Abstract 1514 FK506-Binding Protein 51 (FKBP51), a New Regulator of Insulin Receptor Alternative Splicing and PPARα Activation That May Control Metabolic Disorder Developments

FK506-binding protein-51 (FKBP51) is a molecular chaperone protein that has great potential to serve as a treatment target for obesity and type II diabetes (T2DM). FKBP51 has been known to regulate nuclear receptors such as glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor γ (PPARγ). However, the connections between FKBP51 and other PPAR family members, such as peroxisome proliferator-activated receptor α (PPARα), are yet to be identified. FKBP51 can also inhibit protein kinase B (AKT) activation, which may impact the insulin receptor signaling pathway. It has been reported that FKBP51 knockout mice presented less adiposity, reduced liver steatosis, and increased insulin sensitivity and insulin clearance, indicating that FKBP51 plays a role in insulin resistance and fatty liver development. However, how FKBP51 regulates insulin resistance, especially in the liver, still needs to be unveiled. It has been shown that insulin receptor (IR) alternative splicing is associated with insulin sensitivity and that PPARα activation is critical in reducing insulin resistance. Thus, we hypothesize that FKBP51 can regulate hepatic insulin resistance through insulin receptor alternative splicing and PPARα suppression. To test this hypothesis, we developed an FKBP51 knockout mouse hepatocyte cell line, 51KO AML12, and treated the cells with insulin for 1hr. We measured RNA and protein expressions in the cells through RT-PCR and western blotting and found that 51KO AML12 had increased phospho-AKT Ser473 (pAKT S473) and IR isoform B (IR-B), indicating increased insulin signaling activity. We also found increased IR isoform A (IR-A) and IR-B expression in 51KO AML12. In addition, we found an increased ratio of IR-B: IR-A in 51KO AML12 treated with insulin. These data indicate a great potential for FKBP51 to be a novel treatment target for hepatic insulin resistance and T2DM.