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FXR/Menin-mediated epigenetic regulation of E2F3 expression controls β-cell proliferation and is increased in islets from diabetic GK rats after RYGB.
- Source :
-
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Jun; Vol. 1870 (5), pp. 167136. Date of Electronic Publication: 2024 Mar 26. - Publication Year :
- 2024
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Abstract
- Farnesoid X receptor (FXR) improves the function of islets, especially in the setting of Roux-en-Y gastric bypass (RYGB). Here we investigated how FXR activation regulates β-cell proliferation and explored the potential link between FXR signaling and the menin pathway in controlling E2F3 expression, a key transcription factor for controlling adult β-cell proliferation. Stimulation with the FXR agonist GW4064 or chenodeoxycholic acid (CDCA) increased E2F3 expression and β-cell proliferation. Consistently, E2F3 knockdown abolished GW4064-induced proliferation. Treatment with GW4064 increased E2F3 expression in β-cells via enhancing Steroid receptor coactivator-1 (SRC1) recruitment, increasing the pro-transcriptional acetylation of histone H3 at the E2f3 promoter. GW4064 treatment also decreased the association between FXR and menin, leading to the induction of FXR-mediated SRC1 recruitment. Mimicking the impact of FXR agonists, RYGB also increased E2F3 expression and β-cell proliferation in GK rats and SD rats. These findings unravel the crucial role of the FXR/menin signaling in epigenetically controlling E2F3 expression and β-cell proliferation, a mechanism possibly underlying RYGB-induced β-cell proliferation.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Rats
Male
Rats, Wistar
Histones metabolism
Isoxazoles pharmacology
Signal Transduction drug effects
Islets of Langerhans metabolism
Islets of Langerhans drug effects
Diabetes Mellitus, Experimental metabolism
Diabetes Mellitus, Experimental genetics
Diabetes Mellitus, Experimental pathology
Cell Proliferation drug effects
Epigenesis, Genetic drug effects
Receptors, Cytoplasmic and Nuclear metabolism
Receptors, Cytoplasmic and Nuclear agonists
Receptors, Cytoplasmic and Nuclear genetics
Insulin-Secreting Cells metabolism
Insulin-Secreting Cells drug effects
E2F3 Transcription Factor metabolism
E2F3 Transcription Factor genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1879-260X
- Volume :
- 1870
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Publication Type :
- Academic Journal
- Accession number :
- 38531483
- Full Text :
- https://doi.org/10.1016/j.bbadis.2024.167136