| First Author | Chen X | Year | 2017 |
| Journal | Toxicol Sci | Volume | 158 |
| Issue | 2 | Pages | 275-285 |
| PubMed ID | 28482072 | Mgi Jnum | J:321352 |
| Mgi Id | MGI:6883084 | Doi | 10.1093/toxsci/kfx096 |
| Citation | Chen X, et al. (2017) Endoplasmic Reticulum Stress-Induced CHOP Inhibits PGC-1alpha and Causes Mitochondrial Dysfunction in Diabetic Embryopathy. Toxicol Sci 158(2):275-285 |
| abstractText | Endoplasmic reticulum (ER) stress has been implicated in the development of maternal diabetes-induced neural tube defects (NTDs). ER stress-induced C/EBP homologous protein (CHOP) plays an important role in the pro-apoptotic execution pathways. However, the molecular mechanism underlying ER stress- and CHOP-induced neuroepithelium cell apoptosis in diabetic embryopathy is still unclear. Deletion of the Chop gene significantly reduced maternal diabetes-induced NTDs. CHOP deficiency abrogated maternal diabetes-induced mitochondrial dysfunction and neuroepithelium cell apoptosis. Further analysis demonstrated that CHOP repressed the expression of peroxisome-proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), an essential regulator for mitochondrial biogenesis and function. Both CHOP deficiency in vivo and knockdown in vitro restore high glucose-suppressed PGC-1alpha expression. In contrast, CHOP overexpression mimicked inhibition of PGC-1alpha by high glucose. In response to the ER stress inducer tunicamycin, PGC-1alpha expression was decreased, whereas the ER stress inhibitor 4-phenylbutyric acid blocked high glucose-suppressed PGC-1alpha expression. Moreover, maternal diabetes in vivo and high glucose in vitro promoted the interaction between CHOP and the PGC-1alpha transcriptional regulator CCAAT/enhancer binding protein-beta (C/EBPbeta), and reduced C/EBPbeta binding to the PGC-1alpha promoter leading to markedly decrease in PGC-1alpha expression. Together, our findings support the hypothesis that maternal diabetes-induced ER stress increases CHOP expression which represses PGC-1alpha through suppressing the C/EBPbeta transcriptional activity, subsequently induces mitochondrial dysfunction and ultimately results in NTDs. |
