TAZ inhibits GR and coordinates hepatic glucose homeostasis in normal physiologic states

Abstract

The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiologic and pathologic states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ interacts via its WW domain with the ligand-binding domain of GR to limit the binding of GR to gluconeogenic gene promoters. Therefore, liver-specific TAZ knockout mice show increases in glucose production and blood glucose concentration. Conversely, the overexpression of TAZ in mouse liver reduces the binding of GR to gluconeogenic gene promoters and glucose production. Thus, our findings demonstrate distinct roles of the hippo pathway effector proteins yes-associated protein 1 (YAP) and TAZ in liver physiology: while deletion of hepatic YAP has little effect on glucose homeostasis, hepatic TAZ protein expression decreases upon fasting and coordinates gluconeogenesis in response to physiologic fasting and feeding.