Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.

Autor: Sáenz de Urturi D; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain., Buqué X; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.; Biocruces Bizkaia Health Research Institute, Barakaldo, Spain., Porteiro B; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain., Folgueira C; Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., Mora A; Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., Delgado TC; Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain., Prieto-Fernández E; Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, Leioa, Spain., Olaizola P; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain., Gómez-Santos B; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain., Apodaka-Biguri M; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain., González-Romero F; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain., Nieva-Zuluaga A; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain., Ruiz de Gauna M; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain., Goikoetxea-Usandizaga N; Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain., García-Rodríguez JL; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain., Gutierrez de Juan V; Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain., Aurrekoetxea I; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.; Biocruces Bizkaia Health Research Institute, Barakaldo, Spain., Montalvo-Romeral V; Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., Novoa EM; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain., Martín-Guerrero I; Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country UPV/EHU, Leioa, Spain., Varela-Rey M; Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain.; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain.; Gene Regulatory Control in Disease Laboratory, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain., Bhanot S; IONIS Pharmaceuticals, Carlsbad, CA, USA., Lee R; IONIS Pharmaceuticals, Carlsbad, CA, USA., Banales JM; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain., Syn WK; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.; Section of Gastroenterology, Ralph H Johnson, VAMC, Charleston, SC, USA.; Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, USA., Sabio G; Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., Martínez-Chantar ML; Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain.; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain., Nogueiras R; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.; Galician Agency of Investigation, Xunta de Galicia, Spain., Aspichueta P; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain. patricia.aspichueta@ehu.eus.; Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. patricia.aspichueta@ehu.eus.; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain. patricia.aspichueta@ehu.eus.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Mar 01; Vol. 13 (1), pp. 1096. Date of Electronic Publication: 2022 Mar 01.
DOI: 10.1038/s41467-022-28749-z
Abstrakt: Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, is still unknown. By using antisense oligonucleotides (ASO) and genetic depletion of Mat1a, here, we demonstrate that Mat1a deficiency in diet-induce obese or genetically obese mice prevented and reversed obesity and obesity-associated insulin resistance and hepatosteatosis by increasing energy expenditure in a hepatocyte FGF21 dependent fashion. The increased NRF2-mediated FGF21 secretion induced by targeting Mat1a, mobilized plasma lipids towards the BAT to be catabolized, induced thermogenesis and reduced body weight, inhibiting hepatic de novo lipogenesis. The beneficial effects of Mat1a ASO were abolished following FGF21 depletion in hepatocytes. Thus, targeting Mat1a activates the liver-BAT axis by increasing NRF2-mediated FGF21 secretion, which prevents obesity, insulin resistance and hepatosteatosis.
(© 2022. The Author(s).)
Databáze: MEDLINE
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