Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD

Drug combination and repurposing are potential therapeutic strategies for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we have demonstrated that, in rats, both pemafibrate and telmisartan reverse hepatic steatosis induced by a high-fat, high-fructose diet....

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Autores: Bentanachs Raset, Roger, Ramírez-Carrasco, Patricia, Braster, Bianca, Emmanouilidou, Anastasia, Mujica, Endrina, Rodrigo Calvo, María Teresa, Rodríguez, Carla, Roglans i Ribas, Núria, den Hoed, Marcel, Laguna Egea, Juan Carlos, Alegret i Jordà, Marta
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
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:2445/225588
Acceso en línea:https://hdl.handle.net/2445/225588
Access Level:acceso abierto
Palabra clave:Gliconeogènesi
Angiotensines
Metabolòmica
Gluconeogenesis
Angiotensins
Metabolomics
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spelling Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLDBentanachs Raset, RogerRamírez-Carrasco, PatriciaBraster, BiancaEmmanouilidou, AnastasiaMujica, EndrinaRodrigo Calvo, María TeresaRodríguez, CarlaRoglans i Ribas, Núriaden Hoed, MarcelLaguna Egea, Juan CarlosAlegret i Jordà, MartaGliconeogènesiAngiotensinesMetabolòmicaGluconeogenesisAngiotensinsMetabolomicsDrug combination and repurposing are potential therapeutic strategies for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we have demonstrated that, in rats, both pemafibrate and telmisartan reverse hepatic steatosis induced by a high-fat, high-fructose diet. Pemafibrate attenuated liver steatosis via a PPARα-mediated increase in fatty acid catabolism, while the antisteatotic response to telmisartan did not rely on PPAR modulation. Our results in rats and in a zebrafish larva model of liver lipid accumulation suggest that part of telmisartan's antisteatotic effects are driven through the blockade of the angiotensin II type 1 receptor, along with a reduction in the expression of several lipogenic genes, which also contributes to some extent. Telmisartan's response is mediated by the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) expression. Liver metabolomic analysis revealed that by increasing PCK1, telmisartan diverted the metabolic flux of fructose from lipid towards glucose synthesis, which was subsequently fueled to the polyol pathway, thereby preserving glucose homeostasis. Moreover, telmisartan increased the hepatic levels of spermine and spermidine, which may counteract the putative detrimental effects caused by the accumulation of metabolites of the polyol route. Targeting different intrahepatic pathways, both PPAR-dependent and independent, the combination of pemafibrate and telmisartan, each at half the individual dose, was equally effective as the full dose of either drug alone to reduce liver lipid accumulation in the rat model. Our findings support the repurposing potential of these drugs, with the additional advantage of addressing both hepatic and cardiometabolic MASLD-associated complications.Elsevier B.V.2026202620252026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion19 p.application/pdfhttps://hdl.handle.net/2445/225588Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.phrs.2025.107860Pharmacological Research, 2025, num.107860https://doi.org/10.1016/j.phrs.2025.107860cc-by-nc-nd (c) Roger Bentanachs Raset, et al., 2025http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2255882026-05-29T05:05:01Z
dc.title.none.fl_str_mv Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD
title Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD
spellingShingle Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD
Bentanachs Raset, Roger
Gliconeogènesi
Angiotensines
Metabolòmica
Gluconeogenesis
Angiotensins
Metabolomics
title_short Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD
title_full Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD
title_fullStr Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD
title_full_unstemmed Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD
title_sort Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD
dc.creator.none.fl_str_mv Bentanachs Raset, Roger
Ramírez-Carrasco, Patricia
Braster, Bianca
Emmanouilidou, Anastasia
Mujica, Endrina
Rodrigo Calvo, María Teresa
Rodríguez, Carla
Roglans i Ribas, Núria
den Hoed, Marcel
Laguna Egea, Juan Carlos
Alegret i Jordà, Marta
author Bentanachs Raset, Roger
author_facet Bentanachs Raset, Roger
Ramírez-Carrasco, Patricia
Braster, Bianca
Emmanouilidou, Anastasia
Mujica, Endrina
Rodrigo Calvo, María Teresa
Rodríguez, Carla
Roglans i Ribas, Núria
den Hoed, Marcel
Laguna Egea, Juan Carlos
Alegret i Jordà, Marta
author_role author
author2 Ramírez-Carrasco, Patricia
Braster, Bianca
Emmanouilidou, Anastasia
Mujica, Endrina
Rodrigo Calvo, María Teresa
Rodríguez, Carla
Roglans i Ribas, Núria
den Hoed, Marcel
Laguna Egea, Juan Carlos
Alegret i Jordà, Marta
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Gliconeogènesi
Angiotensines
Metabolòmica
Gluconeogenesis
Angiotensins
Metabolomics
topic Gliconeogènesi
Angiotensines
Metabolòmica
Gluconeogenesis
Angiotensins
Metabolomics
description Drug combination and repurposing are potential therapeutic strategies for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we have demonstrated that, in rats, both pemafibrate and telmisartan reverse hepatic steatosis induced by a high-fat, high-fructose diet. Pemafibrate attenuated liver steatosis via a PPARα-mediated increase in fatty acid catabolism, while the antisteatotic response to telmisartan did not rely on PPAR modulation. Our results in rats and in a zebrafish larva model of liver lipid accumulation suggest that part of telmisartan's antisteatotic effects are driven through the blockade of the angiotensin II type 1 receptor, along with a reduction in the expression of several lipogenic genes, which also contributes to some extent. Telmisartan's response is mediated by the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) expression. Liver metabolomic analysis revealed that by increasing PCK1, telmisartan diverted the metabolic flux of fructose from lipid towards glucose synthesis, which was subsequently fueled to the polyol pathway, thereby preserving glucose homeostasis. Moreover, telmisartan increased the hepatic levels of spermine and spermidine, which may counteract the putative detrimental effects caused by the accumulation of metabolites of the polyol route. Targeting different intrahepatic pathways, both PPAR-dependent and independent, the combination of pemafibrate and telmisartan, each at half the individual dose, was equally effective as the full dose of either drug alone to reduce liver lipid accumulation in the rat model. Our findings support the repurposing potential of these drugs, with the additional advantage of addressing both hepatic and cardiometabolic MASLD-associated complications.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
2026
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 https://hdl.handle.net/2445/225588
url https://hdl.handle.net/2445/225588
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.phrs.2025.107860
Pharmacological Research, 2025, num.107860
https://doi.org/10.1016/j.phrs.2025.107860
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Roger Bentanachs Raset, et al., 2025
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Roger Bentanachs Raset, et al., 2025
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 19 p.
application/pdf
dc.publisher.none.fl_str_mv Elsevier B.V.
publisher.none.fl_str_mv Elsevier B.V.
dc.source.none.fl_str_mv Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
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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score 15,812429

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