Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations
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 dis...
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| Format: | Article |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Nutrition |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnut.2022.1051157/full |
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| author | Camille Pichon Maxime Nachit Justine Gillard Greetje Vande Velde Nicolas Lanthier Nicolas Lanthier Isabelle A. Leclercq |
| author_facet | Camille Pichon Maxime Nachit Justine Gillard Greetje Vande Velde Nicolas Lanthier Nicolas Lanthier Isabelle A. Leclercq |
| author_sort | Camille Pichon |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T16:16:08Z |
| format | Article |
| id | doaj.art-0e0e13ee4966406880ac31e13720af6d |
| institution | Directory Open Access Journal |
| issn | 2296-861X |
| language | English |
| last_indexed | 2024-04-11T16:16:08Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Nutrition |
| spelling | doaj.art-0e0e13ee4966406880ac31e13720af6d2022-12-22T04:14:30ZengFrontiers Media S.A.Frontiers in Nutrition2296-861X2022-11-01910.3389/fnut.2022.10511571051157Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterationsCamille Pichon0Maxime Nachit1Justine Gillard2Greetje Vande Velde3Nicolas Lanthier4Nicolas Lanthier5Isabelle A. Leclercq6Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, BelgiumLaboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, BelgiumLaboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, BelgiumDepartment of Imaging and Pathology, Molecular Small Animal Imaging Center, Katholieke Universiteit Leuven, Leuven, BelgiumLaboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, BelgiumService d’Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, Brussels, BelgiumLaboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, BelgiumBackgroundMetabolic 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.https://www.frontiersin.org/articles/10.3389/fnut.2022.1051157/fullMAFLD (metabolic-associated fatty liver disease)NASH (non-alcoholic steatohepatitis)ammoniamyosteatosisL-ornithine L-aspartate |
| spellingShingle | Camille Pichon Maxime Nachit Justine Gillard Greetje Vande Velde Nicolas Lanthier Nicolas Lanthier Isabelle A. Leclercq Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations Frontiers in Nutrition MAFLD (metabolic-associated fatty liver disease) NASH (non-alcoholic steatohepatitis) ammonia myosteatosis L-ornithine L-aspartate |
| title | Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations |
| title_full | Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations |
| title_fullStr | Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations |
| title_full_unstemmed | Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations |
| title_short | Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations |
| title_sort | impact of l ornithine l aspartate on non alcoholic steatohepatitis associated hyperammonemia and muscle alterations |
| topic | MAFLD (metabolic-associated fatty liver disease) NASH (non-alcoholic steatohepatitis) ammonia myosteatosis L-ornithine L-aspartate |
| url | https://www.frontiersin.org/articles/10.3389/fnut.2022.1051157/full |
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