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Forkhead box protein O1 (FoxO1) regulates hepatic serine protease inhibitor B1 (serpinB1) expression in a non-cell-autonomous fashion.
- Source :
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The Journal of biological chemistry [J Biol Chem] 2019 Jan 18; Vol. 294 (3), pp. 1059-1069. Date of Electronic Publication: 2018 Nov 20. - Publication Year :
- 2019
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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.<br />Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- Subjects :
- Animals
Forkhead Box Protein O1 genetics
Hepatocytes cytology
Insulin-Like Growth Factor Binding Protein 1 genetics
Insulin-Like Growth Factor Binding Protein 1 metabolism
Liver cytology
Male
Mice
Mice, Transgenic
Phosphoenolpyruvate Carboxykinase (ATP) genetics
Phosphoenolpyruvate Carboxykinase (ATP) metabolism
Serpins genetics
Forkhead Box Protein O1 metabolism
Gene Expression Regulation
Hepatocytes metabolism
Liver metabolism
Serpins biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 294
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30459233
- Full Text :
- https://doi.org/10.1074/jbc.RA118.006031