Sucrase-isomaltase (SI) gene expression is negatively regulated by glucose, but its molecular mechanism is not completely clear. The purpose of this study is to investigate whether HNF-1 alpha and HNF-1 beta contribute to glucose regulation of SI gene expression. To explore this question, we examined the association of gene expressions between SI and HNF-1 alpha and HNF-1 beta in Caco-2 cells cultured in medium containing 2.0 and 16.7 mM glucose. We found that gene expression of HNF-1 alpha but not HNF-1 beta exhibits a positive correlation with that of SI regulated by glucose. Moreover, to elucidate whether glucose regulation of SI gene expression is changed when HNF-1 alpha and HNF-1 beta are inhibited, we produced three stable cell lines, in which dominant-negative mutant HNF-1 alpha T539fsdelC, mutant HNF-1 beta R177X, and empty vector (as a control), respectively, were stably expressed. We found that the glucose regulation of SI gene expression was significantly attenuated in HNF-1 alpha T539fsdelC cells, but it was well maintained in empty vector and HNF-1 beta R177X cells. These results suggest that HNF-1 alpha participates in glucose regulation of SI gene expression. (c) 2006 Elsevier Inc. All rights reserved.