title: A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice.
abstract: Because nonalcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the effects of G49, a dual glucagon-like peptide-1/glucagon receptor agonist, on NASH and hepatic regeneration. C57Bl/6 mice fed chow or a methionine and choline-deficient (MCD) diet for 1 week were divided into 4 groups: control (chow diet), MCD diet, chow diet plus G49, and M+G49 (MCD diet plus G49). Mice fed a high-fat diet (HFD) for 10 weeks were divided into groups: HFD and H+G49 (HFD plus G49). Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy (PH) was performed, and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration, and comprehensive genomic and metabolic profiling were conducted. NASH was ameliorated in the M+G49 group, manifested by reduced inflammation, steatosis, oxidative stress, and apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose use through the pentose phosphate cycle and oxidative metabolism. Following PH, G49 treatment increased survival, restored the cytokine-mediated priming phase, and enhanced the proliferative capacity and hepatic regeneration ratio in mice on the MCD diet. NASH markers remained decreased in M+G49 mice after PH, and glucose use was shifted to the pentose phosphate cycle and oxidative metabolism. G49 administered immediately after PH was also effective at alleviating the pathological changes induced by the MCD diet. Benefits in terms of liver regeneration were also found in mice fed HFD and treated with G49.
  
  
  
  Dual-acting glucagon-like peptide-1/glucagon receptor agonists such as G49 represent a novel therapeutic approach for patients with NASH and particularly those requiring PH. (Hepatology 2017;65:950-968).
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: M Pilar
authors.initials: MP
authors.lastname: Valdecantos
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pardo
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Ruiz
authors.affiliation: University of Colima, Colima, Mexico.
authors.forename: Luis
authors.initials: L
authors.lastname: Castro-Sánchez
authors.affiliation: Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Madrid, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Lanzón
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Fernández-Millán
authors.affiliation: Liver Research Unit, Instituto de Investigación Sanitaria Princesa, University Hospital Santa Cristina, CIBERehd, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Carmelo
authors.initials: C
authors.lastname: García-Monzón
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Arroba
authors.affiliation: Liver Research Unit, Instituto de Investigación Sanitaria Princesa, University Hospital Santa Cristina, CIBERehd, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Águeda
authors.initials: Á
authors.lastname: González-Rodríguez
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Escrivá
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Álvarez
authors.affiliation: Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Rupérez
authors.affiliation: Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Madrid, Spain.
authors.forename: Coral
authors.initials: C
authors.lastname: Barbas
authors.affiliation: MedImmune LLC, Gaithersburg, MD.
authors.forename: Anish
authors.initials: A
authors.lastname: Konkar
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Naylor
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Hornigold
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: Ana Dos
authors.initials: AD
authors.lastname: Santos
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Bednarek
authors.affiliation: MedImmune LLC, Gaithersburg, MD.
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
authors.affiliation: MedImmune LLC, Gaithersburg, MD.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Rondinone
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ángela M
authors.initials: ÁM
authors.lastname: Valverde
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D015227:Lipid Peroxidation; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress; D011897:Random Allocation; D018027:Receptors, Glucagon / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1