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Phosphatidylcholine Transfer Protein Interacts with Thioesterase Superfamily Member 2 to Attenuate Insulin Signaling

A phospholipid-binding protein and its interacting partner suppress insulin signaling through dual mechanisms. Linking Phospholipids to Insulin Signaling Insulin promotes the uptake of glucose by the liver, skeletal muscle, and adipose tissue. Individuals with diabetes do not produce enough insulin to control their blood sugar concentrations. Thus, an understanding of the regulation of insulin signaling could provide new therapeutic avenues. Ersoy et al. found that the phospholipid-binding protein PC-TP (phosphatidylcholine transfer protein) and its interacting partner THEM2 (thioesterase superfamily member 2) attenuated insulin signaling by promoting the inhibition of two different effectors downstream of the insulin receptor. Both of these mechanisms were inhibited by a compound that prevented binding of phosphatidylcholine to PC-TP. The authors propose that PC-TP links the changes in membrane composition that occur after feeding or fasting to modulation of the activity of the insulin signaling pathway. Phosphatidylcholine transfer protein (PC-TP) is a phospholipid-binding protein that is enriched in liver and that interacts with thioesterase superfamily member 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 knockdown of THEM2, providing support for a role for the interaction of PC-TP with THEM2 in suppressing insulin signaling. Additionally, we showed that PC-TP bound 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-TP with 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 IRS2 were increased, whereas those of TSC2 were decreased. These findings reveal a phospholipid-dependent mechanism that suppresses insulin signaling downstream of its receptor.