STAT3 targets the regulatory regions of gluconeogenic genes in vivo
Open accessAbstract
The regulation of expression of gluconeogenic genes including glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver plays an important role in glucose homeostasis, because aberrant expression of these genes contributes to the development of type 2 diabetes. Previous reports demonstrate that signal transducer and activator of transcription 3 (STAT3) plays a key role in regulating gluconeogenic gene expression, but the mechanism remains unclear. Herein we demonstrate that phosphorylated STAT3 is required for repression of G6Pase expression by IL-6 in both HepG2 cells and mouse liver. Interestingly, PEPCK expression is regulated by STAT3 independent of IL-6 activation. Using in vivo chromatin immunoprecipitation, we demonstrate that STAT3 binds to the promoters of the G6Pase, PEPCK, and suppressor of cytokine signaling (SOCS)3 genes, and its recruitment increases at the G6Pase and SOCS3 promoters with IL-6 treatment. Whereas persistent recruitment of RNA polymerase II is seen on the SOCS3 promoter, consistent with its induction by IL-6, a decrease in polymerase II recruitment and histone H4 acetylation is seen at the G6Pase promoter with IL-6 treatment. Thus STAT3 mediates negative regulation of hepatic gluconeogenic gene expression in vivo by interacting with regulatory regions of these genes.
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The effects of the loss of STAT3β on STAT3α regulation are further supported by a study in liver showing that adenoviral delivery of STAT3β, followed by cytokine stimulation with IL-6, potentiates phosphorylation of STAT3α.
“These observations indicate that the effects of the loss of STAT3β on STAT3α regulation are further supported by a study in liver showing that the adenoviral delivery of STAT3β, followed by cytokine stimulation with IL-6, potentiates phosphorylation of STAT3α [40].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [40]
The ‘STAT3 is required in vivo for repression of G6Pase by IL-6’ section reports adenoviral STAT3β overexpression in mouse liver, increased basal phosphorylated STAT3, and IL-6-induced phosphorylation in both control and STAT3β-overexpressing livers. It does not say that STAT3β potentiated IL-6-induced phosphorylation or identify the phosphorylated protein as STAT3α. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSTAT3 in hepatocytes regulates glucose homeostasis by transcriptionally suppressing expression of gluconeogenic genes, e.g., glucose-6-phosphatase and phosphoenolpyruvate carboxykinase.
“which in turn regulates glucose homeostasis by transcriptionally suppressing (Ramadoss et al., 2009) expression of gluconeogenic genes, e.g., glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (Inoue et al., 2004).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Ramadoss et al., 2009
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References 35 · Cited by 103
- Authors
- Ramadoss, P., Unger-Smith, N. E., Lam, F. S., & Hollenberg, A. N.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Hollenberg, Anthony N.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2009-06-01
- Volume
- 23
- Issue
- 6
- Pages
- 827-837
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC5419286
- OpenAlex
- W1989177817
- Cited by
- 103
- References
- 35
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 6 · 2022: 2 · 2021: 8 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 7 · 2016: 11 · 2015: 7 · 2014: 13 · 2013: 7 · 2012: 7
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Beth Israel Deaconess Medical Center
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- STAT3, gluconeogenic gene expression, glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, interleukin-6, SOCS3, hepatic glucose homeostasis, promoter binding, histone H4 acetylation, RNA polymerase II recruitment, type 2 diabetes, liver
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Acetylation, Animals, Colforsin, Gluconeogenesis, Glucose-6-Phosphatase, Histones, Humans, Liver, Models, Genetic, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Regulatory Sequences, Nucleic Acid, Repressor Proteins, RNA Polymerase II, RNA, Messenger, Transcription, Genetic, Interleukin-6, Phosphoenolpyruvate Carboxykinase (ATP), STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice
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