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

24 Citations (Scopus)

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

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S-Adenosylmethionine
Methionine
Autophagy
Hepatocytes
Fatty Liver
Methylation
Lipids
Glycine N-Methyltransferase
Serum
Liver

Keywords

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

ASJC Scopus subject areas

  • Hepatology

Cite this

Zubiete-Franco, I., García-Rodríguez, J. L., Martínez-Uña, M., Martínez-Lopez, N., Woodhoo, A., Juan, V. G. D., ... 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

Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis. / Zubiete-Franco, Imanol; García-Rodríguez, Juan Luis; Martínez-Uña, Maite; Martínez-Lopez, Nuria; Woodhoo, Ashwin; Juan, Virginia Gutiérrez De; Beraza, Naiara; Lage-Medina, Sergio; Andrade, Fernando; Fernandez, Marta Llarena; Aldámiz-Echevarría, Luis; Fernández-Ramos, David; Falcon-Perez, Juan Manuel; Lopitz-Otsoa, Fernando; Fernandez-Tussy, Pablo; Barbier-Torres, Lucía; Luka, Zigmund; Wagner, Conrad; García-Monzón, Carmelo; Lu, Shelly C.; Aspichueta, Patricia; Mato, José María; Martínez-Chantar, María Luz; Varela-Rey, Marta.

In: Journal of Hepatology, Vol. 64, No. 2, 01.02.2016, p. 409-418.

Research output: Contribution to journalArticle

Zubiete-Franco, I, García-Rodríguez, JL, Martínez-Uña, M, Martínez-Lopez, N, Woodhoo, A, Juan, VGD, Beraza, N, Lage-Medina, S, Andrade, F, Fernandez, ML, Aldámiz-Echevarría, L, Fernández-Ramos, D, Falcon-Perez, JM, Lopitz-Otsoa, F, Fernandez-Tussy, P, Barbier-Torres, L, Luka, Z, Wagner, C, García-Monzón, C, Lu, SC, Aspichueta, P, Mato, JM, Martínez-Chantar, ML & Varela-Rey, M 2016, 'Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis', Journal of Hepatology, vol. 64, no. 2, pp. 409-418. https://doi.org/10.1016/j.jhep.2015.08.037
Zubiete-Franco I, García-Rodríguez JL, Martínez-Uña M, Martínez-Lopez N, Woodhoo A, Juan VGD et al. Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis. Journal of Hepatology. 2016 Feb 1;64(2):409-418. https://doi.org/10.1016/j.jhep.2015.08.037
Zubiete-Franco, Imanol ; García-Rodríguez, Juan Luis ; Martínez-Uña, Maite ; Martínez-Lopez, Nuria ; Woodhoo, Ashwin ; Juan, Virginia Gutiérrez De ; Beraza, Naiara ; Lage-Medina, Sergio ; Andrade, Fernando ; Fernandez, Marta Llarena ; Aldámiz-Echevarría, Luis ; Fernández-Ramos, David ; Falcon-Perez, Juan Manuel ; Lopitz-Otsoa, Fernando ; Fernandez-Tussy, Pablo ; Barbier-Torres, Lucía ; Luka, Zigmund ; Wagner, Conrad ; García-Monzón, Carmelo ; Lu, Shelly C. ; Aspichueta, Patricia ; Mato, José María ; Martínez-Chantar, María Luz ; Varela-Rey, Marta. / Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis. In: Journal of Hepatology. 2016 ; Vol. 64, No. 2. pp. 409-418.
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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.",
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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

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

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JO - Journal of Hepatology

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