Regulatory mechanisms underlying endoplasmic reticulum stress involvement in the development of gestational diabetes mellitus entail the CHOP-PPARa-NF-?B pathway

Objective: We investigated the proinflammatory functions of endoplasmic reticulum stress and peroxisome proliferator-activated receptor a (PPARa) in the development of gestational diabetes mellitus (GDM) and their relationship in regulating inflammation in GDM.Methods: This study was performed on placentas of normal pregnant women, women with GDM, and HTR8 cells. Transmission electron microscopy, immunohistochemistry, Western blot analysis, and RT-PCR were performed to analyze ERS and PPARa expression on both normal and GDM pregnancy placentas. ELISA was performed to analyze inflammatory biomarkers. To generate models of the GDM-like state, placentas of normal pregnancy were treated with LPS and polyinosinic-polycytidylic acid (poly [I:C]). TG, CHOP plasmid, and CHOP siRNA were assessed as to their regulation of HTR8 cells to discern the relationship between ERS and PPARa in regulating the inflammation associated with GDM.Results: ERS was elevated in GDM placentas, induced the secretion of IL-6 and TNF-a, and attenuated the expression of GLUT-4. PPARa was diminished in GDM placentas and inhibited the inflammatory responses via the NF-?B nuclear-transport process. 4-PBA reduced CHOP and augmented PPARa, and it decreased IL-6 and TNF-a in our GDM-like explant. However, with both 4-PBA and MK886 treatment, we noted no significant difference in CHOP expression. The level of PPARa was reduced, and that of NF-?B p65 in the nucleus was elevated with TG treatment in the HTR8/Svneo. Knockdown of CHOP increased PPARa and reduced NF-?B p65, while expression of PPARa declined, and that of NF-?B p65 rose with the application of CHOP when HTR8 cells were treated with TG.Conclusions: ERS contributes to the pathophysiology of GDM in pregnancy via the CHOP-PPARa-NF-?B-signal-ling pathway by inducing aberrant activation of inflammation and insulin resistance.