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

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  • dc.contributor.author Marsal Beltran, Anna
  • dc.contributor.author Llauradó Cabot, Gemma
  • dc.contributor.author Fernández Veledo, Sonia
  • dc.date.accessioned 2024-03-12T07:22:35Z
  • dc.date.available 2024-03-12T07:22:35Z
  • dc.date.issued 2023
  • dc.description.abstract 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.
  • dc.description.sponsorship 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.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Marsal-Beltran A, Rodríguez-Castellano A, Astiarraga B, Calvo E, Rada P, Madeira A et al. Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD. Metabolism. 2023 Aug;145:155630. DOI: 10.1016/j.metabol.2023.155630
  • dc.identifier.doi http://dx.doi.org/10.1016/j.metabol.2023.155630
  • dc.identifier.issn 0026-0495
  • dc.identifier.uri http://hdl.handle.net/10230/59377
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.relation.ispartof Metabolism. 2023 Aug;145:155630
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-65019-R
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-093919-B-100
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-122480OB-100
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-122766OB-100
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124425OB-I00
  • dc.rights © 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/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword Glycogen
  • dc.subject.keyword Hepatocyte
  • dc.subject.keyword NASH
  • dc.subject.keyword SUCNR1
  • dc.subject.keyword Steatosis
  • dc.subject.keyword Succinate
  • dc.title Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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