Loss of HNF-1α Function in Mice Leads to Abnormal Expression of Genes Involved in Pancreatic Islet Development and Metabolism
| Autor: | Kenneth S. Polonsky, Markus Stoffel, Moshe Yaniv, Karla N. Munoz, David Q. Shih, Marco Pontoglio, Seamus Screenan, Lou Philipson |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Transcriptional Activation
medicine.medical_specialty Endocrinology Diabetes and Metabolism medicine.medical_treatment Gene Expression Receptors Cytoplasmic and Nuclear In Vitro Techniques Biology digestive system Cell Line Islets of Langerhans Mice Fetus Downregulation and upregulation Reference Values Internal medicine Insulin Secretion Gene expression Internal Medicine medicine Animals Insulin Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 1-beta Mice Knockout Orphan receptor geography geography.geographical_feature_category Nuclear Proteins Islet DNA-Binding Proteins Glucose Endocrinology Liver Hepatocyte Nuclear Factor 1 embryonic structures Hepatocyte Nuclear Factor 1-Beta Small heterodimer partner biology.protein GLUT2 Transcription Factors |
| Zdroj: | Diabetes. 50:2472-2480 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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