1. Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting.
- Author
-
Capelo-Diz A, Lachiondo-Ortega S, Fernández-Ramos D, Cañas-Martín J, Goikoetxea-Usandizaga N, Serrano-Maciá M, González-Rellan MJ, Mosca L, Blazquez-Vicens J, Tinahones-Ruano A, Fondevila MF, Buyan M, Delgado TC, 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 Á, Crujeiras AB, 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 JM, Aspichueta P, Rodríguez-Cuesta J, Porcelli M, Pajares MA, Ameneiro C, Fidalgo M, Aransay AM, Lama-Díaz T, Blanco MG, López M, Villa-Bellosta R, Müller TD, Nogueiras R, Woodhoo A, Martínez-Chantar ML, and Varela-Rey M
- Subjects
- Mice, Animals, Liver metabolism, Fasting, Adenosine Triphosphate metabolism, Methionine Adenosyltransferase metabolism, Phosphatidylethanolamine N-Methyltransferase metabolism, S-Adenosylmethionine metabolism, Liver Neoplasms metabolism
- 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., Competing Interests: Declaration of interests M.L.M.-C. advises for Mitotherapeutix., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF