Abstract
The liver is critical in maintaining metabolic homeostasis, regulating both anabolic and catabolic processes. Scaffold protein IQ motif-containing GTPase activating protein 2 (IQGAP2) is highly expressed in the liver and implicated in fatty acid uptake. However, its role in coordinating either fed or fasted responses is not well understood. Here we report that IQGAP2 is widely expressed in the liver that is pronounced in the pericentral region. Although control and IQGAP2 knockout mouse model showed comparable hepatic gene expression in the fasted state, we found significant defects in fed state responses. Glycogen levels were reduced in the periportal region when IQGAP2 was deleted. Consistently, we observed a decrease in phosphorylated glycogen synthase kinase 3α and total glycogen synthase protein in the fed IQGAP2 knockout mice which suggest inadequate glycogen synthesis. Moreover, immunoprecipitation of IQGAP2 revealed its interaction with GSK3 and GYS. Furthermore, our study demonstrated that knocking down IQGAP2 in vitro significantly decreased the phosphorylation of AKT and forkhead box O3 proteins downstream of insulin signaling. These findings suggest that IQGAP2 contributes to liver fed state metabolism by interacting with glycogen synthesis regulators and affecting the phosphorylation of insulin pathway components. Our results suggest that IQGAP2 plays a role in regulating fed state metabolism.