и соавт.…”

Non‐alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion

“…However, such reports are mainly based on association studies providing limited insight into functional consequences of the altered gene expression and specifically, a possible gene regulatory basis for the deficient urea synthesis capacity has not been studied in NAFLD. The issue is important because compromised urea synthesis may lead to such clinical problems as hyperammonaemic cognitive dysfunction, as is already described in NAFLD and favour the progression of disease . Moreover, description of a gene regulatory component may provide new clues of how fatty liver disturbs liver function.…”

“…The issue is important because compromised urea synthesis may lead to such clinical problems as hyperammonaemic cognitive dysfunction, as is already described in NAFLD 11 and favour the progression of disease. 12 Moreover, description of a gene regulatory component may provide new clues of how fatty liver disturbs liver function.…”