title: Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-L-methionine and glutathione.
abstract: The pathogenesis and treatment of nonalcoholic steatohepatitis (NASH) are not well established. Feeding a diet deficient in both methionine and choline (MCD) is one of the most common models of NASH, which is characterized by steatosis, mitochondrial dysfunction, hepatocellular injury, oxidative stress, inflammation, and fibrosis. However, the individual contribution of the lack of methionine and choline in liver steatosis, advanced pathology and impact on mitochondrial S-adenosyl-L-methionine (SAM) and glutathione (GSH), known regulators of disease progression, has not been specifically addressed. Here, we examined the regulation of mitochondrial SAM and GSH and signs of disease in mice fed a MCD, methionine-deficient (MD), or choline-deficient (CD) diet. The MD diet reproduced most of the deleterious effects of MCD feeding, including weight loss, hepatocellular injury, oxidative stress, inflammation, and fibrosis, whereas CD feeding was mainly responsible for steatosis, characterized by triglycerides and free fatty acids accumulation. These findings were preceded by MCD- or MD-mediated SAM and GSH depletion in mitochondria due to decreased mitochondrial membrane fluidity associated with a lower phosphatidylcholine/phosphatidylethanolamine ratio. MCD and MD but not CD feeding resulted in increased ceramide levels by acid sphingomyelinase. Moreover, GSH ethyl ester or SAM therapy restored mitochondrial GSH and ameliorated hepatocellular injury in mice fed a MCD or MD diet. Thus, the depletion of SAM and GSH in mitochondria is an early event in the MCD model of NASH, which is determined by the lack of methionine. Moreover, therapy using permeable GSH prodrugs may be of relevance in NASH.
authors.affiliation: Liver Unit, Centro de Investigaciones Biomédicas Esther Koplowitz, Instituto Malalties Digestivas i Metaboliques, Hospital Clínic i Provincial, 08036 Barcelona, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Caballero
authors.forename: Anna
authors.initials: A
authors.lastname: Fernández
authors.forename: Nuria
authors.initials: N
authors.lastname: Matías
authors.forename: Laura
authors.initials: L
authors.lastname: Martínez
authors.forename: Raquel
authors.initials: R
authors.lastname: Fucho
authors.forename: Montserrat
authors.initials: M
authors.lastname: Elena
authors.forename: Joan
authors.initials: J
authors.lastname: Caballeria
authors.forename: Albert
authors.initials: A
authors.lastname: Morales
authors.forename: José C
authors.initials: JC
authors.lastname: Fernández-Checa
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Ruiz
mesh_terms: D000821:Animal Feed; D000818:Animals; D002518:Ceramides / Q000737:chemistry; D002794:Choline / Q000737:chemistry*; D005234:Fatty Liver / Q000378:metabolism*; D005978:Glutathione / Q000737:chemistry*; D007249:Inflammation; D008055:Lipids / Q000737:chemistry; D008297:Male; D008715:Methionine / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry; D012436:S-Adenosylmethionine / Q000737:chemistry*; D013108:Sphingomyelin Phosphodiesterase / Q000737:chemistry
chemical_list: D002518:Ceramides; D008055:Lipids; D011355:Prodrugs; D012436:S-Adenosylmethionine; D008715:Methionine; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D005978:Glutathione; D002794:Choline
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