PERK/eIF2α contributes to changes of insulin signaling in HepG2 cell induced by intermittent hypoxia

Abstract

AimsObstructive sleep apnea hypopnea syndrome (OSAHS) is associated with abnormal glucose metabolism. Nowadays, endoplasmic reticulum (ER) stress emerges as an important mechanism underlying the development of type 2 diabetes mellitus (T2DM). However, it remains unclear that intermittent hypoxia (IH) could induce ER stress, resulting in abnormality of glucose metabolism. Thus, in the current study we explore the changes of insulin signaling under IH and the role of ER stress underlying these changes. Main methodsHepG2 cells were exposed to room air (RA) or IH for 8h, 16h and 24h respectively. Oxygen concentration in IH groups was in a dynamic cycle from 21% to 1% every 5min, while it remained at 21% in RA groups. Insulin was added into cell culture medium for AKT and p-AKT measurement. In another experiment set, HepG2 cells were pre-cultured with 4-PBA prior to IH or RA exposure. Expression of AKT, p-AKT, p-JNK, p-IRE1, p-PERK and p-eIF2α was examined by Western Blot. Key findingsCompared with RA, p-AKT expression in HepG2 cells under IH for 24h was significantly lower even with insulin treatment. Expression of p-JNK, p-IRE1, ATF6, p-PERK and p-eIF2α were upregulated. p-AKT level in HepG2 with 4-PBA preculture under IH was restored. p-PERK and p-eIF2α expression in HepG2 cells in IH groups with 4-PBA preculture were inhibited while levels of p-JNK and p-IRE1 remained unchanged. SignificanceIH, the hallmarker of OSAHS, could disturb insulin signaling via activating PERK/eIF2α.