Hepatocyte Nuclear Factor 4α Regulates the Expression of Pancreatic β-Cell Genes Implicated in Glucose Metabolism and Nutrient-induced Insulin Secretion

Mutations in the HNF4α gene are associated with the subtype 1 of maturity-onset diabetes of the young (MODY1), which is characterized by impaired insulin secretory response to glucose in pancreatic β-cells. Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor critical for liver development and hepatocyte-specific gene expression. However, the role of HNF4α in the regulation of pancreatic β-cell gene expression and its correlation with metabolism secretion coupling have not been previously investigated. The tetracycline-inducible system was employed to achieve tightly controlled expression of both wild type (WT) and dominant-negative mutant (DN) of HNF4α in INS-1 cells. The induction of WT-HNF4α resulted in a left shift in glucose-stimulated insulin secretion, whereas DN-HNF4α selectively impaired nutrient-stimulated insulin release. Induction of DN-HNF4α also caused defective mitochondrial function substantiated by reduced [14C]pyruvate oxidation, attenuated substrate-evoked mitochondrial membrane hyperpolarization, and blunted nutrient-generated cellular ATP production. Quantitative evaluation of HNF4α-regulated pancreatic β-cell gene expression revealed altered mRNA levels of insulin, glucose transporter-2, L-pyruvate kinase, aldolase B, 2-oxoglutarate dehydrogenase E1 subunit, and mitochondrial uncoupling protein-2. The patterns of HNF4α-regulated gene expression are strikingly similar to that of its downstream transcription factor HNF1α. Indeed, HNF4α changed the HNF1α mRNA levels and HNF1α promoter luciferase activity through altered HNF4α binding. These results demonstrate the importance of HNF4α in β-cell metabolism-secretion coupling.