Imanol Zubiete-Franco1, Juan Luis García-Rodríguez1, Maite Martínez-Uña2, Nuria Martínez-Lopez1, Ashwin Woodhoo3, Virginia Gutiérrez-De Juan1, Naiara Beraza3, Sergio Lage-Medina4, Fernando Andrade4, Marta Llarena Fernandez4, Luis Aldámiz-Echevarría4, David Fernández-Ramos1, Juan Manuel Falcon-Perez3, Fernando Lopitz-Otsoa1, Pablo Fernandez-Tussy1, Lucía Barbier-Torres1, Zigmund Luka5, Conrad Wagner5, Carmelo García-Monzón6, Shelly C Lu7, Patricia Aspichueta2, José María Mato1, María Luz Martínez-Chantar8, Marta Varela-Rey9. 1. Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio 48160, Spain. 2. Department of Physiology, University of the Basque Country UPV/EHU, Medical School, Biocruces Research Institute, Bilbao 48008, Spain. 3. Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio 48160, Spain; IKERBASQUE, Basque Foundation for Science, Maria Diaz de Haro 3, 48013 Bilbao, Spain. 4. Metabolism Department, Cruces University Hospital, Barakaldo 48903, Spain. 5. Department of Biochemistry, Vanderbilt University, Nashville, TN 37232-0146, USA. 6. Liver Research Unit, Instituto de Investigación Sanitaria Princesa, University Hospital Santa Cristina, CIBERehd, Madrid 28009, Spain. 7. Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; USC Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, CA, USA. 8. Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio 48160, Spain; Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), P. O. BOX 644, E-48080 Bilbao, Spain. Electronic address: mlmartinez@cicbiogune.es. 9. Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio 48160, Spain. Electronic address: mvarela.ciberehd@cicbiogune.es.
Abstract
BACKGROUND & AIMS: Glycine N-methyltransferase (GNMT) expression is decreased in some patients with severe non-alcoholic fatty liver disease. Gnmt deficiency in mice (Gnmt-KO) results in abnormally elevated serum levels of methionine and its metabolite S-adenosylmethionine (SAMe), and this leads to rapid liver steatosis development. Autophagy plays a critical role in lipid catabolism (lipophagy), and defects in autophagy have been related to liver steatosis development. Since methionine and its metabolite SAMe are well known inactivators of autophagy, we aimed to examine whether high levels of both metabolites could block autophagy-mediated lipid catabolism. METHODS: We examined methionine levels in a cohort of 358 serum samples from steatotic patients. We used hepatocytes cultured with methionine and SAMe, and hepatocytes and livers from Gnmt-KO mice. RESULTS: We detected a significant increase in serum methionine levels in steatotic patients. We observed that autophagy and lipophagy were impaired in hepatocytes cultured with high methionine and SAMe, and that Gnmt-KO livers were characterized by an impairment in autophagy functionality, likely caused by defects at the lysosomal level. Elevated levels of methionine and SAMe activated PP2A by methylation, while blocking PP2A activity restored autophagy flux in Gnmt-KO hepatocytes, and in hepatocytes treated with SAMe and methionine. Finally, normalization of methionine and SAMe levels in Gnmt-KO mice using a methionine deficient diet normalized the methylation capacity, PP2A methylation, autophagy, and ameliorated liver steatosis. CONCLUSIONS: These data suggest that elevated levels of methionine and SAMe can inhibit autophagic catabolism of lipids contributing to liver steatosis.
BACKGROUND & AIMS:Glycine N-methyltransferase (GNMT) expression is decreased in some patients with severe non-alcoholic fatty liver disease. Gnmt deficiency in mice (Gnmt-KO) results in abnormally elevated serum levels of methionine and its metabolite S-adenosylmethionine (SAMe), and this leads to rapid liver steatosis development. Autophagy plays a critical role in lipid catabolism (lipophagy), and defects in autophagy have been related to liver steatosis development. Since methionine and its metabolite SAMe are well known inactivators of autophagy, we aimed to examine whether high levels of both metabolites could block autophagy-mediated lipid catabolism. METHODS: We examined methionine levels in a cohort of 358 serum samples from steatotic patients. We used hepatocytes cultured with methionine and SAMe, and hepatocytes and livers from Gnmt-KO mice. RESULTS: We detected a significant increase in serum methionine levels in steatotic patients. We observed that autophagy and lipophagy were impaired in hepatocytes cultured with high methionine and SAMe, and that Gnmt-KO livers were characterized by an impairment in autophagy functionality, likely caused by defects at the lysosomal level. Elevated levels of methionine and SAMe activated PP2A by methylation, while blocking PP2A activity restored autophagy flux in Gnmt-KO hepatocytes, and in hepatocytes treated with SAMe and methionine. Finally, normalization of methionine and SAMe levels in Gnmt-KO mice using a methionine deficient diet normalized the methylation capacity, PP2A methylation, autophagy, and ameliorated liver steatosis. CONCLUSIONS: These data suggest that elevated levels of methionine and SAMe can inhibit autophagic catabolism of lipids contributing to liver steatosis.
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