Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling

Phosphatidylcholine transfer protein (PC-TP) is a phospholipid-binding protein that is enriched in liver and that interactswith thioesterase superfamilymember 2 (THEM2).Mice lacking either protein exhibit improved hepatic glucose homeostasis and are resistant to diet-induced diabetes. Insulin receptor substrate 2 (IRS2) and mammalian target of rapamycin complex 1 (mTORC1) are key effectors of insulin signaling, which is attenuated in diabetes. We found that PC-TP inhibited IRS2, as evidenced by insulin-independent IRS2 activation after knockdown, genetic ablation, or chemical inhibition of PC-TP. In addition, IRS2 was activated after knockdownofTHEM2, providing support for a role for the interaction ofPC-TPwith THEM2in suppressing insulin signaling.Additionally,we showed thatPC-TPbound to tuberous sclerosis complex 2 (TSC2) and stabilized the components of the TSC1-TSC2 complex, which functions to inhibit mTORC1. Preventing phosphatidylcholine from binding to PC-TP disrupted interactions of PC-TPwith THEM2 and TSC2, and disruption of the PC-TP-THEM2 complex was associated with increased activation of both IRS2 and mTORC1. In livers of mice with genetic ablation of PC-TP or that had been treated with a PC-TP inhibitor, steady-state amounts of IRS2were increased,whereas those of TSC2were decreased. These findings reveal a phospholipiddependent mechanism that suppresses insulin signaling downstream of its receptor.