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Vitamin D (VD) prevents oxidative stress via regulating NOX4/Nrf2/Trx signaling cascade and upregulates SIRT1‐mediated AMPK/IRS1/GLUT4 pathway and glucose uptake in high glucose treated 3T3L1 adipocytes
Author(s) -
Manna Prasenjit,
Jain Sushil
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.253.1
Subject(s) - glut4 , ampk , chemistry , irs1 , nox4 , signal transduction , glucose uptake , glucose transporter , gene knockdown , medicine , endocrinology , oxidative stress , protein kinase b , phosphorylation , microbiology and biotechnology , insulin receptor , protein kinase a , biology , nadph oxidase , insulin resistance , insulin , biochemistry , apoptosis
This study examined the hypothesis that VD regulates cellular redox signaling cascade and upregulates insulin signaling in diabetes. 3T3L1 adipocytes were treated with VD (1,25(OH) 2 D 3, 0‐50 nM, 2 h) and high glucose (HG, 25mM, 20 h). Results (n=3) showed that VD supplementation decreased ROS production (31%), NOX4 protein expression (71%), and NF‐κB phosphorylation, and increased the protein expression of Nrf2 (78%) and Trx (30%) in HG‐treated cells. VD also upregulated SIRT1 protein expression and AMPK phosphorylation and stimulated the IRS1/PI3K/PIP3/PKCζ/λ signaling cascade, GLUT4 translocation (44%), and glucose uptake (34%) in HG‐treated cells. The effect of VD on AMPK/IRS1/GLUT4 signaling pathway was significantly inhibited in SIRT1 knockdown cells. In VD‐receptor knockdown cells the effect of VD on redox signaling cascade, SIRT1/AMPK/GLUT4 pathway, and glucose uptake was also inhibited against HG exposure, suggesting a receptor mediated role for VD in maintaining cellular redox equilibria and glucose homeostasis in HG‐treated cells. This study demonstrates a novel molecular mechanism by which VD prevents oxidative stress via modulating NOX4/Nrf2/Trx redox signaling and upregulates SIRT1‐mediated AMPK/IRS1/GLUT4 pathway and glucose uptake in HG‐treated adipocytes. (Supported by NIH RO1 AT007442 and Malcolm Feist Chair in Diabetes)