Dataset Information

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

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.

SUBMITTER: Capelo-Diz A

PROVIDER: S-EPMC10432853 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Capelo-Diz Alba A Lachiondo-Ortega Sofía S Fernández-Ramos David D Cañas-Martín Jorge J Goikoetxea-Usandizaga Naroa N Serrano-Maciá Marina M González-Rellan Maria J MJ Mosca Laura L Blazquez-Vicens Joan J Tinahones-Ruano Alberto A Fondevila Marcos F MF Buyan Mason M Delgado Teresa C TC Gutierrez de Juan Virginia V Ayuso-García Paula P Sánchez-Rueda Alejandro A Velasco-Avilés Sergio S Fernández-Susavila Héctor H Riobello-Suárez Cristina C Dziechciarz Bartlomiej B Montiel-Duarte Cristina C Lopitz-Otsoa Fernando F Bizkarguenaga Maider M Bilbao-García Jon J Bernardo-Seisdedos Ganeko G Senra Ana A Soriano-Navarro Mario M Millet Oscar O Díaz-Lagares Ángel Á Crujeiras Ana B AB Bao-Caamano Aida A Cabrera Diana D van Liempd Sebastiaan S Tamayo-Carro Miguel M Borzacchiello Luigi L Gomez-Santos Beatriz B Buqué Xabier X Sáenz de Urturi Diego D González-Romero Francisco F Simon Jorge J Rodríguez-Agudo Rubén R Ruiz Asier A Matute Carlos C Beiroa Daniel D Falcon-Perez Juan M JM Aspichueta Patricia P Rodríguez-Cuesta Juan J Porcelli Marina M Pajares María A MA Ameneiro Cristina C Fidalgo Miguel M Aransay Ana M AM Lama-Díaz Tomas T Blanco Miguel G MG López Miguel M Villa-Bellosta Ricardo R Müller Timo D TD Nogueiras Rubén R Woodhoo Ashwin A Martínez-Chantar María Luz ML Varela-Rey Marta M

Cell metabolism 20230731 8

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, ...[more]

PMID: 37527658

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Project description:The effects of fasting have been studied extensively, predominantly on isolated processes, within a specific organ. No comprehensive study of the adaptations was available for different organs, let alone interrelating them, which left the understanding of the body’s orchestration of fasting response limited. The gene expression profiles of brain, small intestine, kidney, liver and skeletal muscle were therefore studied in mice subjected to short, moderate and prolonged fasting. Functional category enrichment, network, and text-mining analyses were employed to scrutinize the overall adaptive response, aiming to identify responsive pathways, processes and networks, and their regulation. The implicated processes did not follow the accepted carbohydrate-lipid-protein succession of energy substrates expenditure. Instead, they were activated simultaneously in different organs during the whole duration of fasting. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney, which showed biochemically similar, orchestrated responses. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, tied in with increased proteolysis in the muscle. Enhanced defence against oxidative damage, obvious in all the organs, was the top reaction of the brain, otherwise shown to be extremely well protected from starvation. The major transcription regulators of fasting response in different organs were FoxO transcription factors, AP-1, p53, cMyc, Sp1, EGF and HNF4α. The revealed interorgan interactions between metabolic, inflammatory and cell turnover responses are essential when designing strategies to treat the starvation affected individuals, while stressing the significance of using complimentary bioinformatics tools in the high-throughput data analysis. 6 week-old male FVB mice were fasted for 0, 12, 24, 48 or 72 hours before sacrifice (N = 5 per group). From each mouse total RNA was isolated from five organs - liver, small intestine, kidney, brain, and calf muscle. Five microarrays per experimental condition (five tissues, five timepoints) were performed. We used a common reference design. The single common-reference sample was a pool of equal amounts of RNA from all the samples investigated, including additional samples from 5 mice that were fasted for 48 hours and supplemented with vitamin B complex after 24 and 36 hours of fasting.

Dataset Information

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

Publications

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

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