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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Elsevier
2025-08-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825002853 |
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| author | Roger Bentanachs Patricia Ramírez-Carrasco Bianca Braster Anastasia Emmanouilidou Endrina Mujica Maite Rodrigo-Calvo Cristina Rodríguez Núria Roglans Marcel den Hoed Juan C. Laguna Marta Alegret |
| author_facet | Roger Bentanachs Patricia Ramírez-Carrasco Bianca Braster Anastasia Emmanouilidou Endrina Mujica Maite Rodrigo-Calvo Cristina Rodríguez Núria Roglans Marcel den Hoed Juan C. Laguna Marta Alegret |
| author_sort | Roger Bentanachs |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-46f491b5ae7b4b0fabbd1ad2a5a15f4b |
| institution | DOAJ |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-46f491b5ae7b4b0fabbd1ad2a5a15f4b2025-08-20T02:45:50ZengElsevierPharmacological Research1096-11862025-08-0121810786010.1016/j.phrs.2025.107860Telmisartan reverses hepatic steatosis via PCK1 upregulation: A novel PPAR-independent mechanism in experimental models of MASLDRoger Bentanachs0Patricia Ramírez-Carrasco1Bianca Braster2Anastasia Emmanouilidou3Endrina Mujica4Maite Rodrigo-Calvo5Cristina Rodríguez6Núria Roglans7Marcel den Hoed8Juan C. Laguna9Marta Alegret10Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona 08028, Spain; Institute of Biomedicine IBUB, University of Barcelona, Barcelona 08028, SpainDepartment of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona 08028, Spain; Institute of Biomedicine IBUB, University of Barcelona, Barcelona 08028, SpainDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75105, Sweden; SciLifeLab, Uppsala 752 37, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75105, Sweden; SciLifeLab, Uppsala 752 37, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75105, Sweden; SciLifeLab, Uppsala 752 37, SwedenPathology Department, Center of Biomedical Diagnosis (CDB), Hospital Clinic, Barcelona 08036, SpainInstitut de Recerca Sant Pau (IR SANT PAU), Barcelona 08041, Spain; Spanish Biomedical Research Centre in Cardiovascular diseases (CIBERCV), Instituto de Salud Carlos III, Madrid 28029, SpainDepartment of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona 08028, Spain; Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain; Institute of Biomedicine IBUB, University of Barcelona, Barcelona 08028, SpainDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75105, Sweden; SciLifeLab, Uppsala 752 37, SwedenDepartment of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona 08028, Spain; Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain; Institute of Biomedicine IBUB, University of Barcelona, Barcelona 08028, SpainDepartment of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona 08028, Spain; Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain; Institute of Biomedicine IBUB, University of Barcelona, Barcelona 08028, Spain; Correspondence to: Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Av. Joan XXIII 27–31, Barcelona 08028, Spain.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.http://www.sciencedirect.com/science/article/pii/S1043661825002853Liver steatosisPPARAngiotensin receptor blockersMetabolomicsPhosphoenolpyruvate carboxykinase 1Gluconeogenesis |
| spellingShingle | Roger Bentanachs Patricia Ramírez-Carrasco Bianca Braster Anastasia Emmanouilidou Endrina Mujica Maite Rodrigo-Calvo Cristina Rodríguez Núria Roglans Marcel den Hoed Juan C. Laguna Marta Alegret Telmisartan reverses hepatic steatosis via PCK1 upregulation: A novel PPAR-independent mechanism in experimental models of MASLD Pharmacological Research Liver steatosis PPAR Angiotensin receptor blockers Metabolomics Phosphoenolpyruvate carboxykinase 1 Gluconeogenesis |
| title | 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_short | 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 |
| topic | Liver steatosis PPAR Angiotensin receptor blockers Metabolomics Phosphoenolpyruvate carboxykinase 1 Gluconeogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825002853 |
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