Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting
Alba Capelo-Diz, Sofía Lachiondo‐Ortega, David Fernández‐Ramos, Jorge Cañas-Martín, Naroa Goikoetxea‐Usandizaga, Marina Serrano‐Maciá, María J. Gonzalez-Rellan, Laura Mosca, Joan Blazquez-Vicens, Alberto Tinahones, Marcos F. Fondevila, Mason Buyan, Teresa C. Delgado, Virginia Gutiérrez de Juan, Paula Ayuso-García, Alejandro Sánchez-Rueda, Sergio Velasco-Avilés, Héctor Fernández‐Susavila, Cristina Riobello, Bartlomiej Dziechciarz, Cristina Montiel‐Duarte, Fernando Lopitz‐Otsoa, Maider Bizkarguenaga, Jon Bilbao-García, Ganeko Bernardo‐Seisdedos, Ana Senra, Mario Soriano‐Navarro, Óscar Millet, Ángel Díaz‐Lagares, Ana B. Crujeiras, Aida Bao‐Caamano, Diana Cabrera, Sebastiaan van Liempd, Miguel Tamayo-Caro, Luigi Borzacchiello, Beatriz Gómez‐Santos, Xabier Buqué, Diego Sáenz de Urturi, Francisco González‐Romero, Jorge Simón, Rubén Rodríguez‐Agudo, Asier Ruiz, Carlos Matute, Daniel Beiroa, Juan Manuel Falcón‐Pérez, Patricia Aspichueta, Juan Rodríguez‐Cuesta, Marina Porcelli, Marı́a A. Pajares, Cristina Ameneiro, Miguel Fidalgo, Ana M. Aransay, Tomás Lama-Díaz, Miguel G. Blanco, Miguel López, Ricardo Villa‐Bellosta, Timo D. Müller, Rubén Nogueiras, Ashwin Woodhoo, Maria Luz Martínez‐Chantar, Marta Varela‐Rey
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.