Abstract
IQ motif-containing GTPase Activating Protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that integrates signaling from multiple cellular processes including motility, adhesion, and proliferation. Here, we show that IQGAP1 is induced in the liver upon fasting and can also regulate β-oxidation and ketone body synthesis. Utilizing ketogenic diet and pharmacologic activation we identified that hepatic PPARα activity is compromised in Iqgap1-/- mice. Our data show that IQGAP1 interacts with the mechanistic target of rapamycin (mTOR) and IQGAP1 deletion results in enhanced mTOR complex 1 (mTORC1) activation. Conversely, ectopic expression of IQGAP1 in Iqgap1-/- mice was sufficient to suppress mTORC1 signaling. We also confirmed that modulation of mTORC1 signaling by IQGAP1 is cell autonomous. This increased mTORC1 activation impedes PPARα signaling since mTORC1 inhibition restored a subset of metabolic genes in Iqgap1-/- mice. Overall, we demonstrate a previously unidentified role for IQGAP1 as an important regulator of mTORC1 activity and long-term ketosis.
