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A novel GLP-1/glucagon receptor dual agonist improves non-alcoholic fatty steatohepatitis and liver regeneration in mice

AuthorsValdecantos, M. P.; Pardo, Virginia; Fernández-Millán, Elisa; García-Monzón, Carmelo; Arroba, Ana I. ; Ruiz, Laura; González-Rodríguez, Águeda; Escrivá, Fernando; Álvarez, Carmen; Grimsby, J.; Rondinone, Cristina M.; Valverde, Ángela M.
Issue Date2016
CitationCIBERDEM Annual Meeting (2016)
Abstract[Background and aims]: Since non-alcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we aimed to investigate the effects of a dual acting glucagon-like peptide-1(GLP1)/glucagon (GCG) receptor agonist, termed G49, on NASH and hepatic regeneration. [Methods]: C57/Bl6 male mice fed chow or methionine and choline-deficient (MCD) diet for one week were divided into 4 groups: C (chow diet plus vehicle), MCD (MCD diet plus vehicle), C+G49 (chow diet plus G49) and M+G49 (MCD diet plus G49). Following 2 weeks of treatment, partial hepatectomy (PH) was performed and mice were maintained on the same treatment schedule for an additional 2 weeks. Treatment effects on liver function, hepatic regeneration and comprehensive genomic and metabolic profiling was conducted throughout the study. [Results]: NASH significantly improved in the M+G49 group manifested by reduced inflammation, steatosis, oxidative stress, apoptosis and increased mitochondria biogenesis. G49 treatment was also associated with a replenishment of hepatic glucose stores due to enhanced gluconeogenesis and reduced glucose utilization via pentose phosphate cycle (PPC) and oxidative metabolism. Following PH, treatment with G49 increased survival rates, restored the cytokine-mediated priming phase and enhanced proliferative capacity and hepatic regeneration ratio in mice on MCD diet. All NASH markers remained decreased in M+G49 mice after PH and glucose utilization was shifted to PPC and oxidative metabolism. Initiating G49 treatment immediately after PH was also effective in alleviating the pathological changes induced by the MCD diet. [Conclusion]: Dual acting GLP-1R/GCGR agonists such as G49 represent a novel therapeutic approach for patients with NASH and particularly in those requiring PH.
DescriptionResumen del trabajo presentado presentado al CIBERDEM Annual Meeting, celebrado en Cerdanyola del Vallès, Barcelona (España) del 11 al 13 de mayo de 2016.-- et al.
Appears in Collections:(IIBM) Comunicaciones congresos
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