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Forkhead box protein O1 (FoxO1) regulates hepatic serine protease inhibitor B1 (serpinB1) expression in a non-cell-autonomous fashion.

Citation
Ouaamari, A. E., et al. “Forkhead Box Protein O1 (Foxo1) Regulates Hepatic Serine Protease Inhibitor B1 (Serpinb1) Expression In A Non-Cell-Autonomous Fashion.”. The Journal Of Biological Chemistry, pp. 1059-1069.
Center Joslin Diabetes Center University of Chicago
Multicenter
Multicenter
Author Abdelfattah El Ouaamari, InSug O-Sullivan, Jun Shirakawa, Giorgio Basile, Wenwei Zhang, Sandra Roger, Thomas Thomou, Shanshan Xu, Guifen Qiang, Chong Wee Liew, Rohit N Kulkarni, Terry G Unterman
Keywords FoxO, FoxO1, SerpinB1, cell proliferation, diabetes, Insulin resistance, serpin, β-Cell, β-cell proliferation
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 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.

Year of Publication
2019
Journal
The Journal of biological chemistry
Volume
294
Issue
3
Number of Pages
1059-1069
Date Published
12/2019
ISSN Number
1083-351X
DOI
10.1074/jbc.RA118.006031
Alternate Journal
J. Biol. Chem.
PMID
30459233
PMCID
PMC6341384
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