Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations

Abstract

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease in the world. Progression toward non-alcoholic steatohepatitis (NASH) is associated with alterations of skeletal muscle. One plausible mechanism for altered muscle compartment in liver disease is changes in ammonia metabolism. In the present study, we explored the hypothesis that NASH-associated hyperammonemia drives muscle changes as well as liver disease progression.Materials and methodsIn Alms1-mutant mice (foz/foz) fed a 60% fat diet (HFD) for 12 weeks; we investigated hepatic and muscular ammonia detoxification efficiency. We then tested the effect of an 8 week-long supplementation with L-ornithine L-aspartate (LOLA), a known ammonia-lowering treatment, given after either 4 or 12 weeks of HFD for a preventive or a curative intervention, respectively. We monitored body composition, liver and muscle state by micro computed tomography (micro-CT) as well as muscle strength by four-limb grip test.ResultsAccording to previous studies, 12 weeks of HFD induced NASH in all foz/foz mice. Increase of hepatic ammonia production and alterations of urea cycle efficiency were observed, leading to hyperammonemia. Concomitantly mice developed marked myosteatosis. First signs of myopenia occurred after 20 weeks of diet. Early LOLA treatment given during NASH development, but not its administration in a curative regimen, efficiently prevented myosteatosis and muscle quality, but barely impacted liver disease or, surprisingly, ammonia detoxification.ConclusionOur study confirms the perturbation of hepatic ammonia detoxification pathways in NASH. Results from the interventional experiments suggest a direct beneficial impact of LOLA on skeletal muscle during NASH development, though it does not improve ammonia metabolism or liver disease.

Role of ammonia in NAFLD: An unusual suspect

“…19 Also in methionine-and choline-deficient mice with fatty liver, urea cycle enzyme genes were found to be downregulated 48 and similar findings, alongside hyperammonaemia, were observed in foz/foz mice fed a high-fat diet. 49 In vitro, the findings were confirmed in primary steatotic hepatocytes, demonstrating decreased gene expression of urea cycle enzymes and increased ammonia levels in the supernatant, alongside increased gene expression of pro-fibrogenic markers. Also, in precision cut liver slices, we demonstrated increased gene expression of pro-fibrogenic markers following lipid and/or ammonia exposure.…”

“…In 1988, Kaiser et al observed that glutamine synthesis was decreased in vitro in steatotic liver slices exposed to ammonium, 50 whereas in vivo, increased hepatic gene and protein levels of glutamine synthetase have been observed in various animal models of NAFLD. 21,22,49 In patients with NAFLD, one study found a reduction in hepatic glutamine synthetase that correlated with disease severity, 19 whereas another study found an increase at the gene level. 20 Also, glutaminolysis seems to be increased in NAFLD.…”

“…47 Another study in a NAFLD mouse model used LOLA as an ammonia-lowering strategy, which had a beneficial effect on skeletal muscle, but failed to reduce ammonia levels, which was probably the explanation for the lack of improvement on liver histology. 49…”

Rescue strategies for valproic acid overdose poisoning: Case series and literature review

“…Ornithine involves the activation of the urea cycle and the entire process of ammonia detoxification. Aseptic acid synthesizes nucleic acid in hepatocytes to facilitate the repair of damaged hepatocytes 23 . L‐carnitine may treat hyperammonia by VPA, but there is no standard for treating VPA toxicity 24 .…”

Myosteatosis: Diagnosis, pathophysiology and consequences in metabolic dysfunction-associated steatotic liver disease

“…However, decreasing muscle lipid content in a mouse model of MASH did not improve ammonia metabolism. 16 Therefore, the relationship between ammonia and myosteatosis will not be further discussed in this review, considering the current lack of data.…”