Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting

Capelo-Diz, A., Lachiondo-Ortega, S., Fernández-Ramos, D., Cañas-Martín, J., Goikoetxea-Usandizaga, N., Serrano-Maciá, M., González-Rellan, M.J., Mosca, L., Blazquez-Vicens, J., Tinahones-Ruano, A., Fondevila, M.F., Buyan, M., Delgado, T.C., Gutierrez de Juan, V., Ayuso-García, P., Sánchez-Rueda, A., Velasco-Avilés, S., Fernández-Susavila, H., Riobello-Suárez, C., Dziechciarz, B., Montiel-Duarte, C. ORCID: 0000-0002-9144-8809, Lopitz-Otsoa, F., Bizkarguenaga, M., Bilbao-García, J., Bernardo-Seisdedos, G., Senra, A., Soriano-Navarro, M., Millet, O., Díaz-Lagares, ?., Crujeiras, A.B., Bao-Caamano, A., Cabrera, D., van Liempd, S., Tamayo-Carro, M., Borzacchiello, L., Gomez-Santos, B., Buqué, X., Sáenz de Urturi, D., González-Romero, F., Simon, J., Rodríguez-Agudo, R., Ruiz, A., Matute, C., Beiroa, D., Falcon-Perez, J.M., Aspichueta, P., Rodríguez-Cuesta, J., Porcelli, M., Pajares, M.A., Ameneiro, C., Fidalgo, M., Aransay, A.M., Lama-Díaz, T., Blanco, M.G., López, M., Villa-Bellosta, R., Müller, T.D., Nogueiras, R., Woodhoo, A., Martínez-Chantar, M.L. and Varela-Rey, M., 2023. Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting. Cell Metabolism, 35 (8), 1373-1389.e8. ISSN 1550-4131

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Abstract

There has been an intense focus to uncover the molecular mechanisms by which fasting triggers the adaptive cellular responses in the major organs of the body. Here, we show that in mice, hepatic S-adenosylmethionine (SAMe)—the principal methyl donor—acts as a metabolic sensor of nutrition to fine-tune the catabolic-fasting response by modulating phosphatidylethanolamine N-methyltransferase (PEMT) activity, endoplasmic reticulum-mitochondria contacts, β-oxidation, and ATP production in the liver, together with FGF21-mediated lipolysis and thermogenesis in adipose tissues. Notably, we show that glucagon induces the expression of the hepatic SAMe-synthesizing enzyme methionine adenosyltransferase α1 (MAT1A), which translocates to mitochondria-associated membranes. This leads to the production of this metabolite at these sites, which acts as a brake to prevent excessive β-oxidation and mitochondrial ATP synthesis and thereby endoplasmic reticulum stress and liver injury. This work provides important insights into the previously undescribed function of SAMe as a new arm of the metabolic adaptation to fasting.

Item Type: Journal article
Publication Title: Cell Metabolism
Creators: Capelo-Diz, A., Lachiondo-Ortega, S., Fernández-Ramos, D., Cañas-Martín, J., Goikoetxea-Usandizaga, N., Serrano-Maciá, M., González-Rellan, M.J., Mosca, L., Blazquez-Vicens, J., Tinahones-Ruano, A., Fondevila, M.F., Buyan, M., Delgado, T.C., Gutierrez de Juan, V., Ayuso-García, P., Sánchez-Rueda, A., Velasco-Avilés, S., Fernández-Susavila, H., Riobello-Suárez, C., Dziechciarz, B., Montiel-Duarte, C., Lopitz-Otsoa, F., Bizkarguenaga, M., Bilbao-García, J., Bernardo-Seisdedos, G., Senra, A., Soriano-Navarro, M., Millet, O., Díaz-Lagares, ?., Crujeiras, A.B., Bao-Caamano, A., Cabrera, D., van Liempd, S., Tamayo-Carro, M., Borzacchiello, L., Gomez-Santos, B., Buqué, X., Sáenz de Urturi, D., González-Romero, F., Simon, J., Rodríguez-Agudo, R., Ruiz, A., Matute, C., Beiroa, D., Falcon-Perez, J.M., Aspichueta, P., Rodríguez-Cuesta, J., Porcelli, M., Pajares, M.A., Ameneiro, C., Fidalgo, M., Aransay, A.M., Lama-Díaz, T., Blanco, M.G., López, M., Villa-Bellosta, R., Müller, T.D., Nogueiras, R., Woodhoo, A., Martínez-Chantar, M.L. and Varela-Rey, M.
Publisher: Elsevier BV
Date: 8 August 2023
Volume: 35
Number: 8
ISSN: 1550-4131
Identifiers:
NumberType
10.1016/j.cmet.2023.07.002DOI
1790409Other
Divisions: Schools > School of Science and Technology
Record created by: Jeremy Silvester
Date Added: 11 Aug 2023 15:49
Last Modified: 11 Aug 2023 15:49
Related URLs:
URI: https://irep.ntu.ac.uk/id/eprint/49543

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