Loss of HNF-1 alpha function in mice leads to abnormal expression of genesinvolved in pancreatic islet development and metabolism

Mutations in hepatocyte nuclear factor 1 alpha (HNF-1 alpha) lead to maturi ty-onset diabetes of the young type 3 as a result of impaired insulin secre tory response in pancreatic beta -cells. The expression of 50 genes essenti al for normal beta -cell function was studied to better define the molecula r mechanism underlying the insulin secretion defect in Hnf-1 alpha (-/-) mi ce. We found decreased steady-state mRNA levels of genes encoding glucose t ransporter 2 (Glut2), neutral and basic amino acid transporter, liver pyruv ate kinase (L-Pk), and insulin in Hnf-1 alpha (-/-) mice. In addition, we d etermined that the expression of several islet-enriched transcription facto rs, including Pdx-1, Hnf-4 alpha, and Neuro-D1/Beta-2, was reduced in Hnf-1 alpha (-/-) mice. These changes in pancreatic islet mRNA levels were alrea dy apparent in newborn animals, suggesting that loss of Hnf-1 alpha functio n rather than chronic hyperglycemia is the primary cause of the altered gen e expression. This expression profile was pancreatic islet-specific and dis tinct from hepatocytes, where we found normal expression of Glut2, L-Pk, an d Hnf-4 alpha in the liver of Hnf-1 alpha (-/-) mice. The expression of sma ll heterodimer partner (Shp-1), an orphan receptor that can heterodimerize with Hnf-4a and inhibit its transcriptional activity, was also reduced in H qf-1 alpha (-/-) islets. We characterized a 0.58-kb Shp-1 promoter and dete rmined that the decreased expression of Shp-1 may be indirectly mediated by a downregulation of Hnf-4a. We further showed that Shp-1 can repress its o wn transcriptional activation by inhibiting Hnf-4 alpha function, thereby e stablishing a feedback autoregulatory loop. Our results indicate that loss of Hnf-1 alpha function leads to altered expression of genes involved in gl ucose-stimulated insulin secretion, insulin synthesis, and beta -cell diffe rentiation.