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

Autor: Castro MC; Centro de Endocrinología Experimental y Aplicada - CENEXA (UNLP-CONICET CCT LA PLATA CEAS CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina. Electronic address: mccastro@cenexa.org., Villagarcía HG; Centro de Endocrinología Experimental y Aplicada - CENEXA (UNLP-CONICET CCT LA PLATA CEAS CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina. Electronic address: hvillagarcia@med.unlp.edu.ar., Schinella G; Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina; Instituto de Ciencias de la Salud, UNAJ-CICPBA, Street Avenue Calchaqui 6200, Florencio Varela 1888, Argentina. Electronic address: schinell@med.unlp.edu.ar., Massa ML; Centro de Endocrinología Experimental y Aplicada - CENEXA (UNLP-CONICET CCT LA PLATA CEAS CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina. Electronic address: mlmassa@cenexa.org., Francini F; Centro de Endocrinología Experimental y Aplicada - CENEXA (UNLP-CONICET CCT LA PLATA CEAS CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina. Electronic address: direccion-cenexa@laplata-conicet.gov.ar.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular and cell biology of lipids [Biochim Biophys Acta Mol Cell Biol Lipids] 2023 Sep; Vol. 1868 (9), pp. 159363. Date of Electronic Publication: 2023 Jul 08.
DOI: 10.1016/j.bbalip.2023.159363
Abstrakt: 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.
Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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