Hypoxia reduces HNF4α/MODY1 protein expression in pancreatic β-cells by activating AMP-activated protein kinase

Hypoxia plays a role in the deterioration of beta-cell function. Hepatocyte nuclear factor 4 (HNF4 alpha) has an important role in pancreatic beta-cells, and mutations of the human HNF4A gene cause a type of maturity-onset diabetes of the young (MODY1). However, it remains unclear whether hypoxia affects the expression of HNF4 alpha in beta-cells. Here, we report that hypoxia reduces HNF4 alpha protein expression in beta-cells. Hypoxia-inducible factor was not involved in the down-regulation of HNF4 alpha under hypoxic conditions. The down-regulation of HNF4 alpha was dependent on the activation of AMP-activated protein kinase (AMPK), and the reduction of HNF4 alpha protein expression by metformin, an AMPK activator, and hypoxia was inhibited by the overexpression of a kinase-dead (KD) form of AMPK alpha 2. In addition, hypoxia decreased the stability of the HNF4 alpha protein, and the down-regulation of HNF4 alpha was sensitive to proteasome inhibitors. Adenovirus-mediated overexpression of KD-AMPK alpha 2 improved insulin secretion in metformin-treated islets, hypoxic islets, and ob/ob mouse islets. These results suggest that down-regulation of HNF4 alpha could be of importance in beta-cell dysfunction by hypoxia.