| Autor: |
Shih, David Q., Screenan, Seamus, Munoz, Karla N., Philipson, Lou, Pontoglio, Marco, Yaniv, Moshe, Polonsky, Kenneth S., Stoffel, Markus, Shih, D Q, Screenan, S, Munoz, K N, Philipson, L, Pontoglio, M, Yaniv, M, Polonsky, K S, Stoffel, M |
| Předmět: |
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| Zdroj: |
Diabetes; Nov2001, Vol. 50 Issue 11, p2472-2480, 9p, 1 Color Photograph, 3 Black and White Photographs, 1 Diagram, 1 Graph |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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