Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis

Imanol Zubiete-Franco, Juan Luis García-Rodríguez, Maite Martínez-Uña, Nuria Martínez-Lopez, Ashwin Woodhoo, Virginia Gutiérrez De Juan, Naiara Beraza, Sergio Lage-Medina, Fernando Andrade, Marta Llarena Fernandez, Luis Aldámiz-Echevarría, David Fernández-Ramos, Juan Manuel Falcon-Perez, Fernando Lopitz-Otsoa, Pablo Fernandez-Tussy, Lucía Barbier-Torres, Zigmund Luka, Conrad Wagner, Carmelo García-Monzón, Shelly C. LuPatricia Aspichueta, José María Mato, María Luz Martínez-Chantar, Marta Varela-Rey

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)409-418
Number of pages10
JournalJournal of Hepatology
Volume64
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Keywords

  • Autophagy
  • Gnmt
  • Liver
  • Methionine
  • SAMe
  • Steatosis

ASJC Scopus subject areas

  • Hepatology

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    Zubiete-Franco, I., García-Rodríguez, J. L., Martínez-Uña, M., Martínez-Lopez, N., Woodhoo, A., Juan, V. G. D., Beraza, N., Lage-Medina, S., Andrade, F., Fernandez, M. L., Aldámiz-Echevarría, L., Fernández-Ramos, D., Falcon-Perez, J. M., Lopitz-Otsoa, F., Fernandez-Tussy, P., Barbier-Torres, L., Luka, Z., Wagner, C., García-Monzón, C., ... Varela-Rey, M. (2016). Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis. Journal of Hepatology, 64(2), 409-418. https://doi.org/10.1016/j.jhep.2015.08.037