SAT-150 Forkhead Box Protein O1 (foxo1) Regulates Hepatic Serine Protease Inhibitor B1 (serpinb1) Expression In A Cell Non-autonomous Fashion

Forkhead box O (FoxO) proteins are major targets of insulin action, and FoxO1 mediates insulin’s effects on hepatic glucose metabolism. We previously reported that serine protease inhibitor B1 (serpinB1) is a liver-secreted factor (hepatokine) that promotes adaptive β-cell proliferation in response to insulin resistance in liver-specific insulin receptor knockout (LIRKO) mice. Here, we report that FoxO1 promotes serpinB1 expression in hepatic insulin resistance in a cell non-autonomous manner. Mice lacking both the insulin receptor and FoxO1 in the liver (LIRFKO) exhibited lower β-cell mass than LIRKO mice due to attenuated β-cell proliferation. Hepatic expression of serpinb1mRNA and protein levels were increased in the LIRKO mice, whereas in the LIRFKO mice, these levels returned to those in control mice. Furthermore, liver-specific expression of constitutively active FoxO1 increased hepatic serpinB1 mRNA and protein levels. Conversely, serpinB1 mRNA and protein levels were reduced in FoxOKO mice lacking FoxO proteins in the liver. ChIP experiments indicated that FoxO1 binds to three distinct DNA sites located ~9 kb upstream of the serpinb1 gene in primary mouse hepatocytes and that this binding is enhanced in LIRKO hepatocytes. However, although adenoviral expression of wildtype or constitutively active FoxO1 and insulin treatment regulated other known FoxO1 target genes (IGFBP-1, PEPCK, G6Pase), it did not alter serpinB1 expression in mouse primary hepatocytes. These results indicate that liver FoxO1 promotes serpinB1 expression in hepatic insulin resistance and that cell non-autonomous mechanisms contribute to FoxO1-dependent effects on hepatic serpinB1 expression.