TY - JOUR
T1 - Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis
AU - Zubiete-Franco, Imanol
AU - García-Rodríguez, Juan Luis
AU - Martínez-Uña, Maite
AU - Martínez-Lopez, Nuria
AU - Woodhoo, Ashwin
AU - Juan, Virginia Gutiérrez De
AU - Beraza, Naiara
AU - Lage-Medina, Sergio
AU - Andrade, Fernando
AU - Fernandez, Marta Llarena
AU - Aldámiz-Echevarría, Luis
AU - Fernández-Ramos, David
AU - Falcon-Perez, Juan Manuel
AU - Lopitz-Otsoa, Fernando
AU - Fernandez-Tussy, Pablo
AU - Barbier-Torres, Lucía
AU - Luka, Zigmund
AU - Wagner, Conrad
AU - García-Monzón, Carmelo
AU - Lu, Shelly C.
AU - Aspichueta, Patricia
AU - Mato, José María
AU - Martínez-Chantar, María Luz
AU - Varela-Rey, Marta
N1 - Funding Information:
This work is supported by NIH (US Department of Health and Human services)-R01AR001576-11A1 (to SCL, JMM and MLM-C). ISCIII: PI12/00005 (to AW), ISCIII: PI12/00402 (to NB and MVR), ISCIII: PI10/00067 (to CG-M), MINECO : RYC-2010-06901 (to AW), MINECO : RYC-2008-02347 (to NB), integrated in Plan nacional de I+d+I 2008-2011 , and co-financed by FEDER . ISCIII : PIE14/00031 (to MLM-C and JMM), ISCIII : PI13/01299 (to CG-M), MINECO : SAF2014-54658-R (to MLM-C) and MINECO : SAF2014-52097-R (to JMM) integrated in Plan Estatal de Investigación Cientifica y Técnica y Innovacion 2013-2016 , and co-financed by FEDER . Fundación AECC ( Cancer Infantil ) (to AW). GV- Departamento de desarrollo económico y Competitividad -IE13-370 (to MLM-C), GV- Departamento de Salud -2013111114 (to MLM-C) and -2011111106 (to MVR), GV- Departamento de Educación Politica Lingüística y Cultura -PI2011-29 (to MLM-C), -PI2012-48 (to JMM) and PI2013-46 (to AW). Junta Provincial de Bizkaia- AECC (PFT and MLM-C). Basque Government IT-336-10, Unidad de Formación e Investigación UFI11/20, and University of Basque Country (to PA). Ciberehd_ISCIII_MINECO .
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
KW - Autophagy
KW - Gnmt
KW - Liver
KW - Methionine
KW - SAMe
KW - Steatosis
UR - http://www.scopus.com/inward/record.url?scp=84954402163&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84954402163&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2015.08.037
DO - 10.1016/j.jhep.2015.08.037
M3 - Article
AN - SCOPUS:84954402163
SN - 0168-8278
VL - 64
SP - 409
EP - 418
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 2
ER -