Telmisartan reverses hepatic steatosis via PCK1 upregulation: A novel PPAR-independent mechanism in experimental models of MASLD
Por:
Bentanachs, R, Ramirez-Carrasco, P, Braster, B, Emmanouilidou, A, Mujica, E, Rodrigo-Calvo, M, Rodriguez, C, Roglans, N, Den Hoed, M, Laguna, JC, Alegret, M
Publicada:
1 ago 2025
Ahead of Print:
1 jul 2025
Resumen:
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 PPAR alpha-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 PPARdependent 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.
Filiaciones:
Bentanachs, R:
Univ Barcelona, Sch Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Ave Joan XXIII-31, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed IBUB, Barcelona 08028, Spain
Ramirez-Carrasco, P:
Univ Barcelona, Sch Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Ave Joan XXIII-31, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed IBUB, Barcelona 08028, Spain
Braster, B:
Uppsala Univ, Dept Immunol Genet & Pathol, S-75105 Uppsala, Sweden
SciLifeLab, S-75237 Uppsala, Sweden
Emmanouilidou, A:
Uppsala Univ, Dept Immunol Genet & Pathol, S-75105 Uppsala, Sweden
SciLifeLab, S-75237 Uppsala, Sweden
Mujica, E:
Uppsala Univ, Dept Immunol Genet & Pathol, S-75105 Uppsala, Sweden
SciLifeLab, S-75237 Uppsala, Sweden
Rodrigo-Calvo, M:
Hosp Clin Barcelona, Ctr Biomed Diag CDB, Pathol Dept, Barcelona 08036, Spain
Rodriguez, C:
Inst Recerca St Pau IR St PAU, Barcelona 08041, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Cardiovasc Dis CIBERCV, Madrid 28029, Spain
Roglans, N:
Univ Barcelona, Sch Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Ave Joan XXIII-31, Barcelona 08028, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Physiopathol Obes & Nutr CI, Madrid 28029, Spain
Den Hoed, M:
Uppsala Univ, Dept Immunol Genet & Pathol, S-75105 Uppsala, Sweden
SciLifeLab, S-75237 Uppsala, Sweden
Laguna, JC:
Univ Barcelona, Sch Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Ave Joan XXIII-31, Barcelona 08028, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Physiopathol Obes & Nutr CI, Madrid 28029, Spain
Univ Barcelona, Inst Biomed IBUB, Barcelona 08028, Spain
Alegret, M:
Univ Barcelona, Sch Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Ave Joan XXIII-31, Barcelona 08028, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Physiopathol Obes & Nutr CI, Madrid 28029, Spain
Univ Barcelona, Inst Biomed IBUB, Barcelona 08028, Spain
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