2. Academic Validation
  3. Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD

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

  • Metabolism. 2023 Jun 12;155630. doi: 10.1016/j.metabol.2023.155630.
Anna Marsal-Beltran 1,  Adrià Rodríguez-Castellano 2,  Brenno Astiarraga 3,  Enrique Calvo 3,  Patricia Rada 4,  Ana Madeira 3,  M-Mar Rodríguez-Peña 3,  Gemma Llauradó 5,  Catalina Núñez-Roa 3,  Beatriz Gómez-Santos 6,  Elsa Maymó-Masip 3,  Ramon Bosch 7,  María Dolores Frutos 8,  José-María Moreno-Navarrete 9,  Bruno Ramos-Molina 10,  Patricia Aspichueta 11,  Jorge Joven 12,  José-Manuel Fernández-Real 9,  Juan Carlos Quer 2,  Ángela M Valverde 4,  Albert Pardo 2,  Joan Vendrell 1,  Victòria Ceperuelo-Mallafré 13,  Sonia Fernández-Veledo 14
Affiliations

Affiliations

  • 1 Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain.
  • 2 Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain.
  • 3 Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.
  • 4 CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain.
  • 5 CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Department of Endocrinology and Nutrition, Hospital del Mar, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
  • 6 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940 Leioa, Spain.
  • 7 Department of Pathology, Oncological Pathology and Bioinformatics Research Group, Hospital de Tortosa Verge de la Cinta - IISPV, 43500 Tortosa, Spain.
  • 8 Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, 30120 Murcia, Spain.
  • 9 Department of Diabetes, Endocrinology and Nutrition and Insititut d'Investigació Biomèdica de Girona (IDIBGI), Dr. Josep Trueta University Hospital, Department of Medicine, University of Girona, 17007 Girona, Spain; CIBER de Fisiopatología de la Obesidad (CIBEROBN) - Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • 10 Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain.
  • 11 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940 Leioa, Spain; Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain; CIBER de Enfermedades Hepáticas y Digestivas (CIBEREHD)- Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain.
  • 12 Universitat Rovira i Virgili (URV), 43201 Reus, Spain; Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili, 43204 Reus, Spain.
  • 13 Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain. Electronic address: victoria.ceperuelo@urv.cat.
  • 14 Hospital Universitari Joan XXIII de Tarragona, Institut d'Investigació Sanitària Pere Virgili (IISPV), 43005 Tarragona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; Universitat Rovira i Virgili (URV), 43201 Reus, Spain. Electronic address: sonia.fernandez@iispv.cat.
PMID: 37315889 DOI: 10.1016/j.metabol.2023.155630
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.

Keywords

Glycogen; Hepatocyte; NASH; SUCNR1; Steatosis; Succinate.

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