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Artículo

Mechanism of preventive effects of exendin-4 and des-fluoro-sitagliptin in a murine model of fructose-induced prediabetes

Castro, María CeciliaIcon ; Villagarcía, Hernán GonzaloIcon ; Schinella, Guillermo Raúl; Massa, Maria LauraIcon ; Francini, FlavioIcon
Fecha de publicación: 09/2023
Editorial: Elsevier Science
Revista: Biochimica Et Biophysica Acta - Molecular and Cell Biology of Lipids
ISSN: 1388-1981
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Farmacología y Farmacia

Resumen

Protective effects of exendin-4 (glucagon-like peptide-1 -GLP-1- receptor agonist) and des-fluoro-sitagliptin (dipeptidyl peptidase-4 inhibitor) on fructose-induced hepatic disturbances were evaluated in prediabetic rats. Complementary, a possible direct effect of exendin-4 in human hepatoblastoma-derived cell line HepG2 incubated with fructose in presence/absence of exendin-9-39 (GLP-1 receptor antagonist) was investigated. In vivo, after 21 days of fructose rich diet, we determined: glycemia, insulinemia, and triglyceridemia; hepatic fructokinase, AMP-deaminase, and G-6-P dehydrogenase (G-6-P DH) activities; carbohydrate-responsive element-binding protein (ChREBP) expression; triglyceride content and lipogenic gene expression (glycerol-3-phosphate acyltransferase -GPAT-, fatty acid synthase -FAS-, sterol regulatory element-binding protein-1c -SREBP-1c); oxidative stress and inflammatory markers expression. In HepG2 cells we measured fructokinase activity and triglyceride content. Hypertriglyceridemia, hyperinsulinemia, enhanced liver fructokinase, AMP-deaminase, and G-6-P DH activities, increased ChREBP and lipogenic genes expression, enhanced triglyceride level, oxidative stress and inflammatory markers recorded in fructose fed animals, were prevented by co-administration of either exendin-4 or des-fluoro-sitagliptin. Exendin-4 prevented fructose-induced increase in fructokinase activity and triglyceride contain in HepG2 cells. These effects were blunted co-incubating with exendin-9-39. The results demonstrated for the first time that exendin-4/des-fluro-sitagliptin prevented fructose-induced endocrine-metabolic oxidative stress and inflammatory changes probably acting on the purine degradation pathway. Exendin 9–39 blunted in vitro protective exendin-4 effects, thereby suggesting a direct effect of this compound on hepatocytes through GLP-1 receptor. Direct effect on fructokinase and AMP-deaminase activities, with a key role in the pathogenesis of liver dysfunction induced by fructose, suggests purine degradation pathway constitute a potential therapeutic objective for GLP-1 receptor agonists.
Palabras clave: DES-FLUORO-SITAGLIPTIN , EXENDIN-4 , FRUCTOSE-RICH DIET , GLP-1 RECEPTOR AGONIST , INFLAMMATION , LIVER FRUCTOKINASE , OXIDATIVE STRESS , PREDIABETES
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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/227146
URL: https://linkinghub.elsevier.com/retrieve/pii/S1388198123000872
DOI: https://doi.org/10.1016/j.bbalip.2023.159363
Colecciones
Articulos(CENEXA)
Articulos de CENTRO DE ENDOCRINOLOGIA EXP.Y APLICADA (I)
Citación
Castro, María Cecilia; Villagarcía, Hernán Gonzalo; Schinella, Guillermo Raúl; Massa, Maria Laura; Francini, Flavio; Mechanism of preventive effects of exendin-4 and des-fluoro-sitagliptin in a murine model of fructose-induced prediabetes; Elsevier Science; Biochimica Et Biophysica Acta - Molecular and Cell Biology of Lipids; 1868; 9; 9-2023; 1-7
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