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

26 p.-6 fig.-1 tab.-1 graph. abst.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.M.V.-R. is supported by Proyecto PID2020-119486RB-100 (funded by MCIN/AEI/10.13039/501100011033), Gilead Sciences International Research Scholars Program in Liver Disease, Acción Estratégica Ciberehd Emergentes 2018 (ISCIII), Fundación BBVA, HORIZON-TMA-MSCA-Doctoral Networks 2021 (101073094), and Redes de Investigación 2022 (RED2022-134485-T). M.L.M.-C. is supported by La CAIXA Foundation (LCF/PR/HP17/52190004), Proyecto PID2020-117116RB-I00 (funded by MCIN/AEI/10.13039/501100011033), Ayudas Fundación BBVA a equipos de investigación científica (Umbrella 2018), and AECC Scientific Foundation (Rare Cancers 2017). A.W. is supported by RTI2018-097503-B-I00 and PID2021-127169OB-I00, (funded by MCIN/AEI/10.13039/501100011033) and by “ERDF A way of making Europe,” Xunta de Galicia (Ayudas PRO-ERC), Fundación Mutua Madrileña, and European Community’s H2020 Framework Programme (ERC Consolidator grant no. 865157 and MSCA Doctoral Networks 2021 no. 101073094). C.M. is supported by CIBERNED. P.A. is supported by Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT1476-22), PID2021-124425OB-I00 (funded by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe,” MCI/UE/ISCiii [PMP21/00080], and UPV/EHU [COLAB20/01]). M.F. and M.G.B. are supported by PID2019-105739GB-I00 and PID2020-115472GB-I00, respectively (funded by MCIN/AEI/10.13039/501100011033). M.G.B. is supported by Xunta de Galicia (ED431C 2019/013). C.A., T.L.-D., and J.B.-V. are recipients of pre-doctoral fellowships from Xunta de Galicia (ED481A-2020/046, ED481A-2018/042, and ED481A 2021/244, respectively). T.C.D. is supported by Fundación Científica AECC. A.T.-R. is a recipient of a pre-doctoral fellowship from Fundación Científica AECC. S.V.A. and C.R. are recipients of Margarita Salas postdoc grants under the “Plan de Recuperación Transformación” program funded by the Spanish Ministry of Universities with European Union’s NextGeneration EU funds (2021/PER/00020 and MU-21-UP2021-03071902373A, respectively). T.C.D., A.S.-R., and M.T.-C. are recipients of Ayuda RYC2020-029316-I, PRE2019/088960, and BES-2016/078493, respectively, supported by MCIN/AEI/10.13039/501100011033 and by El FSE invierte en tu futuro. S.L.-O. is a recipient of a pre-doctoral fellowship from the Departamento de Educación del Gobierno Vasco (PRE_2018_1_0372). P.A.-G. is recipient of a FPU pre-doctoral fellowship from the Ministry of Education (FPU19/02704). CIC bioGUNE is supported by Ayuda CEX2021-001136-S financiada por MCIN/AEI/10.13039/501100011033. A.B.-C. was funded by predoctoral contract PFIS (FI19/00240) from Instituto de Salud Carlos III (ISCIII) co-funded by Fondo Social Europeo (FSE), and A.D.-L. was funded by contract Juan Rodés (JR17/00016) from ISCIII. A.B.-C. is a Miguel Servet researcher (CPII22/00008) from ISCIII.Peer reviewe