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

Objective: 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...

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Autores: Marsal Beltran, Anna, Llauradó Cabot, Gemma, Fernández Veledo, Sonia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/59377
Acceso en línea:http://hdl.handle.net/10230/59377
http://dx.doi.org/10.1016/j.metabol.2023.155630
Access Level:acceso abierto
Palabra clave:Glycogen
Hepatocyte
NASH
SUCNR1
Steatosis
Succinate
id ES_e8c367ed045d113bf52baba36666e124
oai_identifier_str oai:recercat.cat:10230/59377
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD
title Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD
spellingShingle Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD
Marsal Beltran, Anna
Glycogen
Hepatocyte
NASH
SUCNR1
Steatosis
Succinate
title_short Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD
title_full Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD
title_fullStr Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD
title_full_unstemmed Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD
title_sort Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD
dc.creator.none.fl_str_mv Marsal Beltran, Anna
Llauradó Cabot, Gemma
Fernández Veledo, Sonia
author Marsal Beltran, Anna
author_facet Marsal Beltran, Anna
Llauradó Cabot, Gemma
Fernández Veledo, Sonia
author_role author
author2 Llauradó Cabot, Gemma
Fernández Veledo, Sonia
author2_role author
author
dc.subject.none.fl_str_mv Glycogen
Hepatocyte
NASH
SUCNR1
Steatosis
Succinate
topic Glycogen
Hepatocyte
NASH
SUCNR1
Steatosis
Succinate
description Objective: 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. Methods: 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. Results: 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. Conclusions: 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.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/59377
http://dx.doi.org/10.1016/j.metabol.2023.155630
url http://hdl.handle.net/10230/59377
http://dx.doi.org/10.1016/j.metabol.2023.155630
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Metabolism. 2023 Aug;145:155630
info:eu-repo/grantAgreement/ES/1PE/SAF2015-65019-R
info:eu-repo/grantAgreement/ES/2PE/RTI2018-093919-B-100
info:eu-repo/grantAgreement/ES/3PE/PID2021-122480OB-100
info:eu-repo/grantAgreement/ES/3PE/PID2021-122766OB-100
info:eu-repo/grantAgreement/ES/3PE/PID2021-124425OB-I00
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLDMarsal Beltran, AnnaLlauradó Cabot, GemmaFernández Veledo, SoniaGlycogenHepatocyteNASHSUCNR1SteatosisSuccinateObjective: 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. Methods: 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. Results: 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. Conclusions: 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.This study was supported by grants from MCIN/AEI/10.13039/501100011033 (SAF2015-65019-R, RTI2018-093919-B-100 and PID2021-122480OB-100 to S.F.-V.; PID2021-122766OB-100 to A.M.V; PID2021-124425OB-I00 to P.A.) co-financed by the European Regional Development Fund (ERDF) and Grupos consolidados Gobierno Vasco IT1476-22 to P.A. This research was funded by the Institute of Health “Carlos III” (ISCIII) and co-financed by ERDF (PI20/00095 to V.C.-M.; PI20/00338 to J.V. and PI20/00505 to B.R.-M.). This study was also supported by a grant from ISCIII and CIBERDEM, DEM19PI01/2019 to V.C.-M. and P.R. The project that gave rise to these results received funding from “La Caixa” Foundation (ID 100010434), under the grant agreement LCF/PR/HR20/52400013 (to S.F.-V.). This study was also supported by Rovira i Virgili University and Tarragona Provincial Council with the Talent Salut fellowship to A.R.-C. A.M.-B. is a recipient of an FPU grant (FPU20/05633) from MCIN/AEI/10.13039/501100011033. B.A. acknowledges support from the PERIS program 2016–2020 (LT017/20/000033), from Departament de Salut de la Generalitat de Catalunya. V.C.-M. acknowledges support from the Ramón y Cajal program (RYC2019-02649-I), from MCIN/AEI/10.13039/501100011033/ and the European Social Fund (ESF), “Investing in your future”. B.R.-M. acknowledges support from the Miguel Servet Type I program (CP19/00098) from the Fondo de Investigación Sanitaria, co-financed by the ERDF. SFV and JVO acknowledge support from the Agency for Management of University Research Grants of the Generalitat de Catalunya (2021 SGR 01409, 2021 SGR 0089). The study was also supported by CIBER–Consorcio Centro de Investigación Biomédica en Red (CB07708/0012), ISCIII, Ministerio de Ciencia e Innovación.Elsevier202420242023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/59377http://dx.doi.org/10.1016/j.metabol.2023.155630reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésMetabolism. 2023 Aug;145:155630info:eu-repo/grantAgreement/ES/1PE/SAF2015-65019-Rinfo:eu-repo/grantAgreement/ES/2PE/RTI2018-093919-B-100info:eu-repo/grantAgreement/ES/3PE/PID2021-122480OB-100info:eu-repo/grantAgreement/ES/3PE/PID2021-122766OB-100info:eu-repo/grantAgreement/ES/3PE/PID2021-124425OB-I00© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/593772026-05-29T05:05:01Z
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