title: GH receptor plays a major role in liver regeneration through the control of EGFR and ERK1/2 activation.
abstract: GH is a pleiotropic hormone that plays a major role in proliferation, differentiation, and metabolism via its specific receptor. It has been previously suggested that GH signaling pathways are required for normal liver regeneration but the molecular mechanisms involved have yet to be determined. The aim of this study was to identify the mechanisms by which GH controls liver regeneration. We performed two thirds partial hepatectomies in GH receptor (GHR)-deficient mice and wild-type littermates and showed a blunted progression in the G(1)/S transition phase of the mutant hepatocytes. This impaired liver regeneration was not corrected by reestablishing IGF-1 expression. Although the initial response to partial hepatectomy at the priming phase appeared to be similar between mutant and wild-type mice, cell cycle progression was significantly blunted in mutant mice. The main defect in GHR-deficient mice was the deficiency of the epidermal growth factor receptor activation during the process of liver regeneration. Finally, among the pathways activated downstream of GHR during G(1) phase progression, namely Erk1/2, Akt, and signal transducer and activator of transcription 3, we only found a reduced Erk1/2 phosphorylation in mutant mice. In conclusion, our results demonstrate that GH signaling plays a major role in liver regeneration and strongly suggest that it acts through the activation of both epidermal growth factor receptor and Erk1/2 pathways.
authors.affiliation: Institut Cochin, Inserm U.1016, Département Endocrinologie, Metabolisme et Cancer, 24 rue du Faubourg Saint Jacques, 75014 Paris, France.
authors.forename: Amal
authors.initials: A
authors.lastname: Zerrad-Saadi
authors.forename: Martine
authors.initials: M
authors.lastname: Lambert-Blot
authors.forename: Claudia
authors.initials: C
authors.lastname: Mitchell
authors.forename: Hugo
authors.initials: H
authors.lastname: Bretes
authors.forename: Alexandra
authors.initials: A
authors.lastname: Collin de l'Hortet
authors.forename: Véronique
authors.initials: V
authors.lastname: Baud
authors.forename: Fanny
authors.initials: F
authors.lastname: Chereau
authors.forename: Athanassia
authors.initials: A
authors.lastname: Sotiropoulos
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
authors.forename: Lan
authors.initials: L
authors.lastname: Liao
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Hélène
authors.initials: H
authors.lastname: Gilgenkrantz
authors.forename: Jacques-Emmanuel
authors.initials: JE
authors.lastname: Guidotti
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D004789:Enzyme Activation; D004790:Enzyme Induction; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000502:physiology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D012333:RNA, Messenger; D011986:Receptors, Somatotropin; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3