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

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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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Official URL: https://doi.org/10.1016/j.cmet.2023.07.002

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:

Number:

ISSN:

1550-4131

Identifiers: