Alpha lipoic acid attenuates ER stress and improves glucose uptake through DNAJB3 cochaperone
| Autor: | Abdoulaye Diane, Hanan Abunada, Ilham Bensmail, Naela Mahmoud, Namat Khattab, Mohammed Dehbi |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
RNA editing XBP1 Science Glucose uptake 030209 endocrinology & metabolism Article Mice 03 medical and health sciences 0302 clinical medicine Insulin resistance Heat shock protein medicine Animals Humans Gene Silencing RNA Small Interfering Heat shock Endoplasmic Reticulum Chaperone BiP Multidisciplinary Thioctic Acid biology Chemistry Tunicamycin Hep G2 Cells HSP40 Heat-Shock Proteins Endoplasmic Reticulum Stress medicine.disease Mitochondria Cell biology Oxidative Stress Insulin receptor Glucose 030104 developmental biology biology.protein Unfolded protein response RNA Medicine Biomarkers GLUT4 Molecular Chaperones |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-15 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-77621-x |
| Popis: | Persistent ER stress, mitochondrial dysfunction and failure of the heat shock response (HSR) are fundamental hallmarks of insulin resistance (IR); one of the early core metabolic aberrations that leads to type 2 diabetes (T2D). The antioxidant α-lipoic acid (ALA) has been shown to attenuate metabolic stress and improve insulin sensitivity in part through activation of the heat shock response (HSR). However, these studies have been focused on a subset of heat shock proteins (HSPs). In the current investigation, we assessed whether ALA has an effect on modulating the expression of DNAJB3/HSP40 cochaperone; a potential therapeutic target with a novel role in mitigating metabolic stress and promoting insulin signaling. Treatment of C2C12 cells with 0.3 mM of ALA triggers a significant increase in the expression of DNAJB3 mRNA and protein. A similar increase in DNAJB3 mRNA was also observed in HepG2 cells. We next investigated the significance of such activation on endoplasmic reticulum (ER) stress and glucose uptake. ALA pre-treatment significantly reduced the expression of ER stress markers namely, GRP78, XBP1, sXBP1 and ATF4 in response to tunicamycin. In functional assays, ALA treatment abrogated significantly the tunicamycin-mediated transcriptional activation of ATF6 while it enhanced the insulin-stimulated glucose uptake and Glut4 translocation. Silencing the expression of DNAJB3 but not HSP72 abolished the protective effect of ALA on tunicamycin-induced ER stress, suggesting thus that DNAJB3 is a key mediator of ALA-alleviated tunicamycin-induced ER stress. Furthermore, the effect of ALA on insulin-stimulated glucose uptake is significantly reduced in C2C12 and HepG2 cells transfected with DNAJB3 siRNA. In summary, our results are supportive of an essential role of DNAJB3 as a molecular target through which ALA alleviates ER stress and improves glucose uptake. |
| Databáze: | OpenAIRE |
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