title: Loss of HNF-1alpha function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism.
abstract: Mutations in hepatocyte nuclear factor 1alpha (HNF-1alpha) lead to maturity-onset diabetes of the young type 3 as a result of impaired insulin secretory response in pancreatic beta-cells. The expression of 50 genes essential for normal beta-cell function was studied to better define the molecular mechanism underlying the insulin secretion defect in Hnf-1alpha(-/-) mice. We found decreased steady-state mRNA levels of genes encoding glucose transporter 2 (Glut2), neutral and basic amino acid transporter, liver pyruvate kinase (L-Pk), and insulin in Hnf-1alpha(-/-) mice. In addition, we determined that the expression of several islet-enriched transcription factors, including Pdx-1, Hnf-4alpha, and Neuro-D1/Beta-2, was reduced in Hnf-1alpha(-/-) mice. These changes in pancreatic islet mRNA levels were already apparent in newborn animals, suggesting that loss of Hnf-1alpha function rather than chronic hyperglycemia is the primary cause of the altered gene expression. This expression profile was pancreatic islet-specific and distinct from hepatocytes, where we found normal expression of Glut2, L-Pk, and Hnf-4alpha in the liver of Hnf-1alpha(-/-) mice. The expression of small heterodimer partner (Shp-1), an orphan receptor that can heterodimerize with Hnf-4alpha and inhibit its transcriptional activity, was also reduced in Hnf-1alpha(-/-) islets. We characterized a 0.58-kb Shp-1 promoter and determined that the decreased expression of Shp-1 may be indirectly mediated by a downregulation of Hnf-4alpha. We further showed that Shp-1 can repress its own transcriptional activation by inhibiting Hnf-4alpha function, thereby establishing a feedback autoregulatory loop. Our results indicate that loss of Hnf-1alpha function leads to altered expression of genes involved in glucose-stimulated insulin secretion, insulin synthesis, and beta-cell differentiation.
authors.affiliation: Laboratory of Metabolic Diseases, the Rockefeller University, New York, New York 10021, USA.
authors.forename: D Q
authors.initials: DQ
authors.lastname: Shih
authors.forename: S
authors.initials: S
authors.lastname: Screenan
authors.forename: K N
authors.initials: KN
authors.lastname: Munoz
authors.forename: L
authors.initials: L
authors.lastname: Philipson
authors.forename: M
authors.initials: M
authors.lastname: Pontoglio
authors.forename: M
authors.initials: M
authors.lastname: Yaniv
authors.forename: K S
authors.initials: KS
authors.lastname: Polonsky
authors.forename: M
authors.initials: M
authors.lastname: Stoffel
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins; D005333:Fetus / Q000502:physiology; D015870:Gene Expression / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000196:embryology* / Q000378:metabolism*; D008099:Liver / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics; D012016:Reference Values; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D007328:Insulin; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099713:nuclear receptor subfamily 0, group B, member 2; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D005947:Glucose