title: Conditional VHL gene deletion causes hypoglycemic death associated with disproportionately increased glucose uptake by hepatocytes through an upregulated IGF-I receptor.
abstract: Our conditional VHL knockout (VHL-KO) mice, having VHL gene deletion induced by tamoxifen, developed severe hypoglycemia associated with disproportionately increased storage of PAS-positive substances in the liver and resulted in the death of these mice. This hypoglycemic state was neither due to impaired insulin secretion nor insulin receptor hypersensitivity. By focusing on insulin-like growth factor I (IGF-I), which has a similar effect on glucose metabolism as the insulin receptor, we demonstrated that IGF-I receptor (IGF-IR) protein expression in the liver was upregulated in VHL-KO mice compared to that in the mice without VHL deletion, as was the expression of glucose transporter (GLUT) 1. The interaction of the receptor for activated C kinase (RACK) 1, which predominantly binds to VHL, was enhanced in VHL-KO livers with IGF-IR, because VHL deletion increased free RACK1 and facilitated the IGF-IR-RACKI interaction. An IGF-IR antagonist retarded hypoglycemic progression and sustained an euglycemic state. These IGF-IR antagonist effects on restoring blood glucose levels also attenuated PAS-positive substance storage in the liver. Because the effect of IGF-I on HIF-1α protein synthesis is mediated by IGF-IR, our results indicated that VHL inactivation accelerated hepatic glucose storage through the upregulation of IGF-IR and GLUT1 and that IGF-IR was a key regulator in VHL-deficient hepatocytes.
authors.affiliation: Department of Pathology, Kochi Medical School, Nankoku, Kochi, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurabayashi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kakinuma
authors.forename: Taku
authors.initials: T
authors.lastname: Morita
authors.forename: Keiji
authors.initials: K
authors.lastname: Inoue
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sato
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Furihata
mesh_terms: D000818:Animals; D002423:Cause of Death; D002460:Cell Line; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics* / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D000075370:Receptors for Activated C Kinase; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D009479:Neuropeptides; C090294:RACK1 protein, mouse; D000075370:Receptors for Activated C Kinase; D052250:Nitric Oxide Synthase Type III; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D017526:Receptor, IGF Type 1; D005947:Glucose