Author, as appears in the article.: Marsal-Beltran, A; Rodríguez-Castellano, A; Astiarraga, B; Calvo, E; Rada, P; Madeira, A; Rodríguez-Peña, MM; Llauradó, G; Núñez-Roa, C; Gómez-Santos, B; Maymó-Masip, E; Bosch, R; Frutos, MD; Moreno-Navarrete, JM; Ramos-Molina, B; Aspichueta, P; Joven, J; Fernández-Real, JM; Quera, JC; Valverde, AM; Pardo, A; Vendrell, J; Ceperuelo-Mallafré, V; Fernández-Veledo, S
Department: Medicina i Cirurgia Bioquímica i Biotecnologia
URV's Author/s: Bosch Príncep, Ramon / Calvo Manso, Enrique / Ceperuelo Mallafré, Maria Victoria / Domínguez Porfirio, Brenno / Fernandez Veledo, Sonia / Joven Maried, Jorge / MARSAL BELTRAN, ANNA / Maymo Masip, Elsa / Pardo Balteiro, Alberto / Quer Boniquet, Juan Carlos / Rodríguez Castellano, Adrià / RODRIGUEZ PEÑA, MARIA DEL MAR / Vendrell Ortega, Juan
Keywords: Sucnr1 Succinate Steatosis Nash Hepatocyte Hepatic stellate cells Glycogen sucnr1 steatosis receptor nash metabolism hepatocyte gpr91 glycogen fibrosis expression antagonist activation
Abstract: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes.We studied the phenotype of wild-type and Sucnr1-/- mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages.Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm.We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.Copyright © 2023. Published by Elsevier Inc.
Thematic Areas: Saúde coletiva Odontología Nutrição Medicina iii Medicina ii Medicina i Interdisciplinar General medicine Farmacia Engenharias ii Enfermagem Endocrinology, diabetes and metabolism Endocrinology & metabolism Endocrinology Educação física Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciência de alimentos Biotecnología Antropologia / arqueologia
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: anna.marsal@urv.cat brenno.dominguez@urv.cat sonia.fernandez@urv.cat alberto.pardo@urv.cat ramon.bosch@urv.cat elsa.maymo@urv.cat juancarlos.quer@urv.cat enrique.calvo@urv.cat victoria.ceperuelo@urv.cat anna.marsal@urv.cat ramon.bosch@urv.cat adria.rodriguez@estudiants.urv.cat jorge.joven@urv.cat juanjose.vendrell@urv.cat
Author identifier: 0000-0003-2216-8974 0000-0003-2906-3788 0000-0002-9133-3120 0000-0002-4460-9761 0000-0003-2749-4541 0000-0002-6994-6115
Record's date: 2024-08-03
Papper version: info:eu-repo/semantics/publishedVersion
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: Metabolism-Clinical And Experimental. 145 155630-155630
APA: Marsal-Beltran, A; Rodríguez-Castellano, A; Astiarraga, B; Calvo, E; Rada, P; Madeira, A; Rodríguez-Peña, MM; Llauradó, G; Núñez-Roa, C; Gómez-Santos, (2023). Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD. Metabolism-Clinical And Experimental, 145(), 155630-155630. DOI: 10.1016/j.metabol.2023.155630
Entity: Universitat Rovira i Virgili
Journal publication year: 2023
Publication Type: Journal Publications
Repositori URV