Abstract
FoxO proteins are major targets of insulin action, and FoxO1 mediates the effects of insulin on hepatic glucose metabolism. We reported previously that serpinB1 is a liver-secreted factor (hepatokine) that promotes adaptive β-cell proliferation in response to insulin resistance in the liver-specific insulin receptor knockout (LIRKO) mouse. Here we report that FoxO1 plays a critical role in promoting serpinB1 expression in hepatic insulin resistance in a non-cell-autonomous manner. Mice lacking both the insulin receptor and FoxO1 (LIRFKO) exhibit reduced β-cell mass compared with LIRKO mice because of attenuation of β-cell proliferation. Although hepatic expression of serpinB1 mRNA and protein levels was increased in LIRKO mice, both the mRNA and protein levels returned to control levels in LIRFKO mice. Furthermore, liver-specific expression of constitutively active FoxO1 in transgenic mice induced an increase in hepatic serpinB1 mRNA and protein levels in refed mice. Conversely, serpinB1 mRNA and protein levels were reduced in mice lacking FoxO proteins in the liver. ChIP studies demonstrated that FoxO1 binds to three distinct sites located ∼9 kb upstream of the serpinb1 gene in primary mouse hepatocytes and that this binding is enhanced in hepatocytes from LIRKO mice. However, adenoviral expression of WT or constitutively active FoxO1 and insulin treatment are sufficient to regulate other FoxO1 target genes (IGFBP-1 and PEPCK) but not serpinB1 expression in mouse primary hepatocytes. These results indicate that liver FoxO1 promotes serpinB1 expression in hepatic insulin resistance and that non-cell-autonomous factors contribute to FoxO1-dependent effects on serpinB1 expression in the liver.
Highlights
FoxO proteins are major targets of insulin action, and FoxO1 mediates the effects of insulin on hepatic glucose metabolism
ChIP studies demonstrated that FoxO1 binds to three distinct sites located ϳ9 kb upstream of the serpinb1 gene in primary mouse hepatocytes and that this binding is enhanced in hepatocytes from liver-specific insulin receptor knockout (LIRKO) mice
Adenoviral expression of WT or constitutively active FoxO1 and insulin treatment are sufficient to regulate other FoxO1 target genes (IGFBP-1 and PEPCK) but not serpinB1 expression in mouse primary hepatocytes. These results indicate that liver FoxO1 promotes serpinB1 expression in hepatic insulin resistance and that non-cell-autonomous factors contribute to FoxO1-dependent effects on serpinB1 expression in the liver
Summary
-cell proliferation and hepatic serpinB1 expression in LIRKO versus LIRFKO mice. We first asked whether hepatic FoxO1 plays a critical role in promoting islet -cell proliferation in the setting of hepatic insulin resistance using LIRKO and LIRFKO mice. Taken together with gene expression studies (Fig. 4), these results indicate that recruitment of FoxO1 to these sites is not sufficient to promote serpinb gene expression in isolated hepatocytes Together, these data suggest the novel concept that, in contrast to igfbp-1, pepck, and g6pase, insulin treatment and FoxO1 are not sufficient to modulate serpinb gene expression in isolated primary hepatocytes despite evidence supporting sequence-specific recruitment of FoxO1 to its binding sites upstream of the serpinb gene and that non-cell-autonomous effects of FoxO1 may contribute to the regulation of hepatic serpinb expression by insulin in vivo
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