Document Type
Article
Publication Date
10-1-2024
Abstract
BACKGROUND: Occludin, a crucial component of tight junctions, has emerged as a promising biomarker for the diagnosis of acute ischemic disease, highlighting its significant potential in clinical applications. In the diabetes, Occludin serves as a downstream target gene intricately regulated by the adiponectin (APN) signaling pathway. However, the specific mechanism by which adiponectin regulates Occludin expression remains unclear.
METHODS AND RESULTS: Endothelial-specific Ocln knockdown reduced APN-mediated blood flow recovery after femoral artery ligation and nullified APN's protection against high-fat diet (HFD)-triggered apoptosis and angiogenesis inhibition in vivo. Mechanically, we have meticulously elucidated APN's regulatory role in Occludin expression through a comprehensive analysis spanning transcriptional and post-translational dimensions. Foxo1 has been elucidated as a crucial transcriptional regulator of Occludin that is modulated by the APN/APPL1 signaling axis, as evidenced by validation through ChIP-qPCR assays and Western blot analysis. APN hindered Occludin degradation via the ubiquitin-proteasome pathway. Mass spectrometry analysis has recently uncovered a novel phosphorylation site, Tyr467, on Occludin. This site responds to APN, playing a crucial role in inhibiting Occludin ubiquitination by APN. The anti-apoptotic and pro-angiogenic effects of APN were attenuated in vitro and in vivo following Foxo1 knockdown or expression of a non-phosphorylatable mutant, OccludinY467A. Clinically, elevated plasma concentrations of Occludin were observed in patients with diabetes. A significant negative correlation was found between Occludin levels and APN concentrations.
CONCLUSION: Our study proposes that APN modulates Occludin expression through mechanisms involving both transcriptional and post-translational interactions, thereby conferring a protective effect on endothelial integrity within diabetic vasculature.
Recommended Citation
Duan, Yanru; Liu, Demin; Yu, Huahui; Zhang, Shihan; Xia, Yihua; Du, Zhiyong; Qin, Yanwen; Wang, Yajing; Ma, Xin-Liang; Liu, Huirong; and Du, Yunhui, "Transcription and Post-translational Mechanisms: Dual Regulation of Adiponectin-Mediated Occludin Expression in Diabetes" (2024). Department of Emergency Medicine Faculty Papers. Paper 253.
https://jdc.jefferson.edu/emfp/253
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
39354565
Language
English
Included in
Amino Acids, Peptides, and Proteins Commons, Biological Factors Commons, Diagnosis Commons, Emergency Medicine Commons, Genetic Phenomena Commons
Comments
This article is the author's final published version in Cell and Bioscience, Volume 14, Issue 1, 2024, Article number 126.
The published version is available at https://doi.org/10.1186/s13578-024-01306-5.
Copyright © The Author(s) 2024