Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD

Autor segons l'article: Marsal-Beltran, Anna; Rodriguez-Castellano, Adria; Astiarraga, Brenno; Calvo, Enrique; Rada, Patricia; Madeira, Ana; Rodriguez-Pena, M-Mar; Llaurado, Gemma; Nunez-Roa, Catalina; Gomez-Santos, Beatriz; Maymo-Masip, Elsa; Bosch, Ramon; Frutos, Maria Dolores; Moreno-Navarrete, Jose Maria; Ramos-Molina, Bruno; Aspichueta, Patricia; Joven, Jorge; Fernandez-Real, Jose-Manuel; Quera, Juan Carlos; Valverde, Angela M; Pardo, Albert; Vendrell, Joan; Ceperuelo-Mallafre, Victoria; Fernandez-Veledo, Sonia

Departament: Medicina i Cirurgia; Bioquímica i Biotecnologia

Autor/s de la URV: 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

Paraules clau: Sucnr1 protein, human; Sucnr1; Succinates; Succinate; Steatosis; Non-alcoholic fatty liver disease; Nash; Mice, inbred c57bl; Mice; Liver; Humans; Hepatocytes; Hepatocyte; Hepatic stellate cells; Gpr91 protein, mouse; Glycogen; Glucose; Fibrosis; Disease models, animal; Animals; sucnr1; steatosis; receptor; nash; metabolism; hepatocyte; gpr91; glycogen; fibrosis; expression; antagonist; activation

Resum: 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.

Àrees temàtiques: 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

Accès a la llicència d'ús: https://creativecommons.org/licenses/by/3.0/es/

Adreça de correu electrònic de l'autor: alberto.pardo@urv.cat; anna.marsal@urv.cat; ramon.bosch@urv.cat; brenno.dominguez@urv.cat; elsa.maymo@urv.cat; juancarlos.quer@urv.cat; victoria.ceperuelo@urv.cat; enrique.calvo@urv.cat; anna.marsal@urv.cat; ramon.bosch@urv.cat; adria.rodriguez@estudiants.urv.cat; sonia.fernandez@urv.cat; jorge.joven@urv.cat; jvortega@iispv.cat

Data d'alta del registre: 2025-02-01

Versió de l'article dipositat: info:eu-repo/semantics/publishedVersion

Enllaç font original: https://www.metabolismjournal.com/article/S0026-0495(23)00234-2/fulltext

URL Document de llicència: https://repositori.urv.cat/ca/proteccio-de-dades/

Referència a l'article segons font original: Metabolism-Clinical And Experimental. 145 155630-155630

Referència de l'ítem segons les normes APA: Marsal-Beltran, Anna; Rodriguez-Castellano, Adria; Astiarraga, Brenno; Calvo, Enrique; Rada, Patricia; Madeira, Ana; Rodriguez-Pena, M-Mar; Llaurado, (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

DOI de l'article: 10.1016/j.metabol.2023.155630

Entitat: Universitat Rovira i Virgili

Any de publicació de la revista: 2023

Tipus de publicació: Journal Publications